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Inheritance

2

Autosomal Recessive HP:0000007

Biallelic damaging ALPK3 variants - homozygous or compound heterozygous, most often two protein-truncating alleles - segregate recessively, and the original families were consanguineous. ClinGen classifies the autosomal recessive ALPK3-hypertrophic cardiomyopathy relationship as Definitive. When both parents carry a causative allele, each pregnancy has a 25% chance of biallelic disease, a 50% chance of heterozygosity and a 25% chance of inheriting neither allele. Heterozygous ALPK3 relatives can themselves develop cardiomyopathy in adulthood.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:26846950 SUPPORT Human Clinical

"The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy."

Homozygosity mapping in consanguineous families is the recessive design that identified the gene.

CGGV:assertion_6312d79f-df12-4ec6-8ce6-0f38f19e617d-2022-02-09T170000.000Z SUPPORT Other

ClinGen classifies the autosomal recessive ALPK3-hypertrophic cardiomyopathy relationship as Definitive.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the ... HCM-related pathogenic variants."

GeneReviews gives recurrence risks when both parents carry an autosomal recessive HCM-related variant; its ALPK3-specific caveat is that heterozygotes can develop adult cardiomyopathy. These are transmission probabilities, not penetrance estimates.

Autosomal Dominant HP:0000006

A single ALPK3 protein-truncating variant is transmitted dominantly, with reduced and age-dependent penetrance. ClinGen classifies the autosomal dominant relationship as Strong. Co-segregation across seven informative families gave a combined LOD score of 2.99. Each child has a 50% chance of inheriting the familial pathogenic variant; inheritance does not guarantee clinical disease because penetrance is incomplete.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:34263907 SUPPORT Human Clinical

"Combined logarithm of odds score in seven families with ALPK3tv was 2.99."

Family co-segregation evidence for dominant transmission of heterozygous truncating alleles.

CGGV:assertion_ace85164-0b70-46a2-ac6b-253088f4514d-2025-01-16T010000.000Z SUPPORT Other

ClinGen classifies the autosomal dominant ALPK3-hypertrophic cardiomyopathy relationship as Strong.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"nonsyndromic HCM has a 50% chance of inheriting the ... pathogenic variant ... and therefore being at risk for developing nonsyndromic HCM."

GeneReviews states that each child of an individual with autosomal dominant nonsyndromic HCM has a 50% chance of inheriting the pathogenic variant. This applies to the dominant ALPK3 form and does not imply complete penetrance.

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Subtypes

2

Biallelic (autosomal recessive) ALPK3 cardiomyopathy

Two damaging ALPK3 alleles, often two protein-truncating variants. Disease commonly presents prenatally or in childhood, but adult diagnoses are reported. Presentation may be hypertrophic, dilated or mixed; some dilated presentations subsequently develop hypertrophy. Craniofacial and musculoskeletal findings are common in clinically ascertained cohorts. Absence of outflow obstruction in reported series is not a diagnostic requirement.

Show evidence (2 references)

PMID:26846950 SUPPORT Human Clinical

"All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood."

Establishes the biallelic form as the severe, early-onset end of the ALPK3 spectrum.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiomyopathy in patients with biallelic ALPK3 variants typically manifested early in life: 4 patients (10%) were diagnosed prenatally, 8 patients (19%) neonatally, and 8 patients (19%) within the first year of birth, highlighting early disease onset."

Systematic curation of 42 biallelic patients quantifies the early age at presentation that defines this subtype.

Heterozygous (autosomal dominant) ALPK3 cardiomyopathy

A single pathogenic ALPK3 allele, usually protein-truncating, is associated predominantly with adult-onset HCM, although adolescent diagnoses occur. Penetrance is incomplete and age-related. Apical and concentric patterns and myocardial fibrosis are reported, but morphology and severity vary; currently unaffected relatives require longitudinal assessment.

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype."

Burden testing plus family co-segregation established the heterozygous truncating form as a distinct, pathogenic adult subtype.

PMID:36321451 SUPPORT REVIEW SYNTHESIS Other

"These heterozygous variants likely have variable and age-dependent penetrance, because obligate carrier relatives of critically ill infants with recessive ALPK3 cardiomyopathy often have no cardiac disease."

States the incomplete, age-related penetrance that distinguishes the heterozygous subtype from the biallelic one.

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Mechanistic Hypotheses

2

Myomesin mislocalization impairs force buffering

alpk3_myomesin_force_buffering EMERGING

Myomesin mislocalization may impair sarcomere integrity and force buffering. The cellular localization phenotype is measured; its specific contribution to impaired contractility remains a mechanistic proposal and varies across ALPK3 models.

Pathograph links

Myomesin Mislocalization -> Sarcomere Disorganization INDIRECT UNKNOWN INTERMEDIATES Proposed consequence of impaired myomesin-mediated force buffering; selective rescue of myomesin localization has not established this causal step.

Myomesin Mislocalization -> Impaired Cardiomyocyte Contractility INDIRECT UNKNOWN INTERMEDIATES Proposed consequence of impaired myomesin-mediated force buffering; selective rescue of myomesin localization has not established this causal step.

Impaired sarcomere protein turnover promotes hypertrophy

alpk3_proteostasis_hypertrophy EMERGING

Dysregulated protein clearance is proposed to drive thick-filament accumulation and hypertrophic remodeling. Timing and phenotype vary across germline, adult-induced and truncation models, and direct mediation of hypertrophy by a specific turnover defect remains unresolved.

Pathograph links

Impaired Sarcomere Proteostasis -> Cardiomyocyte Hypertrophy INDIRECT UNKNOWN INTERMEDIATES Proposed link from impaired thick-filament homeostasis to cardiomyocyte growth; ALPK3 replacement rescues both, but the individual downstream mediator has not been isolated.

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Discussions and Knowledge Gaps

4

Is ALPK3 a catalytically inactive scaffold, or a genuine kinase that phosphorylates SQSTM1 and other M-band proteins?

CONTROVERSY OPEN alpk3_pseudokinase_controversy

Attached to

pathophysiology#Loss of M-Band Scaffolding

ALPK3 catalytic activity remains disputed. One group reported no relevant activity in biochemical assays and normal adult hearts in mice carrying an invariant catalytic-lysine substitution. Another reported increased phosphorylation after recombinant-domain addition to deficient cardiomyocyte lysates and phosphorylation of SQSTM1; the lysate system does not exclude indirect kinase effects. The studies used different constructs and systems. Nuclear localization is also disputed: tagged overexpression supported a nuclear-envelope pool, whereas endogenous tagging localized ALPK3 to the M band without a nuclear signal. Shared M-band localization and protein-interaction findings support a structural role, but neither catalytic activity nor all downstream causal steps are settled.

Show evidence (3 references)

PMID:38048395 SUPPORT Model Organism

"Recent studies present conflicting findings on ALPK3's kinase activity2,3."

States the existence of the disagreement in the primary literature.

PMID:39196058 REFUTE In Vitro

"Finally, ALPK3 phosphorylates and is required for the sarcomeric localization of SQSTM1, an important transporter of polyubiquitinated proteins23,24."

The claim of catalytic activity on a named substrate, which is the position opposing the pseudokinase conclusion.

PMID:38048395 SUPPORT Model Organism

"we investigated the phosphorylation status of the T269/S272 site of SQSTM1 by western blotting, but we did not observe a significant difference in T269/S272 phosphorylation to total SQSTM1 ratios between the hearts of the control mice and those carrying homozygous ALPK3KR/KR mutation"

Directly contests the SQSTM1 substrate claim at the same residues, in vivo, which is the sharpest point of disagreement between the two positions.

Do the conventional hypertrophic cardiomyopathy sudden-death risk models perform adequately in ALPK3 truncating variant carriers?

KNOWLEDGE GAP OPEN alpk3_risk_model_calibration

Attached to

phenotypes#Ventricular tachycardia phenotypes#Cardiac arrest treatments#Implantable Cardioverter-Defibrillator phenotypes#Sudden cardiac death

ALPK3-specific calibration of conventional HCM sudden-death risk models has not been established. Adult heterozygous cohorts document myocardial fibrosis and nonsustained ventricular tachycardia, but one major cohort observed no appropriate ICD shocks during follow-up. Separately, the biallelic case report by Jorholt et al. documents sudden cardiac death at age 12 despite previous surveillance without ventricular tachycardia or syncope. The pediatric event and adult cohort follow-up answer different questions and should not be combined into an unsupported incidence estimate. A later Swedish apical-HCM series did document an appropriate ICD discharge in an ALPK3 heterozygote. Thus the absence of shocks in the earlier cohort does not establish absence of risk across all heterozygous patients.

Show evidence (4 references)

PMID:34263907 SUPPORT Human Clinical

"Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+"

Documents the dissociation the question turns on - wall thickness like sarcomere-negative patients, arrhythmia burden like sarcomere-positive ones.

PMID:34263907 SUPPORT Human Clinical

"The absence of arrhythmic events despite of the high proportion of ICD referrals, fibrosis and non-sustained ventricular tachycardia at baseline and follow-up did not allow modelling of SCD risk in patients with this particular genotype."

The earlier cohort lacked events sufficient for genotype-specific sudden-death risk modeling. This does not negate the pediatric sudden death or the appropriate ICD therapies reported in other series.

PMID:33076350 SUPPORT Human Clinical

"At the age of 12, the patient had no progression of chamber enlargement or reduction of contractility, but died due to sudden cardiac death (SCD) after 30 min of unsuccessful resuscitation."

Case 1 had two reported ALPK3 frameshift variants and severe nonobstructive HCM. Sudden death occurred despite prior rhythm monitoring without documented ventricular tachycardia; a single case cannot establish incidence.

+ 1 more reference

Why does the original constitutive Alpk3 knockout mouse lack fibrosis reported in human ALPK3 cardiomyopathy?

HUMAN MODEL MISMATCH OPEN alpk3_knockout_fibrosis_mismatch

Attached to

pathophysiology#Reactive Interstitial Fibrosis

The 2011 constitutive-null mouse reproduces contractile and ultrastructural abnormalities but lacks interstitial fibrosis and inflammation under the reported conditions. Human cohorts document fibrosis on imaging and histopathology, although it is not present in every patient. This limits the original line as a model of the human fibrotic phenotype; the observation should not be generalized to every Alpk3 mutant model.

Show evidence (2 references)

PMID:21441111 SUPPORT Model Organism

"Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice"

The model-side half of the mismatch.

PMID:34263907 SUPPORT Human Clinical

"Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."

The human-side half of the mismatch.

What is the clinical benefit-risk balance of mavacamten in ALPK3 cardiomyopathy, particularly in patients with severe biallelic disease and systolic dysfunction?

KNOWLEDGE GAP OPEN alpk3_mavacamten_safety

Attached to

treatments#Mavacamten

The ALPK3-specific mavacamten experiment used isolated K201X mouse cardiomyocytes. Treatment improved relaxation in heterozygous cells but did not rescue homozygous relaxation and reduced fractional shortening. Many ALPK3 patients lack outflow obstruction, and severe biallelic disease can include systolic dysfunction. The balance of benefit and negative inotropy therefore requires clinical study; the ex vivo findings do not establish a genotype-specific treatment recommendation.

Show evidence (2 references)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Other

"Although homozygous animals exhibited contractile dysfunction, they did not develop overt ventricular wall thickening, and treatment was restricted to ex vivo isolated cardiomyocytes."

States the two limitations - no overt hypertrophy in the model and ex vivo-only treatment - that leave the question open.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"In heterozygous ALPK3 PTVs, hypertrophy is typically apical or concentric, LVOT obstruction is uncommon (~4% overall), and systolic function is preserved in most."

Documents the mismatch between the ALPK3 phenotype and the approved indication for the drug.

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Pathophysiology

15

ALPK3 Loss of Function

Loss of ALPK3 function is the predominant mechanism associated with pathogenic truncating alleles. Nonsense-mediated decay has been demonstrated for p.W1264X and is partial in the K201X mouse model. The amount of residual transcript or protein depends on the allele and model; not every truncation has been shown to abolish protein expression. Haploinsufficiency is a supported explanation for dominant disease, while more severe loss underlies many biallelic presentations.

cardiomyocyte CL:0000746

ALPK3 hgnc:17574

sarcomere organization GO:0045214 ⚠ ABNORMAL

Downstream

Loss of M-Band Scaffolding Loss of functional ALPK3 disrupts its scaffolding role at the sarcomeric M-band. Nuclear-envelope localization has been reported in some systems but is disputed.

Abnormal Cardiomyocyte Calcium Handling ALPK3 perturbation produces calcium-handling abnormalities in edited human cardiomyocytes and K201X mouse cardiomyocytes; the intermediate mechanism is not established.

Reduced PKA-Target Phosphorylation Observed after K201X perturbation; the intermediates linking ALPK3 loss to this molecular readout are unresolved.

Reduced Myosin Super-Relaxed State Observed after K201X perturbation; the intermediates linking ALPK3 loss to this molecular readout are unresolved.

Abnormal facial shape Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Cleft palate Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Hypotonia Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Flexion contracture Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Pterygium Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Scoliosis Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Short stature Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.

Reactive Interstitial Fibrosis Genotype-associated fibrotic remodeling documented in human cohorts; the responsible intermediates and their relationship to hypertrophy are unresolved.

Intercalated Disc Remodeling ALPK3 deficiency is associated with junctional remodeling; the specific molecular intermediates are unresolved.

Show evidence (3 references)

PMID:27106955 SUPPORT In Vitro

"We performed detailed clinical and genetic analyses of a consanguineous family, identifying a new ALPK3 mutation (c.3792G>A, p.W1264X) which undergoes nonsense-mediated decay in ex vivo and in vivo tissues."

Demonstrates nonsense-mediated decay of a truncating allele, establishing loss of function as the mechanism.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Analysis of ALPK3 pathogenic variants reveals that over 70% are truncating, strongly supporting haploinsufficiency as the principal disease driver."

Establishes truncating loss of function as the predominant allele class across the reported variant spectrum.

PMID:40128237 SUPPORT Model Organism

"In the absence of a working antibody for ALPK3, the consequences on Alpk3 protein levels and the potential presence of truncated protein remain unknown."

The K201X study found reduced transcript levels but could not establish whether truncated protein persists, limiting a universal complete-null interpretation.

Loss of M-Band Scaffolding

ALPK3 localizes to the sarcomeric M band and associates with myomesins, MuRF proteins and SQSTM1/p62 in several experimental systems. Loss of this structural role is a proposed proximal explanation for abnormal sarcomere organization and protein homeostasis. Catalytic activity and nuclear-envelope localization remain disputed; individual binding partners and localization defects differ between models.

sarcomere M-band GO:0031430

Animal models

Alpk3 K1420R kinase-dead knock-in mouse Mouse fails to recapitulate The K1420R substitution does not reproduce the cardiomyopathy of the published null line. This is a negative functional comparison supporting a role for ALPK3 beyond putative kinase activity; M-band scaffold integrity was not directly established by the cardiac readout.

Downstream

Myomesin Mislocalization

Impaired Sarcomere Proteostasis ALPK3 loss alters protein homeostasis, but the specific mediators connecting its structural interactions to turnover remain unresolved.

SQSTM1 Mislocalization ALPK3 interacts with SQSTM1 and ALPK3 deficiency disrupts its M-band localization; the precise binding and phosphorylation requirements remain unresolved.

Show evidence (3 references)

PMID:36321451 SUPPORT In Vitro

"Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase."

The phosphoproteomic basis for treating ALPK3 as a scaffold rather than a kinase. This is one side of an open dispute, not a settled result - see the discussion alpk3_pseudokinase_controversy.

PMID:38048395 SUPPORT Model Organism

"In conclusion, our study presents compelling new evidence from both in vitro and in vivo experiments, supporting that ALPK3 functions as a pseudokinase."

Supports the pseudokinase interpretation in the tested biochemical and knock-in mouse systems; it does not resolve all conflicting reports of catalytic activity.

PMID:40135575 SUPPORT Model Organism

"We found that ALPK3 localizes to the M-band in both neonatal and adult cardiomyocytes and interacts with muscle RING-finger proteins, which may regulate thick filament protein turnover."

Endogenously tagged ALPK3 localized to the M band in neonatal and adult mouse cardiomyocytes; this supports restricting the shared localization claim to the M band.

Myomesin Mislocalization

Mislocalization of myomesin proteins was demonstrated in ALPK3-deficient isogenic cardiomyocytes and some mouse models, with impaired force buffering proposed as a consequence. Nuclear-envelope localization is disputed, and myomesin displacement is not universal: the K201X mouse study did not detect differences in myomesin localization between genotypes.

Myomesin mislocalization impairs force buffering

Experimental models

Isogenic ALPK3 iPSC-derived cardiomyocytes for M-band proteomics IPSC DERIVED MODEL ALPK3 loss-of-function variants displaced MYOM1 and MYOM2 from the M-band and nuclear envelope.

Downstream

Sarcomere Disorganization Proposed consequence of impaired myomesin-mediated force buffering; selective rescue of myomesin localization has not established this causal step.

Impaired Cardiomyocyte Contractility Proposed consequence of impaired myomesin-mediated force buffering; selective rescue of myomesin localization has not established this causal step.

Show evidence (2 references)

PMID:36321451 SUPPORT In Vitro

"Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band."

Establishes the ALPK3-myomesin association whose loss underlies this node.

PMID:40128237 REFUTE Model Organism

"we analysed localisation of the M-band protein myomesin using immunofluorescence staining on cardiac tissue and isolated cells, but failed to detect any differences between the genotypes"

The K201X model limits generalization of myomesin mislocalization across all ALPK3 alleles and experimental systems.

Impaired Sarcomere Proteostasis

ALPK3 deficiency disrupts M-band protein homeostasis. Studies report altered thick-filament abundance, mislocalized SQSTM1 and changes in MuRF-associated networks. The 2023 study did not directly measure turnover; the 2026 replacement study measured impaired proteasome activity and its rescue. The contributions of specific proteasomal and autophagic routes remain under investigation.

Impaired sarcomere protein turnover promotes hypertrophy

proteasome-mediated turnover of sarcomere proteins GO:0043161 ↕ DYSREGULATED

Animal models

Alpk3 exon-3 germline and adult inducible knockout mice Mouse recapitulates Thick-filament proteins accumulate in germline-knockout hearts.

Downstream

Cardiomyocyte Hypertrophy Proposed link from impaired thick-filament homeostasis to cardiomyocyte growth; ALPK3 replacement rescues both, but the individual downstream mediator has not been isolated.

Show evidence (5 references)

PMID:36321451 SUPPORT In Vitro

"We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis."

The paper's own two-arm mechanistic conclusion, of which this node is the hypertrophy arm.

PMID:39196058 SUPPORT In Vitro

"In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis."

Independently links ALPK3 mutation to displacement of the ubiquitin-binding protein that routes damaged sarcomere proteins for clearance.

PMID:40135575 SUPPORT Model Organism

"These data suggest that the loss of ALPK3 leads to selective dysregulation of thick filament protein homeostasis."

Adult germline-knockout hearts accumulated thick-filament proteins without corresponding increases in their transcripts; the MuRF-dependent turnover mechanism remains a proposed explanation.

+ 2 more references

Sarcomere Disorganization

ALPK3-deficient cardiomyocytes show disorganized sarcomeres and M-band abnormalities in several cellular and mouse models. Clinical myocardial disarray is variable and was absent in some neonatal and adult specimens.

cardiomyocyte CL:0000746

sarcomere organization GO:0045214 ⚠ ABNORMAL

Experimental models

ALPK3-null human stem cell-derived cardiomyocytes IPSC DERIVED MODEL Disordered sarcomeres on electron microscopy in patient-derived and edited human cardiomyocytes.

Animal models

Alpk3 constitutive knockout mouse (C57BL/6J, Van Sligtenhorst line) Mouse recapitulates Mild myofibrillar disarray on light and electron microscopy.

Downstream

Myofiber disarray

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."

Direct ultrastructural demonstration of the lesion in ALPK3-null human cardiomyocytes.

Abnormal Cardiomyocyte Calcium Handling

ALPK3-deficient contractile cultures show an extended field potential duration and abnormal calcium handling; a knock-in truncation model shows elevated diastolic calcium and delayed relaxation.

intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL

Experimental models

ALPK3-null human stem cell-derived cardiomyocytes IPSC DERIVED MODEL Extended field potential duration and abnormal calcium handling in mutant contractile cultures.

Animal models

Alpk3 K201X knock-in mouse Mouse recapitulates Elevated diastolic calcium and delayed relaxation in isolated ventricular cardiomyocytes.

Downstream

Impaired Cardiomyocyte Contractility

Prolonged QT interval Cellular calcium abnormalities and prolonged field potentials provide an inferential bridge to patient QT prolongation; a specific intervening electrophysiological pathway has not been established.

Show evidence (3 references)

PMID:27106955 SUPPORT In Vitro

"Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures."

Direct measurement of the repolarization and calcium-handling abnormality in ALPK3-null cardiomyocytes.

PMID:40128237 SUPPORT In Vitro

"Calcium transients from fura2 loaded cardiomyocytes showed dose-dependent increases in diastolic intracellular calcium"

Direct isolated-cell measurement in heterozygous and homozygous K201X mice.

PMID:39196058 SUPPORT In Vitro

"Peak cytosolic calcium levels (Fig. 2f) were elevated while calcium reuptake was delayed in ALPK3mut CMs"

Direct calcium imaging in the initiation-region deletion cell model; distinct from the K201X mouse cardiomyocyte experiment.

Impaired Cardiomyocyte Contractility

Reduced force generation is documented in several ALPK3-deficient heart and organoid models. The 2011 knockout study measured an approximately 50% reduction in regional left ventricular contractility. The relative contributions of myomesin localization, calcium handling and other molecular changes remain unresolved.

cardiac muscle contraction GO:0060048 ↓ DECREASED

Experimental models

ALPK3-deficient human cardiac organoids ORGANOID Contractility is impaired in ALPK3-deficient human cardiac organoids.

Animal models

Alpk3 constitutive knockout mouse (C57BL/6J, Van Sligtenhorst line) Mouse recapitulates Ventricular contractility falls by about half on cardiac MRI.

Alpk3 W1538X knock-in mouse for gene replacement Mouse recapitulates Established systolic and diastolic dysfunction responds to ALPK3 replacement.

Downstream

Reduced left ventricular ejection fraction

Ventricular Dilatation Reduced myocardial performance is associated with chamber dilation in ALPK3-deficient models; remodeling intermediates are not fully established.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"Magnetic resonance imaging showed a 50% reduction in both septal and free wall LV contractility in Alpk3 (-/-) mice."

Quantifies the contractile deficit in the ALPK3-null mouse heart.

Cardiomyocyte Hypertrophy

Individual cardiomyocytes enlarge, seen on myocardial histopathology as focal cardiomyocyte hypertrophy.

cardiomyocyte CL:0000746

cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Downstream

Ventricular Hypertrophy

Show evidence (1 reference)

PMID:32480058 SUPPORT Human Clinical

"Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults."

Direct histopathological demonstration of cardiomyocyte hypertrophy in ALPK3 patients.

Ventricular Dilatation

Ventricular chamber dilation with depressed systolic function occurs particularly in severe early biallelic disease. Some neonatal dilated presentations subsequently become hypertrophic, while other patients present with hypertrophy or retain a dilated phenotype.

Animal models

Alpk3 constitutive knockout mouse (C57BL/6N, MRC Harwell line) Mouse recapitulates Increased left ventricular cavity dimensions with severely depressed function, reproducing the dilated, hypocontractile presentation of biallelic human disease.

Downstream

Congestive heart failure

Dilated cardiomyopathy

Show evidence (3 references)

PMID:36321451 SUPPORT REVIEW SYNTHESIS Other

"Rare surviving children demonstrate a most atypical sequence of cardiac remodeling: biventricular dilation that transitions to biventricular hypertrophy, whereas contractile function remains profoundly depressed."

Describes the dilated phase and its atypical evolution in biallelic ALPK3 disease.

PMID:32480058 SUPPORT Human Clinical

"Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy."

Quantifies neonatal dilatation and its transition to hypertrophy in a paediatric ALPK3 cohort.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"among the 13 patients initially diagnosed with only DCM, 10 (77%) transitioned to HCM, typically within the first year of follow-up"

Quantifies the dilated-to-hypertrophic transition in biallelic patients.

Ventricular Hypertrophy

Increased ventricular wall thickness not explained by loading conditions. Apical and concentric patterns are enriched in several heterozygous cohorts, although asymmetric septal hypertrophy also occurs. Right ventricular involvement is reported. Fibrosis is modeled separately because its presence varies across human patients and experimental models.

cardiomyocyte CL:0000746

cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Downstream

Hypertrophic cardiomyopathy

Apical hypertrophic cardiomyopathy

Concentric hypertrophic cardiomyopathy

Right ventricular hypertrophy Right ventricular involvement of hypertrophic remodeling, documented in the biallelic cohort.

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009)"

Quantifies the distinctive hypertrophy distribution in heterozygous carriers against genotyped comparator cohorts.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"In heterozygous ALPK3 PTVs, hypertrophy is typically apical or concentric, LVOT obstruction is uncommon (~4% overall), and systolic function is preserved in most."

Heterozygous-scoped statement of the hypertrophy distribution and the near-absence of outflow tract obstruction. The review's stronger figure - no outflow obstruction in any patient - is scoped to the biallelic cohort and is quoted on that subtype instead.

Reactive Interstitial Fibrosis

Replacement and interstitial myocardial fibrosis are documented in patients by late gadolinium enhancement and histopathology. Fibrosis is absent or minimal in several ALPK3 mouse models, including the 2011 constitutive-null and K201X models, so it is not an obligate consequence of protein loss across experimental systems. The causal intermediates leading to fibrosis in patients are unresolved.

Animal models

Alpk3 constitutive knockout mouse (C57BL/6J, Van Sligtenhorst line) Mouse fails to recapitulate Interstitial fibrosis documented in human cohorts was absent in this mouse line under the reported conditions.

Downstream

Myocardial fibrosis

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."

Direct imaging and histopathological demonstration of the fibrotic substrate in heterozygous carriers.

PMID:21441111 REFUTE Model Organism

"Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice"

The constitutive knockout mouse does not develop the interstitial fibrosis seen in patients, so this node is not recapitulated by that model.

Reduced PKA-Target Phosphorylation

In isolated cardiomyocytes from K201X mice, phosphorylation of PKA-target proteins, including troponin I Ser23/24, was reduced. Whether ALPK3 directly regulates PKA or this is chronic remodeling remains unresolved.

Show evidence (1 reference)

PMID:40128237 SUPPORT In Vitro

"we observed reduced PKA-mediated phosphorylation in Alpk3 K201X cardiomyocytes, including markedly reduced phosphorylation of troponin I at serine23/24."

In isolated cardiomyocytes from K201X mice, phosphorylation of PKA-target proteins, including troponin I Ser23/24, was reduced. Whether ALPK3 directly regulates PKA or this is chronic remodeling remains unresolved.

Reduced Myosin Super-Relaxed State

Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.

Animal models

Alpk3 K201X knock-in mouse Mouse recapitulates Reduced SRX myosin occupancy in mutant cardiac tissue.

Show evidence (1 reference)

PMID:40128237 SUPPORT In Vitro

"Heterozygous and homozygous mice showed a significantly reduced proportion of myosin heads in the SRX state, compared to WT littermates"

Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.

SQSTM1 Mislocalization

SQSTM1 loses its normal M-band localization and accumulates in cytosolic or membrane-associated aggregates in several ALPK3-mutant human cardiomyocyte lines. Total SQSTM1 abundance was unchanged in the 2023 study. Mislocalization also occurred in the W1538X mouse myocardium; the contribution of phosphorylation to this localization defect is disputed.

Show evidence (1 reference)

PMID:39196058 SUPPORT In Vitro

"SQSTM1 was not detected in the sarcomeres of these patient-specific variant hPSC lines but formed aggregates either within the cytosol or at the cell membrane"

Observed in the L639fs/34, Q1460X and R1792X edited cardiomyocyte models; this localization result is separable from the catalytic-activity controversy.

Intercalated Disc Remodeling

Intercalated-disc abnormalities occur in ALPK3-deficient cellular and mouse models. In one neonatal patient sample, desmoplakin and plakoglobin staining at the discs was absent while other junctional markers were retained. The human immunostaining observation is not a universal ultrastructural finding.

cardiomyocyte CL:0000746

intercalated disc GO:0014704

Experimental models

ALPK3-null human stem cell-derived cardiomyocytes IPSC DERIVED MODEL Abnormal intercalated discs on electron microscopy in ALPK3-deficient human cardiomyocytes.

Animal models

Alpk3 constitutive knockout mouse (C57BL/6J, Van Sligtenhorst line) Mouse recapitulates Abnormal intercalated-disc architecture in the constitutive null mouse.

Show evidence (3 references)

PMID:27106955 SUPPORT In Vitro

"Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."

Direct ultrastructural demonstration of the lesion in ALPK3-null human cardiomyocytes.

PMID:26846950 SUPPORT Human Clinical

"Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling."

Confirms intercalated-disc remodeling in myocardium from patients with biallelic variants.

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf SUPPORT Human Clinical

"Immunoreactive signals for plakoglobin and desmoplakin are absent at intercalated discs in the sample from patient A-IX:2"

Full text of Almomani et al. (2016), PMID:26846950. Direct immunostaining result from one neonatal myocardial sample; other junctional signals were preserved and electron microscopy was unavailable.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

34

Cardiovascular 22

Hypertrophic cardiomyopathy HP:0001639

Sequelae: Congestive heart failure

Show evidence (2 references)

PMID:38356193 SUPPORT Human Clinical

"The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy."

Hypertrophic cardiomyopathy was the phenotype in 26 of 31 adult heterozygous carriers in a large multicentre cohort.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Although LVH and a clinical diagnosis of HCM often become apparent during adolescence or early adulthood, onset can be earlier (in infancy and childhood) or later in life."

General GeneReviews HCM age spectrum, not a genotype-specific frequency estimate. ALPK3-specific cohorts establish the distinction between commonly early biallelic and later heterozygous disease.

Apical hypertrophic cardiomyopathy HP:0031992

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001)"

Quantifies the apical or concentric hypertrophy pattern in heterozygous carriers.

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"Over half (60%, 12/20) of individuals with ALPK3tv had an apical pattern of LVH"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Apical morphology is separately enumerated in this cohort; it should not be derived by splitting the earlier combined apical/concentric proportion.

Concentric hypertrophic cardiomyopathy HP:0005157

Show evidence (2 references)

PMID:38356193 SUPPORT Human Clinical

"including 15% (n = 4) presented with an apical or a concentric form of hypertrophy"

Records the concentric hypertrophy pattern among adult heterozygous carriers.

url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf SUPPORT Human Clinical

"Echocardiography demonstrated severe concentric HCM of both ventricles"

Full text of Grutters et al. (2023), PMID:37671554. The child with an ALPK3-containing deletion and a splice allele in trans had severe concentric biventricular hypertrophy.

Dilated cardiomyopathy HP:0001644

Show evidence (2 references)

PMID:32480058 SUPPORT Human Clinical

"Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy."

Quantifies neonatal dilated cardiomyopathy among live-born biallelic patients.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"DCM in 12 patients (7%)"

The review includes DCM among heterozygous carriers; the pooled group contains both truncating and non-truncating variants.

Left ventricular noncompaction cardiomyopathy HP:0011664

Show evidence (2 references)

PMID:31074094 SUPPORT Human Clinical

"They presented with either dilated cardiomyopathy that progressed to hypertrophic cardiomyopathy (HCM) or HCM with left ventricular noncompaction."

Reports left ventricular noncompaction alongside hypertrophy in a homozygous ALPK3 family.

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"1 had a diagnosis of left ventricular non-compaction with LVH."

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. One heterozygous carrier in the preprint cohort had this imaging diagnosis.

Myocardial fibrosis HP:0001685

Show evidence (3 references)

PMID:34263907 SUPPORT Human Clinical

"Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."

Direct evidence of myocardial fibrosis in heterozygous ALPK3 truncating variant carriers.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac MRI revealed late gadolinium enhancement in 6 of 14 imaged patients (43%)"

Quantifies the imaging correlate of myocardial fibrosis in biallelic patients.

PMID:34263907 SUPPORT Human Clinical

"16 (49%) had extensive myocardial fibrosis (assessed qualitatively as >15% of left ventricular segments affected) in 33 with cardiac magnetic resonance imaging."

Provides the measured-subgroup denominator and the qualitative definition of extensive fibrosis.

Myofiber disarray HP:0031318

Show evidence (3 references)

PMID:32480058 SUPPORT Human Clinical

"Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults."

Reports myofibrillar disarray on myocardial histopathology in ALPK3 patients.

PMID:34263907 REFUTE Human Clinical

"showed cardiomyocyte hypertrophy with focal scarring and no significant cardiomyocyte disarray."

The adult myectomy series limits generalization of disarray across ALPK3 disease.

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf REFUTE Human Clinical

"No apparent myocyte disarray was observed"

Full text of Almomani et al. (2016), PMID:26846950. The original neonatal histology demonstrates that disarray is not an obligate finding.

Endocardial fibroelastosis HP:0001706

Show evidence (1 reference)

PMID:32480058 SUPPORT Human Clinical

"subendocardial fibroelastosis in patients under 4 years of age"

Reports subendocardial fibroelastosis in young ALPK3 patients.

Prolonged QT interval FREQUENT HP:0001657

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"A prolonged QTc interval was observed in 18 of 28 patients with available ECGs (64%), far exceeding the 10-15% reported in large HCM series"

Quantifies QTc prolongation in biallelic ALPK3 patients against the background rate in hypertrophic cardiomyopathy.

Shortened PR interval HP:0005165

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"and of a short PR interval (10%, P = 0.009)"

Quantifies the excess of short PR interval among heterozygous carriers.

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"A short PR-interval was noted in two siblings"

Full text of Herkert et al. (2020), PMID:32480058. The biallelic cohort also includes short PR intervals; this feature is not restricted to heterozygotes.

Ventricular tachycardia FREQUENT HP:0004756

Sequelae: Cardiac arrest

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"non-sustained ventricular tachycardia (31%) at baseline similar to SP+"

Quantifies non-sustained ventricular tachycardia in heterozygous carriers.

PMID:40428316 SUPPORT Human Clinical

"The female patient with a wall thickness of 16 mm experienced an ICD discharge while running due to sustained VT, and a pathogenic variant in the non-sarcomeric ALPK3 gene was detected."

The Swedish apical-HCM series documents an appropriate ICD discharge in the female ALPK3 carrier. The overall cohort event rates and aneurysm prevalence are not ALPK3-specific.

Atrial fibrillation HP:0005110

Show evidence (2 references)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Atrial fibrillation was documented in 10 patients (12.5%), and ventricular tachycardia was also documented in 10 patients (12.5%)."

Systematic curation of the pooled heterozygous cohort (ECG data for 80 of 167 patients) records atrial fibrillation in 12.5%.

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"Afib, % (n/N) 26.3% 5/19 30.5% 40/131 0.79"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Cohort-specific measured-subgroup frequency.

Reduced left ventricular ejection fraction HP:0012664

Show evidence (2 references)

PMID:34263907 SUPPORT Human Clinical

"left ventricular systolic impairment (6%)"

Quantifies baseline systolic impairment in heterozygous carriers.

PMID:36321451 SUPPORT REVIEW SYNTHESIS Other

"biventricular dilation that transitions to biventricular hypertrophy, whereas contractile function remains profoundly depressed"

The 2022 mechanistic paper summarizes severe early biallelic presentations; persistence is not universal across all reported patients.

Congestive heart failure HP:0001635

Show evidence (2 references)

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf SUPPORT Human Clinical

"Three of 5 patients died due to progressive heart failure between 35 weeks of gestation and 5 days after birth."

The 2016 full text distinguishes one fetal and two neonatal deaths; its abstract compresses these into the first week of life.

PMID:34263907 SUPPORT Human Clinical

"4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation"

Records heart failure death or transplantation among adult heterozygous carriers over follow-up.

Cardiac arrest HP:0001695

Show evidence (3 references)

PMID:38356193 SUPPORT Human Clinical

"The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest)."

Records cardiac arrest among the severe outcomes in paediatric biallelic patients.

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf SUPPORT Human Clinical

"Out-of-hospital cardiac arrest occurred at age 7 years due to ventricular arrhythmias"

Full text of Almomani et al. (2016), PMID:26846950. Direct event in patient C-V:2, homozygous for p.Trp1765*.

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"one individual with ALPK3tv had a fatal cardiac arrest at 35 years old"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. The cohort reports a fatal event in a heterozygote. It does not establish a genotype-specific risk score.

Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:33076350 SUPPORT Human Clinical

"At the age of 12, the patient had no progression of chamber enlargement or reduction of contractility, but died due to sudden cardiac death (SCD) after 30 min of unsuccessful resuscitation."

Case 1 had two reported ALPK3 frameshift variants and severe nonobstructive HCM. Sudden death occurred despite prior rhythm monitoring without documented ventricular tachycardia; a single case cannot establish incidence.

Right ventricular hypertrophy HP:0001667

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"eight patients (age N11 months) also had right ventricular hypertrophy (50%; 95% CI: 24.7%-75.3%)."

Full text of Herkert et al. (2020), PMID:32480058. Right ventricular hypertrophy accompanied left ventricular disease in eight of 16 surviving biallelic patients in the 2020 cohort (50%); it is not present in all patients.

Left ventricular apical aneurysm Left ventricular aneurysm HP:6000144

Show evidence (1 reference)

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"Apical aneurysm, % (n/N) 22.2% 4/18 2.4% 3/125 0.005"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.

Mitral regurgitation HP:0001653

Show evidence (1 reference)

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"Mitral regurgitation, % (n/N) 52.6% 10/19 46.9% 60/128 0.81"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.

Left atrial enlargement HP:0031295

Show evidence (1 reference)

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"Left atrial enlargement, % (n/N) 36.8% 7/19 72.7% 93/128 0.0032"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.

Left ventricular diastolic dysfunction HP:0025168

Show evidence (1 reference)

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"Diastolic dysfunction, % (n/N) 17.7% 3/17 47.5% 58/122 0.034"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.

Premature ventricular contraction HP:0006682

Show evidence (1 reference)

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf SUPPORT Human Clinical

"PVCs, % (n/N) 36.8% 7/19 62.3% 81/130 0.046"

Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.

Head and Neck 3

Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:32480058 SUPPORT Human Clinical

"The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms."

Reports facial dysmorphism among the extracardiac features of biallelic ALPK3 disease.

Context-specific annotations (1)

Biallelic FREQUENT

Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"Craniofacial dysmorphic features were present in at least 12/17 patients (70.6%; 95% CI: 44.0%-89.7%)"

Full text of Herkert et al. (2020), PMID:32480058. Craniofacial dysmorphism occurred in at least 12 of 17 assessed biallelic patients in the 2020 cohort (70.6%), with varied individual findings.

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:32480058 SUPPORT Human Clinical

"including contractures, scoliosis, cleft palate, and facial dysmorphisms"

Reports cleft palate among extracardiac features of biallelic ALPK3 disease.

Webbed neck HP:0000465

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"including severe scoliosis ( n =6 ) ( Figure 4 A), webbed neck ( n = 8)"

Full text of Herkert et al. (2020), PMID:32480058. Webbed neck was recorded in eight of 17 assessed biallelic patients in the 2020 cohort, alongside a variable musculoskeletal phenotype.

Integument 1

Pterygium HP:0001059

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"skeletal muscle hypotonia, joint contractures, pterygia, scoliosis, short stature"

Lists pterygia among the extracardiac features of biallelic ALPK3 disease.

Metabolism 2

Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:34263907 SUPPORT Human Clinical

"Seven patients had raised serum creatine kinase out of 35 where it was determined (20%)"

Direct adult cohort laboratory finding, scoped to the tested subgroup.

Hydrops fetalis HP:0001789

Show evidence (1 reference)

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf SUPPORT Human Clinical

"revealing generalized hydrops fetalis and cardiomegaly with reduced contractility."

Full text of Almomani et al. (2016), PMID:26846950. Prenatal findings in patient B-IV:1; the next affected sibling also developed severe fetal hydrops.

Musculoskeletal 4

Flexion contracture HP:0001371

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"including craniofacial dysmorphisms, cleft palate, skeletal muscle hypotonia, joint contractures, pterygia, scoliosis, short stature, and other musculoskeletal anomalies"

Lists joint contractures among the characteristic extracardiac features of biallelic ALPK3 disease.

Context-specific annotations (1)

Biallelic FREQUENT

Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"Five patients had congenital contractures, while one patient developed contractures and scoliosis later in life."

Full text of Herkert et al. (2020), PMID:32480058. Joint contractures were recorded in 8 of 19 biallelic patients in the 2020 cohort (42%), involving knees, shoulders or distal joints; congenital and later-onset presentations occurred.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:32480058 SUPPORT Human Clinical

"including contractures, scoliosis, cleft palate, and facial dysmorphisms"

Reports scoliosis among extracardiac features of biallelic ALPK3 disease.

Context-specific annotations (1)

Biallelic FREQUENT

Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"Short stature 9/15 60% Kyphoscoliosis 6/15 40%"

Full text of Herkert et al. (2020), PMID:32480058. Kyphoscoliosis was recorded in 6 of 15 assessed biallelic patients in the 2020 cohort (40%), and can progress with age.

Hypotonia HP:0001252

Show evidence (2 references)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"This multisystem pattern is biologically plausible, because ALPK3 expression is not confined to the heart: robust expression has been documented in developing and adult skeletal muscle as well as in myocardium, providing a mechanistic rationale for the skeletal-muscle and craniofacial..."

Links skeletal muscle involvement to ALPK3 expression outside the heart.

PMID:33076350 SUPPORT Human Clinical

"The patient with the later onset showed milder extracardiac symptoms, such as decreased muscle tone and distal muscular dystrophy, but had fast progression of cardiac complications leading to the need of heart transplantation."

Case-level report of decreased muscle tone in a patient with biallelic ALPK3 variants.

Context-specific annotations (1)

Biallelic FREQUENT

Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"Hypotonia was present in 4/13 patients (30.8%; 95% CI: 9.1%-61.4%)."

Full text of Herkert et al. (2020), PMID:32480058. Hypotonia occurred in 4 of 13 assessed biallelic patients in the 2020 cohort (30.8%), with muscle involvement varying across patients.

Pectus carinatum HP:0000768

Show evidence (1 reference)

PMID:40447126 SUPPORT Human Clinical

"Patient 1, a 6-year-old girl, presented with HCM, short stature, webbed neck, joint contractures, pectus carinatum, and scoliosis."

The abstract reports this finding in one child; no frequency estimate is inferred.

Nervous System 1

Motor delay HP:0001270

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"Four of 12 patients (33.3%; 95% CI: 9.9%-65.1%) had delayed motor development with independent walking at ages 18 to 32 months"

Full text of Herkert et al. (2020), PMID:32480058. Four of 12 assessed biallelic patients had delayed motor development in the 2020 cohort, with independent walking between 18 and 32 months.

Growth 1

Short stature HP:0004322

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"joint contractures, pterygia, scoliosis, short stature, and other musculoskeletal anomalies"

Lists short stature among the extracardiac features of biallelic ALPK3 disease.

Context-specific annotations (1)

Biallelic FREQUENT

Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.

Show evidence (1 reference)

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf SUPPORT Human Clinical

"The height of 9/15 patients (60%; 95% CI: 32.3%-83.7%) ranged from 2 to 6 SDs below the normal mean."

Full text of Herkert et al. (2020), PMID:32480058. Short stature was recorded in 9 of 15 assessed biallelic patients in the 2020 cohort (60%); this is a clinically ascertained cohort estimate.

🧬

Genetic Associations

1

ALPK3 (Pathogenic Variants)

Gene: ALPK3 hgnc:17574 relationship_type: CAUSATIVE

Show evidence (8 references)

CGGV:assertion_6312d79f-df12-4ec6-8ce6-0f38f19e617d-2022-02-09T170000.000Z SUPPORT Other

ClinGen classifies the autosomal recessive ALPK3-hypertrophic cardiomyopathy relationship as Definitive.

CGGV:assertion_ace85164-0b70-46a2-ac6b-253088f4514d-2025-01-16T010000.000Z SUPPORT Other

ClinGen classifies the autosomal dominant ALPK3-hypertrophic cardiomyopathy relationship as Strong.

PMID:39036505 SUPPORT Human Clinical

"We observed that monoallelic PTVs in ALPK3 were also significantly enriched in Korean patients with HCMP with an odds ratio score of 10-21."

Replicates the truncating-variant enrichment outside European-ancestry cohorts.

+ 5 more references

💊

Medical Actions

13

Beta-Blocker and Non-Dihydropyridine Calcium Channel Blocker Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic blocker NCIT:C29576 non-dihydropyridine calcium channel blocker NCIT:C333

Platform: Small molecule

Symptom-directed HCM therapy chosen according to obstruction, symptoms and ventricular function. GeneReviews lists beta-blockers or calcium channel blockers for symptomatic nonobstructive HCM with preserved ejection fraction and beta-blockers as first-line therapy for symptomatic obstruction. Systolic dysfunction instead requires guideline-based heart-failure management; these HCM symptom-control options are not interchangeable across ventricular-function states. ALPK3-specific comparative treatment trials are lacking.

Show evidence (2 references)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Pharmacological treatments commonly employed include beta-blockers and non-dihydropyridine calcium channel blockers."

Names the pharmacotherapy in common use for this disease.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Pharmacologic therapy to alleviate symptoms, incl beta-blockers, calcium channel blockers"

GeneReviews Table 4 recommendation for symptomatic nonobstructive HCM with preserved ejection fraction; the ventricular-function qualifier is essential.

Cascade Genetic Testing and Cardiac Surveillance of Variant Carriers

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Genetic counseling and cascade testing identify relatives who need continued cardiac surveillance, including heterozygous relatives of children with biallelic disease. GeneReviews recommends echocardiography and ECG every one to two years for relatives with a familial HCM-related pathogenic variant; a normal initial evaluation does not exclude later disease. Counseling distinguishes the 25% biallelic recurrence risk for two carrier parents from the 50% transmission risk for a heterozygous parent, while explaining age-dependent penetrance.

Show evidence (4 references)

PMID:32480058 SUPPORT Human Clinical

"Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy."

States the surveillance recommendation for carriers identified by cascade testing.

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Early genetic diagnosis, genotype-tailored surveillance, and focused development of gene-replacement or editing strategies"

Names early genetic diagnosis and genotype-tailored surveillance as the current actionable management.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years."

GeneReviews recommendation for relatives identified with familial HCM-related pathogenic variants. The chapter explicitly notes adult cardiomyopathy risk in ALPK3 heterozygotes.

+ 1 more reference

Implantable Cardioverter-Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

Device therapy for sudden cardiac death prevention. Referral for ICD implantation was recorded in about a quarter of biallelic patients, including in childhood. No ALPK3-specific risk-stratification rule exists; the conventional hypertrophic cardiomyopathy risk models were developed on sarcomere-gene cohorts and have not been validated in this genotype. In the 2016 series, a homozygous p.Trp1765* child received an ICD after cardiac arrest at age seven and subsequently experienced appropriate shocks, providing a documented secondary-prevention example. A 2025 Swedish apical-HCM series also documented appropriate ICD discharge for sustained ventricular tachycardia in a heterozygous female carrier diagnosed at age 18.

Mechanism Target:

Ventricular tachycardia

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ten patients (24%) were referred for implantable cardioverter-defibrillator (ICD) implantation"

ICD referral is the recorded clinical response to arrhythmic risk in this disease.

Show evidence (3 references)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ten patients (24%) were referred for implantable cardioverter-defibrillator (ICD) implantation, including five females, four males, and one of unspecified sex."

Records ICD referral as part of the management of biallelic ALPK3 cardiomyopathy.

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf SUPPORT Human Clinical

"he has since experienced several appropriate ICD shocks."

Full text of Almomani et al. (2016), PMID:26846950. The homozygous child C-V:2 had cardiac arrest at seven years, followed by ICD implantation and appropriate therapies; this is distinct from primary-prevention referral.

PMID:40428316 SUPPORT Human Clinical

"The female patient with a wall thickness of 16 mm experienced an ICD discharge while running due to sustained VT, and a pathogenic variant in the non-sarcomeric ALPK3 gene was detected."

The Swedish apical-HCM series documents an appropriate ICD discharge in the female ALPK3 carrier. The overall cohort event rates and aneurysm prevalence are not ALPK3-specific.

Heart Transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Platform: Surgery

Definitive treatment for end-stage ALPK3 cardiomyopathy. Among curated biallelic patients, about 12% were referred for transplantation and 4 underwent it, at ages ranging from 4 to 33 years.

Mechanism Target:

Congestive heart failure

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"4 (9.5%) underwent heart transplantation at ages 4, 16, 28, and 33 years"

Records transplantation as the intervention taken for end-stage heart failure in this disease.

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"5 (11.9%) were referred for heart transplantation, and 4 (9.5%) underwent heart transplantation at ages 4, 16, 28, and 33 years"

Quantifies transplantation in the curated biallelic cohort.

Mavacamten

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten CHEBI:756998

Platform: Small molecule

In the ALPK3 K201X mouse study, mavacamten was tested in isolated cardiomyocytes, not as systemic treatment. It improved resting sarcomere length and diastolic calcium; relaxation improved in heterozygous cells but not homozygous cells. Fractional shortening decreased with treatment. These experiments establish partial cellular rescue, not clinical efficacy in ALPK3 cardiomyopathy. Negative inotropy is particularly relevant when systolic function is already impaired; most heterozygous clinical cases nevertheless have preserved systolic function.

Mechanism Target:

Abnormal Cardiomyocyte Calcium Handling

Show evidence (1 reference)

PMID:40128237 SUPPORT In Vitro

"In summary, mavacamten can rescue elevated diastolic calcium levels in the mouse model and has beneficial effects on resting sarcomere length."

Primary ex vivo treatment result from isolated K201X cardiomyocytes.

Show evidence (2 references)

PMID:40128237 SUPPORT In Vitro

"Mavacamten treatment did not improve contraction or relaxation time for homozygous cells"

The primary study limits the relaxation benefit to heterozygous cells, unlike the broader wording of the later review.

PMID:40128237 SUPPORT In Vitro

"However, it caused a reduction in fractional shortening also in these genotypes"

The same isolated-cell experiment found reduced fractional shortening, so rescue was partial and clinical benefit cannot be assumed.

AAV-Delivered miniALPK3 Gene Replacement

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Preclinical gene replacement using a shortened ALPK3 construct. To fit the conventional AAV packaging limit, investigators deleted 1,119 bp from mouse Alpk3 exon 6 and delivered miniALPK3 with a cardiac-specific promoter in MyoAAV-2A to knockout mice at postnatal day 2 or 3. Cardiac function, sarcomere structure and survival improved. This experiment tested neonatal prevention/rescue in a knockout model, not efficacy in patients.

Mechanism Target:

ALPK3 Loss of Function

Show evidence (1 reference)

PMID:41248220 SUPPORT Model Organism

"Contrary to saline-treated Alpk3−/− littermates, those treated with MyoAAV-miniALPK3 survived beyond 12 months without premature mortality"

Primary neonatal treatment experiment supports rescue through replacement of ALPK3 function.

Show evidence (1 reference)

PMID:41248220 SUPPORT Model Organism

"Using CRISPR-Cas9, we successfully removed a 1,119 bp segment from exon 6 to create a miniALPK3 variant"

Primary report of construct design; homozygous miniALPK3 mice retained normal cardiac function through 15 months.

Anticoagulation for atrial fibrillation

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

For patients with HCM who develop atrial fibrillation, the general HCM management baseline recommends oral anticoagulation regardless of standard thromboembolic-risk algorithms. This is phenotype-directed care, not evidence of an ALPK3-specific drug effect.

Mechanism Target:

Atrial fibrillation — Reduces thromboembolic risk associated with atrial fibrillation; does not restore sinus rhythm.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Oral anticoagulation regardless of standard algorithms to predict thromboembolic risk"

GeneReviews Table 4 recommendation for atrial fibrillation in HCM.

Cardiac follow-up and hydration advice

Platform: Other

For clinically established HCM with stable status, GeneReviews recommends echocardiography, ECG and ambulatory rhythm monitoring every one to two years, with earlier reassessment for new symptoms or cardiac events. Avoid dehydration. These are general HCM recommendations; severe pediatric ALPK3 disease requires individualized specialist follow-up.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"In those w/no change in clinical status ... no new cardiac events beginning at diagnosis (regardless of age): repeat every 1-2 yrs"

GeneReviews Table 5 gives this interval for stable echocardiographic follow-up, with ECG and 48-hour ambulatory monitoring also every one to two years; new symptoms or events prompt reassessment.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Avoid dehydration; in general use caution to stay adequately hydrated, particularly when exercising or when insensible losses are increased."

GeneReviews agents/circumstances-to-avoid baseline for HCM.

AAV-Delivered Full-Length ALPK3 Gene Replacement

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Preclinical delivery of full-length human ALPK3 with AAV9 and a cardiac TNNT2 promoter prevented disease after neonatal treatment and reversed established dysfunction and hypertrophy after treatment of six-week-old homozygous W1538X mice. AAV6 delivery also restored force in ALPK3-mutant human cardiac organoids. The 5.8-kb vector exceeds conventional AAV capacity but produced full-length transcript and protein in the tested systems. Human efficacy, long-term safety and response in hearts with substantial pre-existing fibrosis remain unestablished.

Mechanism Target:

ALPK3 Loss of Function — Replaces functional ALPK3 protein in deficient myocardium.

Show evidence (1 reference)

PMID:42618778 SUPPORT Model Organism

"AAV-ALPK3 prevented disease in neonatal Alpk3-mutant mice and reversed established pathology in adults"

Primary gene-replacement evidence supports ALPK3 deficiency as the upstream lesion.

Impaired Sarcomere Proteostasis — Restores protein-quality-control activity in the truncation model.

Show evidence (1 reference)

PMID:42618778 SUPPORT Model Organism

"In sum, truncating variants in Alpk3 impair both global and sarcomere-targeted proteostasis, and ALPK3 gene therapy directly rescues this phenotype."

The study measured proteomic and proteasome-function rescue in treated mutant hearts.

Show evidence (2 references)

PMID:42618778 SUPPORT Model Organism

"AAV9-TNNT2-ALPK3 delivery in 6-week-old mice was sufficient to fully rescue systolic function back to WT levels at all timepoints after treatment"

Adult treatment experiment in homozygous W1538X mice, followed to 18 weeks.

PMID:42618778 SUPPORT In Vitro

"treatment with AAV6-ALPK3 restored active force production to WT levels"

ALPK3-mutant human cardiac organoids provide a separate in vitro rescue system; these were not treated patients.

Disopyramide for symptomatic outflow obstruction

Action: Disopyramide therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: disopyramide NCIT:C61730

Platform: Small molecule

GeneReviews lists disopyramide as an option for symptomatic left ventricular outflow obstruction. Its use is phenotype-driven; this is general HCM guidance and does not establish an ALPK3-specific treatment response.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy ... consideration of calcium channel blockers, disopyramide"

GeneReviews Table 4 places this option under symptomatic LVOTO.

Septal reduction for persistent symptomatic obstruction

Platform: Surgery

Surgical septal myectomy or alcohol septal ablation may be considered for persistent symptomatic obstruction despite pharmacologic therapy, according to the general HCM baseline. Most reported ALPK3 cases are nonobstructive, so candidacy depends on demonstrated obstruction and symptoms.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy."

General HCM treatment recommendation, not genotype-specific trial evidence.

Liwen percutaneous intramyocardial radiofrequency ablation

Action: cardiac radiofrequency ablation Ontology label: Cardiac Radiofrequency Ablation NCIT:C170884

Platform: Surgery

A single 2025 case report describes septal radiofrequency ablation in an 18-year-old with a pathogenic ALPK3 truncation and a trans missense variant of uncertain significance. At six months, septal thickness declined from 29 to 15 mm and exertional symptoms resolved. The uncontrolled observation does not establish durable benefit, prevention of sudden death or a biallelic genotype-specific response. The reported provoked LVOT gradient was 20 mmHg, with a separate intracavitary gradient of 31 mmHg.

Show evidence (2 references)

PMID:41437994 SUPPORT Human Clinical

"septal thickness decreased from 29 mm to 15 mm"

Six-month imaging outcome after the reported Liwen intervention; the missense allele remained of uncertain significance.

PMID:41437994 SUPPORT Human Clinical

"complete resolution of exertional symptoms, including chest tightness and dyspnea"

Single-patient symptom outcome, without a control group or long-term risk assessment.

Heart-failure management for systolic dysfunction

Platform: Other

Systolic dysfunction requires heart-failure management guided by ventricular function and clinical status, including careful volume management and consideration of advanced support when symptoms progress. General HCM symptom therapies require reassessment when pump function deteriorates.

Mechanism Target:

Congestive heart failure

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"Guideline-based medical therapy for heart failure w/reduced ejection fraction"

GeneReviews Table 4 provides the systolic-dysfunction baseline.

🔬

Diagnosis

2

Echocardiography and cardiac MRI

Echocardiography and, when needed, cardiac MRI establish the cardiac phenotype and assess ventricular thickness, function and fibrosis. The GeneReviews HCM criteria are unexplained maximum left ventricular wall thickness of at least 15 mm in adults, or 13–14 mm with a family history; pediatric interpretation uses body-size-adjusted measurements. These general HCM criteria do not exclude ALPK3 disease presenting with ventricular dilatation or systolic dysfunction before hypertrophy.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of HCM is most often established with noninvasive cardiac imaging, including echocardiography and/or cardiac MRI."

General HCM diagnostic baseline, applicable to the hypertrophic presentation of ALPK3 cardiomyopathy.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"If there is a family history of a clinical or molecular diagnosis of HCM, a maximum LV wall thickness ... 13-14 mm supports the diagnosis."

GeneReviews explains the lower imaging threshold in a family with clinical or molecular HCM; this is not an ALPK3-specific criterion.

Molecular diagnosis and family segregation

Use a cardiomyopathy multigene panel that includes ALPK3 and deletion/duplication analysis, or exome/genome sequencing when appropriate. Interpret the allele class, zygosity and family segregation together: one pathogenic truncating allele can cause dominant disease, whereas two damaging alleles can produce severe recessive disease. A variant of uncertain significance alone does not establish the diagnosis. Periodic reanalysis of unresolved sequencing can be useful when inheritance evidence or transcript annotation changes; segregation can reveal both affected and currently asymptomatic carriers. A contiguous deletion including ALPK3 can coexist with a damaging sequence variant on the other allele; copy-number analysis and sequencing therefore answer complementary questions.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/ SUPPORT REVIEW SYNTHESIS Other

"that also includes deletion/duplication analysis is recommended."

In its molecular-testing section GeneReviews recommends a multigene panel including deletion/duplication analysis; ALPK3 is listed in its HCM gene table.

PMID:41645375 SUPPORT Human Clinical

"the mother exhibited severe obstructive HCM, while the brother was asymptomatic, suggesting incomplete or age-dependent penetrance within the family."

The reported family was resolved by reanalysis after recognition of dominant ALPK3 disease. Transcript revision changed the original p.Pro720ThrfsTer53 annotation to NM_020778.5 p.Pro518ThrfsTer53; these describe the same reported allele.

url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf SUPPORT Human Clinical

"cardiac screening uncovered severe HCM."

Full text of Grutters et al. (2023), PMID:37671554. In this child, cleft palate and contractures prompted genetic evaluation before cardiac symptoms; cardiac screening then identified severe concentric biventricular HCM.

📊

Prevalence

1

Adults with hypertrophic cardiomyopathy (pooled sequencing cohorts, North America, Europe and East Asia)

Unknown Unknown

Not a population prevalence. Reported only as the share of adult hypertrophic cardiomyopathy probands carrying an ALPK3 protein-truncating variant, pooled across seven cohorts totalling 27,147 probands. The population-level occurrence of ALPK3-related cardiomyopathy has never been measured directly, and cannot be inferred from this fraction because penetrance is incomplete and age-related.

Show evidence (1 reference)

PMID:41221624 SUPPORT REVIEW SYNTHESIS Human Clinical

"This translates to a pooled prevalence of 0.62% for truncations, 0.36% for non-truncations, and an overall variance prevalence of 0.99%."

Pooled case fraction of ALPK3 variants across large adult hypertrophic cardiomyopathy sequencing cohorts.

📊

Related Datasets

1

Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle geo:GSE215304

Transcriptomic profiling accompanying the study that localized ALPK3 to the sarcomeric M-band and defined the ALPK3-dependent phosphoproteome, using human pluripotent stem cell-derived cardiomyocytes carrying cardiomyopathic ALPK3 mutations.

human BULK RNA SEQ n=16

PMID:39196058

ALPK3-mutant human cardiomyocyte RNA sequencing accompanying PMID:39196058; interpretation is specific to the edited cellular system rather than a patient myocardial cohort.

🧫

Experimental Models

3

ALPK3-null human stem cell-derived cardiomyocytes IPSC_DERIVED_MODEL

Cardiomyocytes differentiated from patient-derived iPSC carrying a homozygous ALPK3 truncating variant and from gene-edited human ESC lines lacking ALPK3, used to define the ultrastructural and electrophysiological consequences of losing the protein in human cells.

Publication

PMID:27106955

Pathograph links

Sarcomere Disorganization recapitulates fidelity: moderate Disordered sarcomeres on electron microscopy in patient-derived and edited human cardiomyocytes.

Limitations: Stem cell-derived cardiomyocytes are immature relative to adult myocardium, and a monolayer culture cannot reproduce the chamber-level remodelling that defines the clinical phenotype.

Readouts

Cardiomyocyte ultrastructure by electron microscopy

Direction: ALTERED

Interpretation: Direct ultrastructural correlate of the node in human cells.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."

Reports the ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."

Human pluripotent stem cell-derived cardiomyocytes model the sarcomeric ultrastructural abnormality.

Intercalated Disc Remodeling recapitulates fidelity: moderate Abnormal intercalated discs on electron microscopy in ALPK3-deficient human cardiomyocytes.

Limitations: Stem cell-derived cardiomyocytes are immature relative to adult myocardium, and a monolayer culture cannot reproduce the chamber-level remodelling that defines the clinical phenotype.

Readouts

Cardiomyocyte ultrastructure by electron microscopy

Direction: ALTERED

Interpretation: Direct intercalated-disc ultrastructural readout in human cells.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."

Reports the ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."

The same cell systems also show abnormal intercalated discs.

Abnormal Cardiomyocyte Calcium Handling recapitulates fidelity: moderate Extended field potential duration and abnormal calcium handling in mutant contractile cultures.

Limitations: Field potential duration in an immature monolayer is not equivalent to the clinical QT interval, so the link to the repolarization phenotype is inferential.

Readouts

Field potential duration and intracellular calcium transients

Direction: ALTERED

Interpretation: Electrophysiological and calcium-handling correlate of the node.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures."

Reports the multi-electrode array and calcium imaging measurements behind this readout.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"Analysis of differentiated contractile cultures identified abnormal calcium handling as a potential feature of cardiomyocytes lacking ALPK3, providing functional insights into the molecular mechanisms underlying ALPK3-mediated cardiomyopathy."

Supports treating this model as informative for the calcium-handling node.

Show evidence (1 reference)

PMID:27106955 SUPPORT In Vitro

"We show that ALPK3-deficient cardiomyocytes derived from pluripotent stem cell models recapitulate the ultrastructural and electrophysiological defects observed in vivo."

The authors' own statement that this model system reproduces the in vivo defects, which is what licenses its use here.

Isogenic ALPK3 iPSC-derived cardiomyocytes for M-band proteomics IPSC_DERIVED_MODEL

Isogenic human iPSC-derived cardiomyocytes carrying frameshift or engineered kinase-domain substitutions. Phosphoproteomics supports a pseudokinase interpretation in the tested systems, and imaging identifies altered myomesin localization. Residual protein differs by allele: the ins/del line has less than 5% of wild-type ALPK3, whereas the later del/del truncation retains approximately 39%.

Publication

PMID:36321451

Pathograph links

Myomesin Mislocalization recapitulates fidelity: moderate ALPK3 loss-of-function variants displaced MYOM1 and MYOM2 from the M-band and nuclear envelope.

Limitations: These immature monolayers had no significant contractility difference by SarcTrack despite molecular changes. Force-buffering impairment was inferred, not directly measured, and nuclear-envelope localization differs from endogenous-tagging studies.

Readouts

Myomesin subcellular localization

Direction: ALTERED

Interpretation: Direct correlate of the myomesin mislocalization node.

Show evidence (1 reference)

PMID:36321451 SUPPORT In Vitro

"ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function."

Reports the localization measurement behind this readout.

Show evidence (1 reference)

PMID:36321451 SUPPORT In Vitro

"Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover."

Supports treating this model as informative for the myomesin mislocalization node.

Show evidence (3 references)

PMID:36321451 SUPPORT In Vitro

"We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues."

Describes the isogenic iPSC-cardiomyocyte system used here.

PMID:36321451 SUPPORT In Vitro

"ALPK3del/del hiPSC-CMs had reduced ALPK3 protein expression (~39% WT), indicating that these cells produce a truncated ALPK3 protein with reduced stability"

Direct evidence that engineered truncations are not equivalent to complete protein absence.

PMID:36321451 SUPPORT In Vitro

"did not detect significant differences between WT, ALPK3ins/del, and ALPK3dIC/dIC hiPSC-CMs"

SarcTrack analysis of more than 40,000 sarcomeres per line found no significant contractility difference; later organoid experiments use a different model and assay.

ALPK3-deficient human cardiac organoids ORGANOID

Three-dimensional human cardiac organoids in which ALPK3 is disrupted, used to test whether loss of ALPK3 impairs force generation in a tissue-level human system rather than a monolayer.

Publication

PMID:39196058

Pathograph links

Impaired Cardiomyocyte Contractility recapitulates fidelity: moderate Contractility is impaired in ALPK3-deficient human cardiac organoids.

Limitations: Cardiac organoids remain developmentally immature and lack the loading conditions, vasculature and chronic time course under which the human ventricle remodels, so they report the cellular contractile deficit but not the hypertrophic or dilated chamber phenotype.

Readouts

Organoid contractile force

Direction: DECREASED

Interpretation: Tissue-level functional correlate of the contractility node in a human system.

Show evidence (1 reference)

PMID:39196058 SUPPORT In Vitro

"ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant."

Reports the contractility measurement behind this readout.

Show evidence (1 reference)

PMID:39196058 SUPPORT In Vitro

"We demonstrate that ALPK3 is required to maintain a functional contractile apparatus in both hPSC-derived and mouse CMs."

Supports treating this model as informative for the contractility node.

Show evidence (1 reference)

PMID:39196058 SUPPORT In Vitro

"ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant."

Establishes that the organoid system reproduces the contractile deficit, alongside a mouse carrying a patient truncating allele.

🐁

Animal Models

6

Alpk3 constitutive knockout mouse (C57BL/6J, Van Sligtenhorst line)

Constitutive Alpk3-null mice develop a non-progressive cardiomyopathy with mixed hypertrophic and dilated features, reduced contractility, and abnormal intercalated discs with mild myofibrillar disarray. This is the first published Alpk3-null line and is distinct from the C57BL/6N line curated below; a later study judged this line inadequate as a model of the human neonatal disease and switched to the C57BL/6N line for that reason.

Species

Mouse

Genotype

Alpk3-/- (constitutive null, C57BL/6J background)

Publication

PMID:21441111

Pathograph links

Impaired Cardiomyocyte Contractility recapitulates fidelity: moderate Ventricular contractility falls by about half on cardiac MRI.

Limitations: A constitutive germline null models the biallelic human genotype, not the heterozygous adult-onset disease that accounts for most human cases. The cardiomyopathy in this line is explicitly non-progressive and the mice survive; a later study reports that this line failed to recapitulate the rapidly progressive, often fatal neonatal disease seen in patients, and acquired a different Alpk3-null line instead.

Readouts

Left ventricular septal and free wall contractility

Direction: DECREASED

Interpretation: Direct functional correlate of the contractility node in this model.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"Magnetic resonance imaging showed a 50% reduction in both septal and free wall LV contractility in Alpk3 (-/-) mice."

Reports the measurement behind this readout.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"Cardiomyopathy developed in mice deficient for α-kinase 3 (ALPK3), a nuclear kinase previously implicated in the differentiation of cardiomyocytes."

Establishes that loss of Alpk3 in mouse produces cardiomyopathy, so the model is informative for this node.

Sarcomere Disorganization recapitulates fidelity: moderate Mild myofibrillar disarray on light and electron microscopy.

Limitations: Disarray in this mouse line is mild. Human histopathology is variable, including neonatal and adult specimens without disarray.

Readouts

Cardiomyocyte ultrastructure

Direction: ALTERED

Interpretation: Ultrastructural correlate of the disorganization node.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"

Reports the ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"

Reports the ultrastructural measurement behind this readout.

Intercalated Disc Remodeling recapitulates fidelity: moderate Abnormal intercalated-disc architecture in the constitutive null mouse.

Limitations: Human evidence includes loss of selected junctional immunostaining in one neonatal sample; equivalent ultrastructure was not measured in that sample.

Readouts

Cardiomyocyte ultrastructure

Direction: ALTERED

Interpretation: Intercalated-disc abnormalities observed by microscopy.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"

Reports the ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"

Reports the ultrastructural measurement behind this readout.

Reactive Interstitial Fibrosis fails to recapitulate fidelity: low Interstitial fibrosis documented in human cohorts was absent in this mouse line under the reported conditions.

Limitations: The absence of spontaneous fibrosis limits this line for studying the human fibrotic phenotype. It does not establish that all Alpk3 models lack fibrosis or preclude other experimental injury contexts.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice"

Directly reports the absence of the fibrotic phenotype in this model.

Show evidence (1 reference)

PMID:21441111 SUPPORT Model Organism

"Alpk3 (-/-) mice were produced according to normal Mendelian ratios and appeared normal except for a nonprogressive cardiomyopathy that had features of both hypertrophic and dilated forms of cardiomyopathy."

Establishes the model and its mixed hypertrophic/dilated cardiac phenotype.

Alpk3 K1420R kinase-dead knock-in mouse

CRISPR knock-in mice carrying an arginine substitution at the predicted invariant catalytic lysine of the alpha-kinase domain. Homozygotes retain normal cardiac function and survival into adulthood, with unchanged cardiac SQSTM1 T269/S272 phosphorylation relative to total SQSTM1. Together with the negative in vitro kinase assay, these results support the pseudokinase interpretation under the tested conditions.

Species

Mouse

Genotype

Alpk3 K1420R/K1420R (invariant catalytic lysine mutated to arginine)

Publication

PMID:38048395

Pathograph links

Loss of M-Band Scaffolding fails to recapitulate fidelity: low The K1420R substitution does not reproduce the cardiomyopathy of the published null line. This is a negative functional comparison supporting a role for ALPK3 beyond putative kinase activity; M-band scaffold integrity was not directly established by the cardiac readout.

Limitations: Mutation of the equivalent lysine disables many other kinases, but absence of an ALPK3 kinase signal in the tested assay prevents direct demonstration of activity loss in this protein. Normal cardiac function in this model supports, but does not conclusively settle, the pseudokinase interpretation or resolve the conflicting SQSTM1 phosphorylation report.

Readouts

Survival and cardiac function to adulthood

Direction: UNCHANGED

Interpretation: Homozygotes maintain normal survival and cardiac function into adulthood, in contrast to the previously published null line. The result supports a functional distinction between the K1420R substitution and removal of ALPK3 protein.

Show evidence (1 reference)

PMID:38048395 SUPPORT Model Organism

"In contrast to the published Alpk3 null mutant mice2, the homozygous Alpk3 KR/KR mice did not exhibit premature mortality and maintained normal cardiac function into adulthood"

Reports the survival and cardiac function measurement behind this readout.

Show evidence (1 reference)

PMID:38048395 SUPPORT Model Organism

"In conclusion, our study presents compelling new evidence from both in vitro and in vivo experiments, supporting that ALPK3 functions as a pseudokinase."

The study's conclusion, which is what makes this model informative about the nature of the scaffolding node.

Show evidence (1 reference)

PMID:38048395 SUPPORT Model Organism

"we utilized CRISPR/Cas9 technology to generate knock-in mice in which the invariant K1420 of ALPK3 is mutated to arginine(R)"

Describes the construction of the knock-in model used here.

Alpk3 constitutive knockout mouse (C57BL/6N, MRC Harwell line)

A second, independently derived Alpk3-null line, acquired specifically because the earlier C57BL/6J null did not reproduce the human neonatal disease course. These mice are normal at birth and then develop a rapidly progressive cardiomyopathy in the first week with no survivors beyond 14 weeks, recapitulating the rapidly progressive neonatal presentation observed in some biallelic patients.

Species

Mouse

Genotype

Alpk3-/- (constitutive null, C57BL/6N background, exon 3 deletion)

Publication

PMID:36321451

Pathograph links

Ventricular Dilatation recapitulates fidelity: moderate Increased left ventricular cavity dimensions with severely depressed function, reproducing the dilated, hypocontractile presentation of biallelic human disease.

Limitations: A germline null models the biallelic genotype only. The human dilated phase characteristically remodels to hypertrophy in survivors; whether this line follows that trajectory is not established from the quoted result, and its mice die early.

Readouts

Left ventricular cavity dimension and survival

Direction: INCREASED

Interpretation: Chamber-level correlate of the dilatation node, with early mortality.

Show evidence (1 reference)

PMID:36321451 SUPPORT Model Organism

"manifested a rapidly progressive cardiomyopathy in the first week of life that resulted in premature death (no survivors beyond 14 weeks)"

Reports the survival measurement behind this readout.

Show evidence (1 reference)

PMID:36321451 SUPPORT Model Organism

"We therefore acquired and studied an alternative model, C57BL/6N Alpk3+/- mice (MRC Harwell Institute), that was created by deleting a region encompassing exon 3"

Establishes the identity and derivation of the line, distinguishing it from the C57BL/6J null.

Show evidence (1 reference)

PMID:36321451 SUPPORT Model Organism

"A previous Alpk3-/- C57BL/6J mouse model14 failed to recapitulate the rapidly progressive and often fatal neonatal disease that is observed in human patients."

States why a second line was needed, and distinguishes it from the C57BL/6J line curated above.

Alpk3 K201X knock-in mouse

Patient-derived truncation model. Homozygotes develop ventricular dilatation, hypertrophy by mass and systolic dysfunction; heterozygotes lack overt baseline disease at three and six months but have an exaggerated hypertrophic response to chronic adrenergic stimulation. Mavacamten was tested in isolated cardiomyocytes only.

Species

Mouse

Genotype

Heterozygous or homozygous Alpk3 K201X on C57BL/6J background

Publication

PMID:40128237

Pathograph links

Abnormal Cardiomyocyte Calcium Handling recapitulates fidelity: moderate Elevated diastolic calcium and delayed relaxation in isolated ventricular cardiomyocytes.

Limitations: Cells are isolated and unloaded; ex vivo response does not establish systemic efficacy or clinical benefit.

Show evidence (1 reference)

PMID:40128237 SUPPORT In Vitro

"Calcium transients from fura2 loaded cardiomyocytes showed dose-dependent increases in diastolic intracellular calcium"

Direct isolated-cell measurement in heterozygous and homozygous K201X mice.

Reduced Myosin Super-Relaxed State recapitulates fidelity: moderate Reduced SRX myosin occupancy in mutant cardiac tissue.

Limitations: The heterozygous mouse has no overt baseline cardiomyopathy at the ages studied, despite molecular abnormalities.

Show evidence (1 reference)

PMID:40128237 SUPPORT In Vitro

"Heterozygous and homozygous mice showed a significantly reduced proportion of myosin heads in the SRX state, compared to WT littermates"

Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.

Show evidence (1 reference)

PMID:40128237 SUPPORT Model Organism

"Homozygous Alpk3 K201X animals were viable and fertile, and showed no gross extra-cardiac abnormalities."

The in vivo phenotype is cardiac and differs from severe human biallelic multisystem disease.

Alpk3 exon-3 germline and adult inducible knockout mice

Germline loss produces early contractile impairment, ventricular dilatation and high neonatal mortality; survivors develop increased ventricular wall thickness. Induced loss in adult hearts produces dilated cardiomyopathy without a significant hypertrophic transition, separating developmental timing from the continuing need for ALPK3.

Species

Mouse

Genotype

Sox2-Cre germline deletion or tamoxifen-inducible cardiac deletion of floxed Alpk3 exon 3

Publication

PMID:40135575

Pathograph links

Impaired Sarcomere Proteostasis recapitulates fidelity: moderate Thick-filament proteins accumulate in germline-knockout hearts.

Limitations: Coexpression experiments support an interaction with MuRF proteins, but do not by themselves prove the proposed turnover pathway.

Show evidence (1 reference)

PMID:40135575 SUPPORT Model Organism

"These data suggest that the loss of ALPK3 leads to selective dysregulation of thick filament protein homeostasis."

Adult germline-knockout hearts accumulated thick-filament proteins without corresponding increases in their transcripts; the MuRF-dependent turnover mechanism remains a proposed explanation.

Show evidence (1 reference)

PMID:40135575 SUPPORT Model Organism

"In contrast, upon the loss of ALPK3 in the adult stage, icKO mice developed DCM without transitioning into LVH."

Direct comparison of germline and adult-inducible loss.

Alpk3 W1538X knock-in mouse for gene replacement

Patient-variant model used for neonatal prevention and reversal of established cardiomyopathy with full-length human ALPK3 delivery. Adult mice received treatment at six weeks and were followed to 18 weeks.

Species

Mouse

Genotype

Homozygous Alpk3 W1538X on C57BL/6J background; models human ALPK3 W1765X

Publication

PMID:42618778

Pathograph links

Impaired Cardiomyocyte Contractility recapitulates fidelity: moderate Established systolic and diastolic dysfunction responds to ALPK3 replacement.

Limitations: Homozygous mice model severe recessive disease. Substantial interstitial fibrosis is absent, so rescue in fibrotic human myocardium remains uncertain.

Show evidence (1 reference)

PMID:42618778 SUPPORT Model Organism

"AAV9-TNNT2-ALPK3 delivery in 6-week-old mice was sufficient to fully rescue systolic function back to WT levels at all timepoints after treatment"

Adult treatment experiment in homozygous W1538X mice, followed to 18 weeks.

Show evidence (1 reference)

PMID:42618778 SUPPORT Model Organism

"We used Alpk3W1538X mice, which model a severe ALPK3-truncating variant, ALPK3W1765X, found in patients"

Specifies the mouse-to-human variant correspondence.

{ }

Source YAML

click to show

name: ALPK3-Related Hypertrophic Cardiomyopathy
creation_date: "2026-09-01T00:00:00Z"
synonyms:
- CMH27
- cardiomyopathy, familial hypertrophic 27
- ALPK3 cardiomyopathy
- alpha-protein kinase 3-related cardiomyopathy
description: >-
  ALPK3-related hypertrophic cardiomyopathy is a Mendelian cardiomyopathy caused by loss-of-function variants in ALPK3, which encodes alpha-protein kinase 3, a muscle-specific atypical alpha-kinase that occupies the sarcomeric M-band and organizes the myomesins and the proteostasis machinery there. Whether it has catalytic activity at all, and whether it also occupies the nuclear envelope, are both actively disputed; the M-band localization and the proteostatic role are not. The entity has a zygosity-dependent architecture that distinguishes it from the sarcomere-gene forms of hypertrophic cardiomyopathy. Biallelic truncating variants commonly cause severe cardiomyopathy presenting in utero, at birth, or in early childhood, sometimes as a dilated, hypocontractile ventricle that subsequently remodels into hypertrophy, and can be accompanied by craniofacial and musculoskeletal features, with proportions varying across clinically ascertained series. Heterozygous truncating variants cause an adult-onset hypertrophic cardiomyopathy with incomplete, age-related penetrance, an apical or concentric hypertrophy pattern, extensive myocardial fibrosis, and a low rate of left ventricular outflow
  tract obstruction. ALPK3 is among the genes most often recovered when sarcomere-negative hypertrophic cardiomyopathy is re-analysed by exome or genome sequencing, ranking second or third in five of seven pooled cohorts, behind cryptic-splice MYBPC3 variants and, in one cohort, FLNC.
category: Mendelian
parents:
- Cardiovascular Disease
- Genetic Disorder
disease_term:
  preferred_term: ALPK3-related hypertrophic cardiomyopathy
  term:
    id: MONDO:0054838
    label: cardiomyopathy, familial hypertrophic 27
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
- reference: PMID:40128237
  title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
- reference: PMID:40135575
  title: α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.
- reference: PMID:41248220
  title: A Novel miniALPK3 Gene Therapy for ALPK3-Associated Cardiomyopathy.
- reference: PMID:42618778
  title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
- reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
  title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
- reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
  title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
- reference: PMID:40447126
  title: Whole-exome sequencing identifies novel truncating ALPK3 variants in a compound heterozygous state associated with pediatric hypertrophic cardiomyopathy and phenotypic heterogeneity.
- reference: PMID:41645375
  title: "[Genetic re-analysis of a Chinese pedigree affected with Hypertrophic cardiomyopathy due to a heterozygous truncating variant of ALPK3 gene and literature review]."
- reference: PMID:40428316
  title: Unravelling the Genotype of the Apical Variant of Hypertrophic Cardiomyopathy in a Swedish Cohort.
- reference: url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
  title: https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
- reference: PMID:41437994
  title: "Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A), causing hypertrophic cardiomyopathy treated with the liwen procedure: case report."
- reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
  title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
has_subtypes:
- name: Biallelic
  display_name: Biallelic (autosomal recessive) ALPK3 cardiomyopathy
  description: >-
    Two damaging ALPK3 alleles, often two protein-truncating variants. Disease commonly presents prenatally or in childhood, but adult diagnoses are reported. Presentation may be hypertrophic, dilated or mixed; some dilated presentations subsequently develop hypertrophy. Craniofacial and musculoskeletal findings are common in clinically ascertained cohorts. Absence of outflow obstruction in reported series is not a diagnostic requirement.
  evidence:
  - reference: PMID:26846950
    reference_title: "Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood."
    explanation: Establishes the biallelic form as the severe, early-onset end of the ALPK3 spectrum.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiomyopathy in patients with biallelic ALPK3 variants typically manifested early in life: 4 patients (10%) were diagnosed prenatally, 8 patients (19%) neonatally, and 8 patients (19%) within the first year of birth, highlighting early disease onset."
    explanation: Systematic curation of 42 biallelic patients quantifies the early age at presentation that defines this subtype.
    quote_role: REVIEW_SYNTHESIS
- name: Heterozygous
  display_name: Heterozygous (autosomal dominant) ALPK3 cardiomyopathy
  description: >-
    A single pathogenic ALPK3 allele, usually protein-truncating, is associated predominantly with adult-onset HCM, although adolescent diagnoses occur. Penetrance is incomplete and age-related. Apical and concentric patterns and myocardial fibrosis are reported, but morphology and severity vary; currently unaffected relatives require longitudinal assessment.
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype."
    explanation: Burden testing plus family co-segregation established the heterozygous truncating form as a distinct, pathogenic adult subtype.
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These heterozygous variants likely have variable and age-dependent penetrance, because obligate carrier relatives of critically ill infants with recessive ALPK3 cardiomyopathy often have no cardiac disease."
    explanation: States the incomplete, age-related penetrance that distinguishes the heterozygous subtype from the biallelic one.
    quote_role: REVIEW_SYNTHESIS
inheritance:
- name: Autosomal Recessive
  description: >-
    Biallelic damaging ALPK3 variants - homozygous or compound heterozygous, most often two protein-truncating alleles - segregate recessively, and the original families were consanguineous. ClinGen classifies the autosomal recessive ALPK3-hypertrophic cardiomyopathy relationship as Definitive. When both parents carry a causative allele, each pregnancy has a 25% chance of biallelic disease, a 50% chance of heterozygosity and a 25% chance of inheriting neither allele. Heterozygous ALPK3 relatives can themselves develop cardiomyopathy in adulthood.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26846950
    reference_title: "Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy."
    explanation: Homozygosity mapping in consanguineous families is the recessive design that identified the gene.
  - reference: CGGV:assertion_6312d79f-df12-4ec6-8ce6-0f38f19e617d-2022-02-09T170000.000Z
    reference_title: "ALPK3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALPK3 | HGNC:17574 | hypertrophic cardiomyopathy | MONDO:0005045 | AR | Definitive"
    explanation: ClinGen classifies the autosomal recessive ALPK3-hypertrophic cardiomyopathy relationship as Definitive.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the ... HCM-related pathogenic variants.
    explanation: GeneReviews gives recurrence risks when both parents carry an autosomal recessive HCM-related variant; its ALPK3-specific caveat is that heterozygotes can develop adult cardiomyopathy. These are transmission probabilities, not penetrance estimates.
    quote_role: REVIEW_SYNTHESIS
- name: Autosomal Dominant
  description: >-
    A single ALPK3 protein-truncating variant is transmitted dominantly, with reduced and age-dependent penetrance. ClinGen classifies the autosomal dominant relationship as Strong. Co-segregation across seven informative families gave a combined LOD score of 2.99. Each child has a 50% chance of inheriting the familial pathogenic variant; inheritance does not guarantee clinical disease because penetrance is incomplete.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combined logarithm of odds score in seven families with ALPK3tv was 2.99."
    explanation: Family co-segregation evidence for dominant transmission of heterozygous truncating alleles.
  - reference: CGGV:assertion_ace85164-0b70-46a2-ac6b-253088f4514d-2025-01-16T010000.000Z
    reference_title: "ALPK3 / hypertrophic cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALPK3 | HGNC:17574 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Strong"
    explanation: ClinGen classifies the autosomal dominant ALPK3-hypertrophic cardiomyopathy relationship as Strong.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: nonsyndromic HCM has a 50% chance of inheriting the ... pathogenic variant ... and therefore being at risk for developing nonsyndromic HCM.
    explanation: GeneReviews states that each child of an individual with autosomal dominant nonsyndromic HCM has a 50% chance of inheriting the pathogenic variant. This applies to the dominant ALPK3 form and does not imply complete penetrance.
    quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Adults with hypertrophic cardiomyopathy (pooled sequencing cohorts, North America, Europe and East Asia)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Not a population prevalence. Reported only as the share of adult hypertrophic
    cardiomyopathy probands carrying an ALPK3 protein-truncating variant, pooled across
    seven cohorts totalling 27,147 probands. The population-level occurrence of
    ALPK3-related cardiomyopathy has never been measured directly, and cannot be
    inferred from this fraction because penetrance is incomplete and age-related.
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This translates to a pooled prevalence of 0.62% for truncations, 0.36% for non-truncations, and an overall variance prevalence of 0.99%."
    explanation: Pooled case fraction of ALPK3 variants across large adult hypertrophic cardiomyopathy sequencing cohorts.
    quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: ALPK3 Loss of Function
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    Loss of ALPK3 function is the predominant mechanism associated with pathogenic truncating alleles. Nonsense-mediated decay has been demonstrated for p.W1264X and is partial in the K201X mouse model. The amount of residual transcript or protein depends on the allele and model; not every truncation has been shown to abolish protein expression. Haploinsufficiency is a supported explanation for dominant disease, while more severe loss underlies many biallelic presentations.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: ABNORMAL
    term:
      id: GO:0045214
      label: sarcomere organization
  genes:
  - preferred_term: ALPK3
    term:
      id: hgnc:17574
      label: ALPK3
  downstream:
  - target: Loss of M-Band Scaffolding
    causal_link_type: DIRECT
    description: Loss of functional ALPK3 disrupts its scaffolding role at the sarcomeric M-band. Nuclear-envelope localization has been reported in some systems but is disputed.
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band."
      explanation: >-
        Ties loss of the ALPK3 protein directly to loss of its sarcomeric localisation. The
        quoted sentence also asserts nuclear-envelope localisation, which this entry does
        not adopt because it is disputed; only the M-band half is relied on here.
  - target: Abnormal Cardiomyocyte Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: ALPK3 perturbation produces calcium-handling abnormalities in edited human cardiomyocytes and K201X mouse cardiomyocytes; the intermediate mechanism is not established.
    evidence:
    - reference: PMID:27106955
      reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures."
      explanation: Direct measurement of the repolarization and calcium-handling abnormality in ALPK3-null cardiomyocytes.
  - target: Reduced PKA-Target Phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed after K201X perturbation; the intermediates linking ALPK3 loss to this molecular readout are unresolved.
    evidence:
    - reference: PMID:40128237
      reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we observed reduced PKA-mediated phosphorylation in Alpk3 K201X cardiomyocytes, including markedly reduced phosphorylation of troponin I at serine23/24.
      explanation: In isolated cardiomyocytes from K201X mice, phosphorylation of PKA-target proteins, including troponin I Ser23/24, was reduced. Whether ALPK3 directly regulates PKA or this is chronic remodeling remains unresolved.
  - target: Reduced Myosin Super-Relaxed State
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed after K201X perturbation; the intermediates linking ALPK3 loss to this molecular readout are unresolved.
    evidence:
    - reference: PMID:40128237
      reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Heterozygous and homozygous mice showed a significantly reduced proportion of myosin heads in the SRX state, compared to WT littermates
      explanation: Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.
  - target: Abnormal facial shape
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:32480058
      reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms."
      explanation: Reports facial dysmorphism among the extracardiac features of biallelic ALPK3 disease.
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:32480058
      reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including contractures, scoliosis, cleft palate, and facial dysmorphisms"
      explanation: Reports cleft palate among extracardiac features of biallelic ALPK3 disease.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This multisystem pattern is biologically plausible, because ALPK3 expression is not confined to the heart: robust expression has been documented in developing and adult skeletal muscle as well as in myocardium, providing a mechanistic rationale for the skeletal-muscle and craniofacial manifestations observed in these patients."
      explanation: Links skeletal muscle involvement to ALPK3 expression outside the heart.
      quote_role: REVIEW_SYNTHESIS
  - target: Flexion contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including craniofacial dysmorphisms, cleft palate, skeletal muscle hypotonia, joint contractures, pterygia, scoliosis, short stature, and other musculoskeletal anomalies"
      explanation: Lists joint contractures among the characteristic extracardiac features of biallelic ALPK3 disease.
      quote_role: REVIEW_SYNTHESIS
  - target: Pterygium
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "skeletal muscle hypotonia, joint contractures, pterygia, scoliosis, short stature"
      explanation: Lists pterygia among the extracardiac features of biallelic ALPK3 disease.
      quote_role: REVIEW_SYNTHESIS
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:32480058
      reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including contractures, scoliosis, cleft palate, and facial dysmorphisms"
      explanation: Reports scoliosis among extracardiac features of biallelic ALPK3 disease.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reported principally in biallelic ALPK3 disease; the tissue-specific intermediates producing this manifestation are unresolved.
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "joint contractures, pterygia, scoliosis, short stature, and other musculoskeletal anomalies"
      explanation: Lists short stature among the extracardiac features of biallelic ALPK3 disease.
      quote_role: REVIEW_SYNTHESIS
  - target: Reactive Interstitial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Genotype-associated fibrotic remodeling documented in human cohorts; the responsible intermediates and their relationship to hypertrophy are unresolved.
    evidence:
    - reference: PMID:34263907
      reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."
      explanation: Direct imaging and histopathological demonstration of the fibrotic substrate in heterozygous carriers.
  - target: Intercalated Disc Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: ALPK3 deficiency is associated with junctional remodeling; the specific molecular intermediates are unresolved.
    evidence:
    - reference: PMID:27106955
      reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
      explanation: Direct ultrastructural demonstration of the lesion in ALPK3-null human cardiomyocytes.
    - reference: PMID:26846950
      reference_title: "Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling."
      explanation: Confirms intercalated-disc remodeling in myocardium from patients with biallelic variants.
    - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
      reference_title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Immunoreactive signals for plakoglobin and desmoplakin are absent at intercalated discs in the sample from patient A-IX:2
      explanation: Full text of Almomani et al. (2016), PMID:26846950. Direct immunostaining result from one neonatal myocardial sample; other junctional signals were preserved and electron microscopy was unavailable.
  evidence:
  - reference: PMID:27106955
    reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We performed detailed clinical and genetic analyses of a consanguineous family, identifying a new ALPK3 mutation (c.3792G>A, p.W1264X) which undergoes nonsense-mediated decay in ex vivo and in vivo tissues."
    explanation: Demonstrates nonsense-mediated decay of a truncating allele, establishing loss of function as the mechanism.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of ALPK3 pathogenic variants reveals that over 70% are truncating, strongly supporting haploinsufficiency as the principal disease driver."
    explanation: Establishes truncating loss of function as the predominant allele class across the reported variant spectrum.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In the absence of a working antibody for ALPK3, the consequences on Alpk3 protein levels and the potential presence of truncated protein remain unknown.
    explanation: The K201X study found reduced transcript levels but could not establish whether truncated protein persists, limiting a universal complete-null interpretation.
- name: Loss of M-Band Scaffolding
  description: >-
    ALPK3 localizes to the sarcomeric M band and associates with myomesins, MuRF proteins and SQSTM1/p62 in several experimental systems. Loss of this structural role is a proposed proximal explanation for abnormal sarcomere organization and protein homeostasis. Catalytic activity and nuclear-envelope localization remain disputed; individual binding partners and localization defects differ between models.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: sarcomere M-band
    term:
      id: GO:0031430
      label: M band
  downstream:
  - target: Myomesin Mislocalization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function."
      explanation: Directly links loss of the ALPK3 scaffold to myomesin mislocalization.
  - target: Impaired Sarcomere Proteostasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "ALPK3 lacks catalytic activity and maintains sarcomeric proteostasis by scaffolding MYOMs (myomesins), MuRF (muscle ring-finger protein) E3 ligases, and SQSTM1 (sequestosome-1)/p62."
      explanation: States that the scaffolding function is what maintains sarcomeric proteostasis, so its loss disrupts proteostasis.
      quote_role: REVIEW_SYNTHESIS
    description: ALPK3 loss alters protein homeostasis, but the specific mediators connecting its structural interactions to turnover remain unresolved.
  - target: SQSTM1 Mislocalization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: ALPK3 interacts with SQSTM1 and ALPK3 deficiency disrupts its M-band localization; the precise binding and phosphorylation requirements remain unresolved.
    evidence:
    - reference: PMID:39196058
      reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: SQSTM1 was not detected in the sarcomeres of these patient-specific variant hPSC lines but formed aggregates either within the cytosol or at the cell membrane
      explanation: Observed in the L639fs/34, Q1460X and R1792X edited cardiomyocyte models; this localization result is separable from the catalytic-activity controversy.
  evidence:
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase."
    explanation: >-
      The phosphoproteomic basis for treating ALPK3 as a scaffold rather than a kinase.
      This is one side of an open dispute, not a settled result - see the discussion
      alpk3_pseudokinase_controversy.
  - reference: PMID:38048395
    reference_title: "ALPK3 Functions as a Pseudokinase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In conclusion, our study presents compelling new evidence from both in vitro and in vivo experiments, supporting that ALPK3 functions as a pseudokinase."
    explanation: Supports the pseudokinase interpretation in the tested biochemical and knock-in mouse systems; it does not resolve all conflicting reports of catalytic activity.
  - reference: PMID:40135575
    reference_title: α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that ALPK3 localizes to the M-band in both neonatal and adult cardiomyocytes and interacts with muscle RING-finger proteins, which may regulate thick filament protein turnover.
    explanation: Endogenously tagged ALPK3 localized to the M band in neonatal and adult mouse cardiomyocytes; this supports restricting the shared localization claim to the M band.
- name: Myomesin Mislocalization
  description: >-
    Mislocalization of myomesin proteins was demonstrated in ALPK3-deficient isogenic cardiomyocytes and some mouse models, with impaired force buffering proposed as a consequence. Nuclear-envelope localization is disputed, and myomesin displacement is not universal: the K201X mouse study did not detect differences in myomesin localization between genotypes.
  biological_scale: MOLECULAR
  downstream:
  - target: Sarcomere Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alpk3_myomesin_force_buffering
    description: Proposed consequence of impaired myomesin-mediated force buffering; selective rescue of myomesin localization has not established this causal step.
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we propose that ALPK3 variants that cause mislocalization of myomesins may compromise force buffering and lead to impaired structural integrity of the sarcomere
      explanation: The discussion explicitly identifies force buffering as a proposed mechanism rather than a direct measurement.
  - target: Impaired Cardiomyocyte Contractility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALPK3 cardiomyopathy may cause impaired contractility and ventricular dilatation because of mislocalization and dysregulation of myomesin proteins, which are critical for force buffering in cardiomyocytes."
      explanation: >-
        The source's proposed causal step from myomesin mislocalization to impaired
        contractility. Its own wording is "may cause", so this is the paper's mechanistic
        proposal rather than a demonstrated step.
    hypothesis_groups:
    - alpk3_myomesin_force_buffering
    description: Proposed consequence of impaired myomesin-mediated force buffering; selective rescue of myomesin localization has not established this causal step.
  evidence:
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band."
    explanation: Establishes the ALPK3-myomesin association whose loss underlies this node.
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: we analysed localisation of the M-band protein myomesin using immunofluorescence staining on cardiac tissue and isolated cells, but failed to detect any differences between the genotypes
    explanation: The K201X model limits generalization of myomesin mislocalization across all ALPK3 alleles and experimental systems.
- name: Impaired Sarcomere Proteostasis
  description: >-
    ALPK3 deficiency disrupts M-band protein homeostasis. Studies report altered thick-filament abundance, mislocalized SQSTM1 and changes in MuRF-associated networks. The 2023 study did not directly measure turnover; the 2026 replacement study measured impaired proteasome activity and its rescue. The contributions of specific proteasomal and autophagic routes remain under investigation.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: proteasome-mediated turnover of sarcomere proteins
    modifier: DYSREGULATED
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  downstream:
  - target: Cardiomyocyte Hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALPK3 cardiomyopathy may cause hypertrophy because of dysregulation of key M-band proteins, which are important for sarcomere protein turnover."
      explanation: >-
        The source's proposed causal step from impaired sarcomere proteostasis to
        hypertrophy. Its own wording is "may cause", so this is the paper's mechanistic
        proposal rather than a demonstrated step.
    hypothesis_groups:
    - alpk3_proteostasis_hypertrophy
    description: Proposed link from impaired thick-filament homeostasis to cardiomyocyte growth; ALPK3 replacement rescues both, but the individual downstream mediator has not been isolated.
  evidence:
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis."
    explanation: The paper's own two-arm mechanistic conclusion, of which this node is the hypertrophy arm.
  - reference: PMID:39196058
    reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis."
    explanation: Independently links ALPK3 mutation to displacement of the ubiquitin-binding protein that routes damaged sarcomere proteins for clearance.
  - reference: PMID:40135575
    reference_title: α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data suggest that the loss of ALPK3 leads to selective dysregulation of thick filament protein homeostasis.
    explanation: Adult germline-knockout hearts accumulated thick-filament proteins without corresponding increases in their transcripts; the MuRF-dependent turnover mechanism remains a proposed explanation.
  - reference: PMID:42618778
    reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Finally, proteasome function was significantly inhibited in the Alpk3W1538X model
    explanation: Direct functional evidence of impaired protein degradation in a truncation model; the same study restored proteasome function after ALPK3 gene delivery.
  - reference: PMID:39196058
    reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: further studies are required to directly establish whether sarcomeric protein turnover is disrupted due to ALPK3 mutations.
    explanation: The 2023 paper explicitly distinguishes protein-network and localization findings from direct measurement of turnover.
- name: Sarcomere Disorganization
  description: >-
    ALPK3-deficient cardiomyocytes show disorganized sarcomeres and M-band abnormalities in several cellular and mouse models. Clinical myocardial disarray is variable and was absent in some neonatal and adult specimens.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: ABNORMAL
    term:
      id: GO:0045214
      label: sarcomere organization
  downstream:
  - target: Myofiber disarray
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27106955
    reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
    explanation: Direct ultrastructural demonstration of the lesion in ALPK3-null human cardiomyocytes.
- name: Abnormal Cardiomyocyte Calcium Handling
  description: >-
    ALPK3-deficient contractile cultures show an extended field potential duration and
    abnormal calcium handling; a knock-in truncation model shows elevated diastolic
    calcium and delayed relaxation.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  downstream:
  - target: Impaired Cardiomyocyte Contractility
    causal_link_type: DIRECT
  - target: Prolonged QT interval
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cellular calcium abnormalities and prolonged field potentials provide an inferential bridge to patient QT prolongation; a specific intervening electrophysiological pathway has not been established.
  evidence:
  - reference: PMID:27106955
    reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures."
    explanation: Direct measurement of the repolarization and calcium-handling abnormality in ALPK3-null cardiomyocytes.
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Calcium transients from fura2 loaded cardiomyocytes showed dose-dependent increases in diastolic intracellular calcium
    explanation: Direct isolated-cell measurement in heterozygous and homozygous K201X mice.
  - reference: PMID:39196058
    reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Peak cytosolic calcium levels (Fig. 2f) were elevated while calcium reuptake was delayed in ALPK3mut CMs
    explanation: Direct calcium imaging in the initiation-region deletion cell model; distinct from the K201X mouse cardiomyocyte experiment.
- name: Impaired Cardiomyocyte Contractility
  description: >-
    Reduced force generation is documented in several ALPK3-deficient heart and organoid models. The 2011 knockout study measured an approximately 50% reduction in regional left ventricular contractility. The relative contributions of myomesin localization, calcium handling and other molecular changes remain unresolved.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  downstream:
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
  - target: Ventricular Dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis."
      explanation: The authors propose a myomesin-mediated explanation for ventricular dilation; the specific mediation is not established by this conclusion alone.
    description: Reduced myocardial performance is associated with chamber dilation in ALPK3-deficient models; remodeling intermediates are not fully established.
  evidence:
  - reference: PMID:21441111
    reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Magnetic resonance imaging showed a 50% reduction in both septal and free wall LV contractility in Alpk3 (-/-) mice."
    explanation: Quantifies the contractile deficit in the ALPK3-null mouse heart.
- name: Cardiomyocyte Hypertrophy
  description: >-
    Individual cardiomyocytes enlarge, seen on myocardial histopathology as focal
    cardiomyocyte hypertrophy.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    modifier: INCREASED
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  downstream:
  - target: Ventricular Hypertrophy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults."
    explanation: Direct histopathological demonstration of cardiomyocyte hypertrophy in ALPK3 patients.
- name: Ventricular Dilatation
  description: >-
    Ventricular chamber dilation with depressed systolic function occurs particularly in severe early biallelic disease. Some neonatal dilated presentations subsequently become hypertrophic, while other patients present with hypertrophy or retain a dilated phenotype.
  biological_scale: TISSUE
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rare surviving children demonstrate a most atypical sequence of cardiac remodeling: biventricular dilation that transitions to biventricular hypertrophy, whereas contractile function remains profoundly depressed."
    explanation: Describes the dilated phase and its atypical evolution in biallelic ALPK3 disease.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy."
    explanation: Quantifies neonatal dilatation and its transition to hypertrophy in a paediatric ALPK3 cohort.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "among the 13 patients initially diagnosed with only DCM, 10 (77%) transitioned to HCM, typically within the first year of follow-up"
    explanation: Quantifies the dilated-to-hypertrophic transition in biallelic patients.
    quote_role: REVIEW_SYNTHESIS
- name: Ventricular Hypertrophy
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Increased ventricular wall thickness not explained by loading conditions. Apical and concentric patterns are enriched in several heterozygous cohorts, although asymmetric septal hypertrophy also occurs. Right ventricular involvement is reported. Fibrosis is modeled separately because its presence varies across human patients and experimental models.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    modifier: INCREASED
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
  - target: Apical hypertrophic cardiomyopathy
    causal_link_type: DIRECT
  - target: Concentric hypertrophic cardiomyopathy
    causal_link_type: DIRECT
  - target: Right ventricular hypertrophy
    causal_link_type: DIRECT
    description: Right ventricular involvement of hypertrophic remodeling, documented in the biallelic cohort.
    evidence:
    - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'eight patients (age N11 months) also had right ventricular hypertrophy (50%; 95% CI: 24.7%-75.3%).'
      explanation: Full text of Herkert et al. (2020), PMID:32480058. Right ventricular hypertrophy accompanied left ventricular disease in eight of 16 surviving biallelic patients in the 2020 cohort (50%); it is not present in all patients.
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009)"
    explanation: Quantifies the distinctive hypertrophy distribution in heterozygous carriers against genotyped comparator cohorts.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In heterozygous ALPK3 PTVs, hypertrophy is typically apical or concentric, LVOT obstruction is uncommon (~4% overall), and systolic function is preserved in most."
    explanation: >-
      Heterozygous-scoped statement of the hypertrophy distribution and the near-absence of
      outflow tract obstruction. The review's stronger figure - no outflow obstruction in
      any patient - is scoped to the biallelic cohort and is quoted on that subtype instead.
    quote_role: REVIEW_SYNTHESIS
- name: Reactive Interstitial Fibrosis
  description: >-
    Replacement and interstitial myocardial fibrosis are documented in patients by late gadolinium enhancement and histopathology. Fibrosis is absent or minimal in several ALPK3 mouse models, including the 2011 constitutive-null and K201X models, so it is not an obligate consequence of protein loss across experimental systems. The causal intermediates leading to fibrosis in patients are unresolved.
  biological_scale: TISSUE
  downstream:
  - target: Myocardial fibrosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."
    explanation: Direct imaging and histopathological demonstration of the fibrotic substrate in heterozygous carriers.
  - reference: PMID:21441111
    reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice"
    explanation: The constitutive knockout mouse does not develop the interstitial fibrosis seen in patients, so this node is not recapitulated by that model.
- name: Reduced PKA-Target Phosphorylation
  description: >-
    In isolated cardiomyocytes from K201X mice, phosphorylation of PKA-target proteins, including troponin I Ser23/24, was reduced. Whether ALPK3 directly regulates PKA or this is chronic remodeling remains unresolved.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we observed reduced PKA-mediated phosphorylation in Alpk3 K201X cardiomyocytes, including markedly reduced phosphorylation of troponin I at serine23/24.
    explanation: In isolated cardiomyocytes from K201X mice, phosphorylation of PKA-target proteins, including troponin I Ser23/24, was reduced. Whether ALPK3 directly regulates PKA or this is chronic remodeling remains unresolved.
- name: Reduced Myosin Super-Relaxed State
  description: >-
    Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Heterozygous and homozygous mice showed a significantly reduced proportion of myosin heads in the SRX state, compared to WT littermates
    explanation: Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.
- name: SQSTM1 Mislocalization
  description: >-
    SQSTM1 loses its normal M-band localization and accumulates in cytosolic or membrane-associated aggregates in several ALPK3-mutant human cardiomyocyte lines. Total SQSTM1 abundance was unchanged in the 2023 study. Mislocalization also occurred in the W1538X mouse myocardium; the contribution of phosphorylation to this localization defect is disputed.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39196058
    reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: SQSTM1 was not detected in the sarcomeres of these patient-specific variant hPSC lines but formed aggregates either within the cytosol or at the cell membrane
    explanation: Observed in the L639fs/34, Q1460X and R1792X edited cardiomyocyte models; this localization result is separable from the catalytic-activity controversy.
- name: Intercalated Disc Remodeling
  description: >-
    Intercalated-disc abnormalities occur in ALPK3-deficient cellular and mouse models. In one neonatal patient sample, desmoplakin and plakoglobin staining at the discs was absent while other junctional markers were retained. The human immunostaining observation is not a universal ultrastructural finding.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: intercalated disc
    term:
      id: GO:0014704
      label: intercalated disc
  evidence:
  - reference: PMID:27106955
    reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
    explanation: Direct ultrastructural demonstration of the lesion in ALPK3-null human cardiomyocytes.
  - reference: PMID:26846950
    reference_title: "Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling."
    explanation: Confirms intercalated-disc remodeling in myocardium from patients with biallelic variants.
  - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    reference_title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunoreactive signals for plakoglobin and desmoplakin are absent at intercalated discs in the sample from patient A-IX:2
    explanation: Full text of Almomani et al. (2016), PMID:26846950. Direct immunostaining result from one neonatal myocardial sample; other junctional signals were preserved and electron microscopy was unavailable.
phenotypes:
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy is the predominant cardiac phenotype across ALPK3 disease, but some patients initially or persistently have dilated or mixed cardiomyopathy. Hypertrophy therefore is not required at every disease stage.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  sequelae:
  - target: Congestive heart failure
  evidence:
  - reference: PMID:38356193
    reference_title: "Prevalence and phenotypes associated with ALPK3 null variants in a large French multicentric cohort: Confirming its involvement in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy."
    explanation: Hypertrophic cardiomyopathy was the phenotype in 26 of 31 adult heterozygous carriers in a large multicentre cohort.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although LVH and a clinical diagnosis of HCM often become apparent during adolescence or early adulthood, onset can be earlier (in infancy and childhood) or later in life.
    explanation: General GeneReviews HCM age spectrum, not a genotype-specific frequency estimate. ALPK3-specific cohorts establish the distinction between commonly early biallelic and later heterozygous disease.
    quote_role: REVIEW_SYNTHESIS
- name: Apical hypertrophic cardiomyopathy
  category: Cardiovascular
  subtype: Heterozygous
  description: >-
    Left ventricular apical hypertrophy is enriched in several heterozygous ALPK3 cohorts. The 2021 and French cohorts combine apical and concentric categories; the Busse preprint separately reports apical involvement in 12 of 20 assessed patients.
  phenotype_term:
    preferred_term: Apical hypertrophic cardiomyopathy
    term:
      id: HP:0031992
      label: Apical hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001)"
    explanation: Quantifies the apical or concentric hypertrophy pattern in heterozygous carriers.
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Over half (60%, 12/20) of individuals with ALPK3tv had an apical pattern of LVH
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Apical morphology is separately enumerated in this cohort; it should not be derived by splitting the earlier combined apical/concentric proportion.
- name: Concentric hypertrophic cardiomyopathy
  category: Cardiovascular
  description: >-
    Concentric hypertrophy is reported in both biallelic children and heterozygous adults. Combined apical/concentric proportions from some adult cohorts do not estimate the frequency of concentric hypertrophy alone.
  phenotype_term:
    preferred_term: Concentric hypertrophic cardiomyopathy
    term:
      id: HP:0005157
      label: Concentric hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:38356193
    reference_title: "Prevalence and phenotypes associated with ALPK3 null variants in a large French multicentric cohort: Confirming its involvement in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including 15% (n = 4) presented with an apical or a concentric form of hypertrophy"
    explanation: Records the concentric hypertrophy pattern among adult heterozygous carriers.
  - reference: url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    reference_title: https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Echocardiography demonstrated severe concentric HCM of both ventricles
    explanation: Full text of Grutters et al. (2023), PMID:37671554. The child with an ALPK3-containing deletion and a splice allele in trans had severe concentric biventricular hypertrophy.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Ventricular dilation with systolic dysfunction occurs particularly in biallelic disease, sometimes before hypertrophy. It is also reported among heterozygous carriers. In the 2020 biallelic series, 8 of 18 live-born patients had neonatal DCM that subsequently developed hypertrophy.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy."
    explanation: Quantifies neonatal dilated cardiomyopathy among live-born biallelic patients.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: DCM in 12 patients (7%)
    explanation: The review includes DCM among heterozygous carriers; the pooled group contains both truncating and non-truncating variants.
    quote_role: REVIEW_SYNTHESIS
- name: Left ventricular noncompaction cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular noncompaction has been reported alongside ALPK3-associated hypertrophy in biallelic families and a heterozygous cohort. The HPO binding records the authors' noncompaction diagnosis alongside HCM; it does not define a separate etiologic subtype or assert a distinct cardiomyopathy mechanism.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  evidence:
  - reference: PMID:31074094
    reference_title: "Phenotypic spectrum of ALPK3-related cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented with either dilated cardiomyopathy that progressed to hypertrophic cardiomyopathy (HCM) or HCM with left ventricular noncompaction."
    explanation: Reports left ventricular noncompaction alongside hypertrophy in a homozygous ALPK3 family.
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 1 had a diagnosis of left ventricular non-compaction with LVH.
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. One heterozygous carrier in the preprint cohort had this imaging diagnosis.
- name: Myocardial fibrosis
  category: Cardiovascular
  description: >-
    Myocardial fibrosis occurs in both zygosity groups. In the 2021 heterozygous cohort, 16 of 33 patients with cardiac MRI had extensive fibrosis, assessed qualitatively by affected segments. This differs from a quantitative scar-mass threshold. A pooled biallelic series reported late gadolinium enhancement in six of 14 imaged patients.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."
    explanation: Direct evidence of myocardial fibrosis in heterozygous ALPK3 truncating variant carriers.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac MRI revealed late gadolinium enhancement in 6 of 14 imaged patients (43%)"
    explanation: Quantifies the imaging correlate of myocardial fibrosis in biallelic patients.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34263907
    reference_title: Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 16 (49%) had extensive myocardial fibrosis (assessed qualitatively as >15% of left ventricular segments affected) in 33 with cardiac magnetic resonance imaging.
    explanation: Provides the measured-subgroup denominator and the qualitative definition of extensive fibrosis.
- name: Myofiber disarray
  category: Cellular
  description: >-
    Myofibrillar disarray has been observed in some ALPK3-associated myocardial samples, but it is variable: the two adult myectomy samples examined in the 2021 heterozygous cohort showed no significant disarray despite fibrosis and myocyte vacuolation. The original 2016 neonatal myocardial specimens also showed no apparent disarray.
  phenotype_term:
    preferred_term: Myofibrillar disarray
    term:
      id: HP:0031318
      label: Myofiber disarray
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults."
    explanation: Reports myofibrillar disarray on myocardial histopathology in ALPK3 patients.
  - reference: PMID:34263907
    reference_title: Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: showed cardiomyocyte hypertrophy with focal scarring and no significant cardiomyocyte disarray.
    explanation: The adult myectomy series limits generalization of disarray across ALPK3 disease.
  - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    reference_title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: No apparent myocyte disarray was observed
    explanation: Full text of Almomani et al. (2016), PMID:26846950. The original neonatal histology demonstrates that disarray is not an obligate finding.
- name: Endocardial fibroelastosis
  category: Cardiovascular
  subtype: Biallelic
  description: >-
    Subendocardial fibroelastosis, reported on myocardial histopathology in ALPK3
    patients under four years of age.
  phenotype_term:
    preferred_term: Subendocardial fibroelastosis
    term:
      id: HP:0001706
      label: Endocardial fibroelastosis
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subendocardial fibroelastosis in patients under 4 years of age"
    explanation: Reports subendocardial fibroelastosis in young ALPK3 patients.
- name: Prolonged QT interval
  category: Cardiovascular
  subtype: Biallelic
  description: >-
    QTc prolongation, present in about two-thirds of biallelic patients with an available
    ECG, far above the rate reported in large hypertrophic cardiomyopathy series.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Prolonged QTc interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A prolonged QTc interval was observed in 18 of 28 patients with available ECGs (64%), far exceeding the 10-15% reported in large HCM series"
    explanation: Quantifies QTc prolongation in biallelic ALPK3 patients against the background rate in hypertrophic cardiomyopathy.
    quote_role: REVIEW_SYNTHESIS
- name: Shortened PR interval
  category: Cardiovascular
  description: >-
    Short PR intervals were reported in 10% of the 2021 heterozygous cohort and in two of 16 biallelic patients with ECGs in the 2020 cohort. The mechanism is unresolved.
  phenotype_term:
    preferred_term: Short PR interval
    term:
      id: HP:0005165
      label: Shortened PR interval
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and of a short PR interval (10%, P = 0.009)"
    explanation: Quantifies the excess of short PR interval among heterozygous carriers.
  - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A short PR-interval was noted in two siblings
    explanation: Full text of Herkert et al. (2020), PMID:32480058. The biallelic cohort also includes short PR intervals; this feature is not restricted to heterozygotes.
- name: Ventricular tachycardia
  category: Cardiovascular
  description: >-
    Non-sustained ventricular tachycardia at baseline in about a third of heterozygous carriers, a rate comparable to sarcomere-positive hypertrophic cardiomyopathy. Sustained ventricular tachycardia requiring appropriate ICD therapy was documented in a heterozygous female carrier in the Swedish apical-HCM series.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Non-sustained ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  sequelae:
  - target: Cardiac arrest
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "non-sustained ventricular tachycardia (31%) at baseline similar to SP+"
    explanation: Quantifies non-sustained ventricular tachycardia in heterozygous carriers.
  - reference: PMID:40428316
    reference_title: Unravelling the Genotype of the Apical Variant of Hypertrophic Cardiomyopathy in a Swedish Cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The female patient with a wall thickness of 16 mm experienced an ICD discharge while running due to sustained VT, and a pathogenic variant in the non-sarcomeric ALPK3 gene was detected.
    explanation: The Swedish apical-HCM series documents an appropriate ICD discharge in the female ALPK3 carrier. The overall cohort event rates and aneurysm prevalence are not ALPK3-specific.
  subtype: Heterozygous
- name: Atrial fibrillation
  category: Cardiovascular
  description: >-
    Atrial fibrillation occurred in about one in eight heterozygous carriers with ECG data in a pooled systematic curation. The Busse preprint recorded five of 19 assessed heterozygous carriers (26.3%), illustrating variation between selected cohorts.
  subtype: Heterozygous
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atrial fibrillation was documented in 10 patients (12.5%), and ventricular tachycardia was also documented in 10 patients (12.5%)."
    explanation: >-
      Systematic curation of the pooled heterozygous cohort (ECG data for 80 of 167
      patients) records atrial fibrillation in 12.5%.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Afib, % (n/N) 26.3% 5/19 30.5% 40/131 0.79
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Cohort-specific measured-subgroup frequency.
- name: Reduced left ventricular ejection fraction
  category: Cardiovascular
  description: >-
    Systolic impairment occurs in both inheritance forms. It affected 6% of heterozygous patients at baseline in the 2021 cohort and can be profound in severe biallelic disease, including during transition from dilation to hypertrophy.
  phenotype_term:
    preferred_term: Left ventricular systolic impairment
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "left ventricular systolic impairment (6%)"
    explanation: Quantifies baseline systolic impairment in heterozygous carriers.
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biventricular dilation that transitions to biventricular hypertrophy, whereas contractile function remains profoundly depressed"
    explanation: The 2022 mechanistic paper summarizes severe early biallelic presentations; persistence is not universal across all reported patients.
    quote_role: REVIEW_SYNTHESIS
- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    Heart failure can cause fetal or neonatal death in severe biallelic disease and later death or transplantation in either inheritance form.
  phenotype_term:
    preferred_term: Heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    reference_title: "https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of 5 patients died due to progressive heart failure between 35 weeks of gestation and 5 days after birth."
    explanation: The 2016 full text distinguishes one fetal and two neonatal deaths; its abstract compresses these into the first week of life.
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation"
    explanation: Records heart failure death or transplantation among adult heterozygous carriers over follow-up.
- name: Cardiac arrest
  category: Cardiovascular
  description: >-
    Cardiac arrest is documented in severe pediatric biallelic disease and in a heterozygous adult in the Busse preprint cohort. These selected reports cannot establish incidence.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:38356193
    reference_title: "Prevalence and phenotypes associated with ALPK3 null variants in a large French multicentric cohort: Confirming its involvement in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest)."
    explanation: Records cardiac arrest among the severe outcomes in paediatric biallelic patients.
  - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    reference_title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Out-of-hospital cardiac arrest occurred at age 7 years due to ventricular arrhythmias
    explanation: Full text of Almomani et al. (2016), PMID:26846950. Direct event in patient C-V:2, homozygous for p.Trp1765*.
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: one individual with ALPK3tv had a fatal cardiac arrest at 35 years old
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. The cohort reports a fatal event in a heterozygote. It does not establish a genotype-specific risk score.
- name: Abnormal facial shape
  category: Craniofacial
  subtype: Biallelic
  description: >-
    Craniofacial dysmorphism occurred in at least 12 of 17 assessed biallelic patients in the 2020 cohort (70.6%), with varied individual findings.
  phenotype_term:
    preferred_term: Craniofacial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms."
    explanation: Reports facial dysmorphism among the extracardiac features of biallelic ALPK3 disease.
  phenotype_contexts:
  - subtype: Biallelic
    frequency: FREQUENT
    notes: Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.
    evidence:
    - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Craniofacial dysmorphic features were present in at least 12/17 patients (70.6%; 95% CI: 44.0%-89.7%)'
      explanation: Full text of Herkert et al. (2020), PMID:32480058. Craniofacial dysmorphism occurred in at least 12 of 17 assessed biallelic patients in the 2020 cohort (70.6%), with varied individual findings.
- name: Cleft palate
  category: Craniofacial
  subtype: Biallelic
  description: Cleft palate, reported among the craniofacial features of biallelic ALPK3 disease.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including contractures, scoliosis, cleft palate, and facial dysmorphisms"
    explanation: Reports cleft palate among extracardiac features of biallelic ALPK3 disease.
- name: Flexion contracture
  category: Musculoskeletal
  subtype: Biallelic
  description: >-
    Joint contractures were recorded in 8 of 19 biallelic patients in the 2020 cohort (42%), involving knees, shoulders or distal joints; congenital and later-onset presentations occurred.
  phenotype_term:
    preferred_term: Joint contractures
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including craniofacial dysmorphisms, cleft palate, skeletal muscle hypotonia, joint contractures, pterygia, scoliosis, short stature, and other musculoskeletal anomalies"
    explanation: Lists joint contractures among the characteristic extracardiac features of biallelic ALPK3 disease.
    quote_role: REVIEW_SYNTHESIS
  phenotype_contexts:
  - subtype: Biallelic
    frequency: FREQUENT
    notes: Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.
    evidence:
    - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Five patients had congenital contractures, while one patient developed contractures and scoliosis later in life.
      explanation: Full text of Herkert et al. (2020), PMID:32480058. Joint contractures were recorded in 8 of 19 biallelic patients in the 2020 cohort (42%), involving knees, shoulders or distal joints; congenital and later-onset presentations occurred.
- name: Scoliosis
  category: Musculoskeletal
  subtype: Biallelic
  description: >-
    Kyphoscoliosis was recorded in 6 of 15 assessed biallelic patients in the 2020 cohort (40%), and can progress with age.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including contractures, scoliosis, cleft palate, and facial dysmorphisms"
    explanation: Reports scoliosis among extracardiac features of biallelic ALPK3 disease.
  phenotype_contexts:
  - subtype: Biallelic
    frequency: FREQUENT
    notes: Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.
    evidence:
    - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Short stature 9/15 60% Kyphoscoliosis 6/15 40%
      explanation: Full text of Herkert et al. (2020), PMID:32480058. Kyphoscoliosis was recorded in 6 of 15 assessed biallelic patients in the 2020 cohort (40%), and can progress with age.
- name: Hypotonia
  category: Musculoskeletal
  subtype: Biallelic
  description: >-
    Hypotonia occurred in 4 of 13 assessed biallelic patients in the 2020 cohort (30.8%), with muscle involvement varying across patients.
  phenotype_term:
    preferred_term: Skeletal muscle hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This multisystem pattern is biologically plausible, because ALPK3 expression is not confined to the heart: robust expression has been documented in developing and adult skeletal muscle as well as in myocardium, providing a mechanistic rationale for the skeletal-muscle and craniofacial manifestations observed in these patients."
    explanation: Links skeletal muscle involvement to ALPK3 expression outside the heart.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:33076350
    reference_title: "Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient with the later onset showed milder extracardiac symptoms, such as decreased muscle tone and distal muscular dystrophy, but had fast progression of cardiac complications leading to the need of heart transplantation."
    explanation: Case-level report of decreased muscle tone in a patient with biallelic ALPK3 variants.
  phenotype_contexts:
  - subtype: Biallelic
    frequency: FREQUENT
    notes: Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.
    evidence:
    - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Hypotonia was present in 4/13 patients (30.8%; 95% CI: 9.1%-61.4%).'
      explanation: Full text of Herkert et al. (2020), PMID:32480058. Hypotonia occurred in 4 of 13 assessed biallelic patients in the 2020 cohort (30.8%), with muscle involvement varying across patients.
- name: Pterygium
  category: Musculoskeletal
  subtype: Biallelic
  description: Pterygia, reported among the musculoskeletal anomalies of biallelic ALPK3 disease.
  phenotype_term:
    preferred_term: Pterygia
    term:
      id: HP:0001059
      label: Pterygium
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skeletal muscle hypotonia, joint contractures, pterygia, scoliosis, short stature"
    explanation: Lists pterygia among the extracardiac features of biallelic ALPK3 disease.
    quote_role: REVIEW_SYNTHESIS
- name: Short stature
  category: Musculoskeletal
  subtype: Biallelic
  description: >-
    Short stature was recorded in 9 of 15 assessed biallelic patients in the 2020 cohort (60%); this is a clinically ascertained cohort estimate.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "joint contractures, pterygia, scoliosis, short stature, and other musculoskeletal anomalies"
    explanation: Lists short stature among the extracardiac features of biallelic ALPK3 disease.
    quote_role: REVIEW_SYNTHESIS
  phenotype_contexts:
  - subtype: Biallelic
    frequency: FREQUENT
    notes: Herkert et al. 2020 clinically assessed cohort; ascertainment and denominators vary by feature.
    evidence:
    - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The height of 9/15 patients (60%; 95% CI: 32.3%-83.7%) ranged from 2 to 6 SDs below the normal mean.'
      explanation: Full text of Herkert et al. (2020), PMID:32480058. Short stature was recorded in 9 of 15 assessed biallelic patients in the 2020 cohort (60%); this is a clinically ascertained cohort estimate.
- name: Sudden cardiac death
  category: Cardiovascular
  subtype: Biallelic
  description: >-
    Sudden cardiac death was reported at age 12 in a child with two ALPK3 frameshift variants and severe nonobstructive hypertrophic cardiomyopathy. Prior Holter monitoring had not detected ventricular tachycardia and no syncope was reported. The case establishes occurrence but does not quantify risk.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:33076350
    reference_title: Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 12, the patient had no progression of chamber enlargement or reduction of contractility, but died due to sudden cardiac death (SCD) after 30 min of unsuccessful resuscitation.
    explanation: Case 1 had two reported ALPK3 frameshift variants and severe nonobstructive HCM. Sudden death occurred despite prior rhythm monitoring without documented ventricular tachycardia; a single case cannot establish incidence.
- name: Right ventricular hypertrophy
  category: Cardiovascular
  subtype: Biallelic
  description: >-
    Right ventricular hypertrophy accompanied left ventricular disease in eight of 16 surviving biallelic patients in the 2020 cohort (50%); it is not present in all patients.
  phenotype_term:
    preferred_term: Right ventricular hypertrophy
    term:
      id: HP:0001667
      label: Right ventricular hypertrophy
  evidence:
  - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'eight patients (age N11 months) also had right ventricular hypertrophy (50%; 95% CI: 24.7%-75.3%).'
    explanation: Full text of Herkert et al. (2020), PMID:32480058. Right ventricular hypertrophy accompanied left ventricular disease in eight of 16 surviving biallelic patients in the 2020 cohort (50%); it is not present in all patients.
- name: Webbed neck
  category: Musculoskeletal
  subtype: Biallelic
  description: >-
    Webbed neck was recorded in eight of 17 assessed biallelic patients in the 2020 cohort, alongside a variable musculoskeletal phenotype.
  phenotype_term:
    preferred_term: Webbed neck
    term:
      id: HP:0000465
      label: Webbed neck
  evidence:
  - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: including severe scoliosis ( n =6 ) ( Figure 4 A), webbed neck ( n = 8)
    explanation: Full text of Herkert et al. (2020), PMID:32480058. Webbed neck was recorded in eight of 17 assessed biallelic patients in the 2020 cohort, alongside a variable musculoskeletal phenotype.
- name: Motor delay
  category: Neurologic
  subtype: Biallelic
  description: >-
    Four of 12 assessed biallelic patients had delayed motor development in the 2020 cohort, with independent walking between 18 and 32 months.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Four of 12 patients (33.3%; 95% CI: 9.9%-65.1%) had delayed motor development with independent walking at ages 18 to 32 months'
    explanation: Full text of Herkert et al. (2020), PMID:32480058. Four of 12 assessed biallelic patients had delayed motor development in the 2020 cohort, with independent walking between 18 and 32 months.
- name: Elevated circulating creatine kinase activity
  category: Biochemical
  subtype: Heterozygous
  description: >-
    Serum creatine kinase was elevated in seven of 35 tested ALPK3 truncating-variant carriers in the 2021 cohort (20%). One biopsied patient had myopathic changes; creatine kinase elevation alone does not establish symptomatic skeletal myopathy.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:34263907
    reference_title: Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seven patients had raised serum creatine kinase out of 35 where it was determined (20%)
    explanation: Direct adult cohort laboratory finding, scoped to the tested subgroup.
- name: Pectus carinatum
  category: Musculoskeletal
  subtype: Biallelic
  description: >-
    Pectus carinatum was reported in a six-year-old girl with compound heterozygous truncating ALPK3 variants, together with short stature, webbed neck, contractures and scoliosis.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:40447126
    reference_title: Whole-exome sequencing identifies novel truncating ALPK3 variants in a compound heterozygous state associated with pediatric hypertrophic cardiomyopathy and phenotypic heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 1, a 6-year-old girl, presented with HCM, short stature, webbed neck, joint contractures, pectus carinatum, and scoliosis.
    explanation: The abstract reports this finding in one child; no frequency estimate is inferred.
- name: Hydrops fetalis
  category: Prenatal
  subtype: Biallelic
  description: >-
    Hydrops fetalis accompanied severe prenatal cardiomyopathy in two homozygous siblings in the original 2016 family series.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    reference_title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: revealing generalized hydrops fetalis and cardiomegaly with reduced contractility.
    explanation: Full text of Almomani et al. (2016), PMID:26846950. Prenatal findings in patient B-IV:1; the next affected sibling also developed severe fetal hydrops.
- name: Left ventricular apical aneurysm
  category: Cardiovascular
  description: >-
    Apical aneurysm occurred in four of 18 assessed heterozygous carriers in the Busse preprint cohort. All four had nonobstructive HCM with apical hypertrophy; the observed proportion is not a population estimate.
  phenotype_term:
    preferred_term: Left ventricular apical aneurysm
    term:
      id: HP:6000144
      label: Left ventricular aneurysm
  evidence:
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Apical aneurysm, % (n/N) 22.2% 4/18 2.4% 3/125 0.005
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.
  subtype: Heterozygous
- name: Mitral regurgitation
  category: Cardiovascular
  description: >-
    Mitral regurgitation was reported in 10 of 19 assessed heterozygous carriers in the Busse preprint cohort.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mitral regurgitation, % (n/N) 52.6% 10/19 46.9% 60/128 0.81
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.
  subtype: Heterozygous
- name: Left atrial enlargement
  category: Cardiovascular
  description: >-
    Left atrial enlargement was reported in seven of 19 assessed heterozygous carriers, less often than in the sarcomeric comparison group in the Busse preprint.
  phenotype_term:
    preferred_term: Left atrial enlargement
    term:
      id: HP:0031295
      label: Left atrial enlargement
  evidence:
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Left atrial enlargement, % (n/N) 36.8% 7/19 72.7% 93/128 0.0032
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.
  subtype: Heterozygous
- name: Left ventricular diastolic dysfunction
  category: Cardiovascular
  description: >-
    The Busse preprint recorded diastolic dysfunction in three of 17 assessed heterozygous carriers; this cohort proportion is not a population frequency.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diastolic dysfunction, % (n/N) 17.7% 3/17 47.5% 58/122 0.034
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.
  subtype: Heterozygous
- name: Premature ventricular contraction
  category: Cardiovascular
  description: >-
    Premature ventricular contractions occurred in seven of 19 assessed heterozygous carriers in the Busse preprint cohort.
  phenotype_term:
    preferred_term: Premature ventricular contraction
    term:
      id: HP:0006682
      label: Premature ventricular contraction
  evidence:
  - reference: url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    reference_title: https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PVCs, % (n/N) 36.8% 7/19 62.3% 81/130 0.046
    explanation: Busse et al., November 2024 preprint full text (PMID:39606411), subsequently published as PMID:40469041; the quoted version is the preprint. Table 3 compares the ALPK3 subgroup with sarcomeric HCM; denominators differ by available measurement.
  subtype: Heterozygous
genetic:
- name: ALPK3
  gene_term:
    preferred_term: ALPK3
    term:
      id: hgnc:17574
      label: ALPK3
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  review_notes: >-
    ALPK3, on chromosome 15q25.2, encodes a muscle-specific protein with a nuclear localization signal, immunoglobulin-like domains and a C-terminal alpha-kinase domain whose catalytic activity is disputed. Protein-truncating variants dominate the reported pathogenic spectrum. The 2021 HCM discovery and validation cohorts each showed approximately 16-fold enrichment versus population controls; non-truncating variants were not significantly enriched in that analysis.
  case_fractions:
  - population: UK hypertrophic cardiomyopathy discovery cohort (770 probands)
    case_fraction_percent: 1.56
    notes: Heterozygous ALPK3 truncating variants, versus gnomAD (OR 16.11).
    evidence:
    - reference: PMID:34263907
      reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv"
      explanation: Quantifies the ALPK3 share of cases in the discovery cohort.
  - population: International hypertrophic cardiomyopathy validation cohort (2047 probands)
    case_fraction_percent: 1.56
    notes: Independent replication of the discovery-cohort fraction (OR 16.17).
    evidence:
    - reference: PMID:34263907
      reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv"
      explanation: Quantifies the ALPK3 share of cases in the independent validation cohort.
  - population: Dutch cardiomyopathy patients referred for initial genetic analysis (1548 probands)
    case_fraction_percent: 2.5
    case_fraction_low: 1.8
    case_fraction_high: 3.4
    notes: Rare heterozygous ALPK3 variants of any class, not restricted to truncating.
    evidence:
    - reference: PMID:32480058
      reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%)"
      explanation: Quantifies the rare heterozygous ALPK3 variant fraction in a Dutch cardiomyopathy cohort.
  - population: Korean nonsyndromic hypertrophic cardiomyopathy diagnostic cohort (2366 unrelated patients)
    case_fraction_percent: 1.52
    notes: 36 patients carried pathogenic or likely pathogenic premature-termination variants; clinical details were incomplete and one also had a segregating MYBPC3 variant.
    evidence:
    - reference: PMID:39036505
      reference_title: High prevalence of ALPK3 premature terminating variants in Korean hypertrophic cardiomyopathy patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A total of 36 unrelated HCMP patients out of 2,366 patients (1.5%) carried rare pathogenic or likely pathogenic (P/LP) PTVs in ALPK3
      explanation: Observed diagnostic-cohort fraction; not population penetrance or proof that ALPK3 explained every individual case.
  evidence:
  - reference: CGGV:assertion_6312d79f-df12-4ec6-8ce6-0f38f19e617d-2022-02-09T170000.000Z
    reference_title: "ALPK3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALPK3 | HGNC:17574 | hypertrophic cardiomyopathy | MONDO:0005045 | AR | Definitive"
    explanation: ClinGen classifies the autosomal recessive ALPK3-hypertrophic cardiomyopathy relationship as Definitive.
  - reference: CGGV:assertion_ace85164-0b70-46a2-ac6b-253088f4514d-2025-01-16T010000.000Z
    reference_title: "ALPK3 / hypertrophic cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALPK3 | HGNC:17574 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Strong"
    explanation: ClinGen classifies the autosomal dominant ALPK3-hypertrophic cardiomyopathy relationship as Strong.
  - reference: PMID:39036505
    reference_title: "High prevalence of ALPK3 premature terminating variants in Korean hypertrophic cardiomyopathy patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed that monoallelic PTVs in ALPK3 were also significantly enriched in Korean patients with HCMP with an odds ratio score of 10-21."
    explanation: Replicates the truncating-variant enrichment outside European-ancestry cohorts.
  - reference: url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    reference_title: https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, functional studies should be carried out to further support our hypothesis.
    explanation: Full text of Herkert et al. (2020), PMID:32480058. The authors qualify their proposed pathogenic interpretation of p.Glu199Asp, highlighting allele-level uncertainty.
  - reference: PMID:39036505
    reference_title: High prevalence of ALPK3 premature terminating variants in Korean hypertrophic cardiomyopathy patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ALPK3 PTV did not segregate with HCMP in the family.
    explanation: Patient 21 also carried a pathogenic MYBPC3 variant that segregated with disease, limiting automatic assignment of causality to every ALPK3 truncation.
  - reference: url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    reference_title: https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A complete gene deletion, as found in our patient, has not been reported previously
    explanation: Full text of Grutters et al. (2023), PMID:37671554. The child had a contiguous deletion and a splice allele in trans. The cardiac presentation supports ALPK3 involvement while the multigene deletion limits attribution of every extracardiac feature.
  - reference: PMID:41437994
    reference_title: "Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A), causing hypertrophic cardiomyopathy treated with the liwen procedure: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: c.3491G > A (p.Arg1164Gln) was classified as a variant of undetermined significance (PM2 + PP3).
    explanation: The primary report explicitly retains uncertain significance for the missense allele despite stronger causal wording in its title and discussion.
  - reference: PMID:34263907
    reference_title: Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the cumulative percentage of diagnosed carriers increased to >95% among males and 80% among females.
    explanation: Cumulative diagnosis by age 75 in an ascertained cohort; not a population-based penetrance estimate.
  notes: >-
    On re-analysis of sarcomere-negative hypertrophic cardiomyopathy by exome or genome sequencing, ALPK3 protein-truncating variants ranked second or third among newly identified variants in five of seven pooled cohorts, behind cryptic-splice MYBPC3 and, in the French cohort, FLNC. Non-truncating ALPK3 variants make up a substantial share of the observed spectrum - 99 of 268 cohort variants (37%), and at least one non-truncating allele in 13 of 42 curated biallelic patients - but were not significantly enriched over population controls, so their contribution is not modelled as a separate mechanism here. Individual missense variants require separate assessment: Herkert et al. reported mixed prediction results for p.Val812Met and p.Glu199Asp and explicitly requested functional validation of the latter. The lack of class-wide missense enrichment does not establish every missense variant as benign, nor does phenotype resemblance alone prove pathogenicity. The Korean cohort also contained one individual whose MYBPC3 variant, rather than the ALPK3 truncation, segregated with familial HCM; co-occurring variants and segregation remain relevant to individual interpretation. Whole-gene deletion
    is also documented: a child carried a paternal contiguous 15q25.2q25.3 deletion including ALPK3 and a maternal c.4736-1G>A splice variant (NM_020778.4). Because the deletion includes other genes, overlapping developmental and congenital features cannot be assigned solely to ALPK3. In the 2025 Liwen-procedure case report, the truncating p.Arg1412Ter allele was classified as pathogenic, but the trans p.Arg1164Gln missense allele remained a variant of uncertain significance. The case does not independently establish pathogenicity of the missense allele or prove a biallelic dose effect. In the clinically ascertained 2021 cohort, cumulative diagnosis by age 75 exceeded 95% in men and reached 80% in women; these selected-family estimates do not measure population penetrance.
treatments:
- name: Beta-Blocker and Non-Dihydropyridine Calcium Channel Blocker Therapy
  description: >-
    Symptom-directed HCM therapy chosen according to obstruction, symptoms and ventricular function. GeneReviews lists beta-blockers or calcium channel blockers for symptomatic nonobstructive HCM with preserved ejection fraction and beta-blockers as first-line therapy for symptomatic obstruction. Systolic dysfunction instead requires guideline-based heart-failure management; these HCM symptom-control options are not interchangeable across ventricular-function states. ALPK3-specific comparative treatment trials are lacking.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: non-dihydropyridine calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pharmacological treatments commonly employed include beta-blockers and non-dihydropyridine calcium channel blockers."
    explanation: Names the pharmacotherapy in common use for this disease.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Pharmacologic therapy to alleviate symptoms, incl beta-blockers, calcium channel blockers
    explanation: GeneReviews Table 4 recommendation for symptomatic nonobstructive HCM with preserved ejection fraction; the ventricular-function qualifier is essential.
    quote_role: REVIEW_SYNTHESIS
- name: Cascade Genetic Testing and Cardiac Surveillance of Variant Carriers
  description: >-
    Genetic counseling and cascade testing identify relatives who need continued cardiac surveillance, including heterozygous relatives of children with biallelic disease. GeneReviews recommends echocardiography and ECG every one to two years for relatives with a familial HCM-related pathogenic variant; a normal initial evaluation does not exclude later disease. Counseling distinguishes the 25% biallelic recurrence risk for two carrier parents from the 50% transmission risk for a heterozygous parent, while explaining age-dependent penetrance.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32480058
    reference_title: "Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy."
    explanation: States the surveillance recommendation for carriers identified by cascade testing.
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early genetic diagnosis, genotype-tailored surveillance, and focused development of gene-replacement or editing strategies"
    explanation: Names early genetic diagnosis and genotype-tailored surveillance as the current actionable management.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: are at increased risk for HCM and should undergo cardiac evaluation with echocardiography and EKG every one to two years.
    explanation: GeneReviews recommendation for relatives identified with familial HCM-related pathogenic variants. The chapter explicitly notes adult cardiomyopathy risk in ALPK3 heterozygotes.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    reference_title: https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: screening at age 41 (father) and 37 (mother), which was normal.
    explanation: Full text of Grutters et al. (2023), PMID:37671554. Normal screening in the heterozygous parents does not establish lifelong nonpenetrance; the authors recommend periodic screening for deletion carriers.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Device therapy for sudden cardiac death prevention. Referral for ICD implantation was recorded in about a quarter of biallelic patients, including in childhood. No ALPK3-specific risk-stratification rule exists; the conventional hypertrophic cardiomyopathy risk models were developed on sarcomere-gene cohorts and have not been validated in this genotype. In the 2016 series, a homozygous p.Trp1765* child received an ICD after cardiac arrest at age seven and subsequently experienced appropriate shocks, providing a documented secondary-prevention example. A 2025 Swedish apical-HCM series also documented appropriate ICD discharge for sustained ventricular tachycardia in a heterozygous female carrier diagnosed at age 18.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: implantable cardioverter-defibrillator
        term:
          id: NCIT:C93238
          label: Implantable Cardioverter-Defibrillator
  target_mechanisms:
  - target: Ventricular tachycardia
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ten patients (24%) were referred for implantable cardioverter-defibrillator (ICD) implantation"
      explanation: ICD referral is the recorded clinical response to arrhythmic risk in this disease.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients (24%) were referred for implantable cardioverter-defibrillator (ICD) implantation, including five females, four males, and one of unspecified sex."
    explanation: Records ICD referral as part of the management of biallelic ALPK3 cardiomyopathy.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    reference_title: https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he has since experienced several appropriate ICD shocks.
    explanation: Full text of Almomani et al. (2016), PMID:26846950. The homozygous child C-V:2 had cardiac arrest at seven years, followed by ICD implantation and appropriate therapies; this is distinct from primary-prevention referral.
  - reference: PMID:40428316
    reference_title: Unravelling the Genotype of the Apical Variant of Hypertrophic Cardiomyopathy in a Swedish Cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The female patient with a wall thickness of 16 mm experienced an ICD discharge while running due to sustained VT, and a pathogenic variant in the non-sarcomeric ALPK3 gene was detected.
    explanation: The Swedish apical-HCM series documents an appropriate ICD discharge in the female ALPK3 carrier. The overall cohort event rates and aneurysm prevalence are not ALPK3-specific.
- name: Heart Transplantation
  description: >-
    Definitive treatment for end-stage ALPK3 cardiomyopathy. Among curated biallelic
    patients, about 12% were referred for transplantation and 4 underwent it, at ages
    ranging from 4 to 33 years.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Congestive heart failure
    evidence:
    - reference: PMID:41221624
      reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "4 (9.5%) underwent heart transplantation at ages 4, 16, 28, and 33 years"
      explanation: Records transplantation as the intervention taken for end-stage heart failure in this disease.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "5 (11.9%) were referred for heart transplantation, and 4 (9.5%) underwent heart transplantation at ages 4, 16, 28, and 33 years"
    explanation: Quantifies transplantation in the curated biallelic cohort.
    quote_role: REVIEW_SYNTHESIS
- name: Mavacamten
  description: >-
    In the ALPK3 K201X mouse study, mavacamten was tested in isolated cardiomyocytes, not as systemic treatment. It improved resting sarcomere length and diastolic calcium; relaxation improved in heterozygous cells but not homozygous cells. Fractional shortening decreased with treatment. These experiments establish partial cellular rescue, not clinical efficacy in ALPK3 cardiomyopathy. Negative inotropy is particularly relevant when systolic function is already impaired; most heterozygous clinical cases nevertheless have preserved systolic function.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
      term:
        id: CHEBI:756998
        label: mavacamten
  target_mechanisms:
  - target: Abnormal Cardiomyocyte Calcium Handling
    evidence:
    - reference: PMID:40128237
      reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In summary, mavacamten can rescue elevated diastolic calcium levels in the mouse model and has beneficial effects on resting sarcomere length.
      explanation: Primary ex vivo treatment result from isolated K201X cardiomyocytes.
  evidence:
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mavacamten treatment did not improve contraction or relaxation time for homozygous cells
    explanation: The primary study limits the relaxation benefit to heterozygous cells, unlike the broader wording of the later review.
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, it caused a reduction in fractional shortening also in these genotypes
    explanation: The same isolated-cell experiment found reduced fractional shortening, so rescue was partial and clinical benefit cannot be assumed.
- name: AAV-Delivered miniALPK3 Gene Replacement
  description: >-
    Preclinical gene replacement using a shortened ALPK3 construct. To fit the conventional AAV packaging limit, investigators deleted 1,119 bp from mouse Alpk3 exon 6 and delivered miniALPK3 with a cardiac-specific promoter in MyoAAV-2A to knockout mice at postnatal day 2 or 3. Cardiac function, sarcomere structure and survival improved. This experiment tested neonatal prevention/rescue in a knockout model, not efficacy in patients.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: ALPK3 Loss of Function
    evidence:
    - reference: PMID:41248220
      reference_title: A Novel miniALPK3 Gene Therapy for ALPK3-Associated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Contrary to saline-treated Alpk3−/− littermates, those treated with MyoAAV-miniALPK3 survived beyond 12 months without premature mortality
      explanation: Primary neonatal treatment experiment supports rescue through replacement of ALPK3 function.
  evidence:
  - reference: PMID:41248220
    reference_title: A Novel miniALPK3 Gene Therapy for ALPK3-Associated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Using CRISPR-Cas9, we successfully removed a 1,119 bp segment from exon 6 to create a miniALPK3 variant
    explanation: Primary report of construct design; homozygous miniALPK3 mice retained normal cardiac function through 15 months.
- name: Anticoagulation for atrial fibrillation
  description: >-
    For patients with HCM who develop atrial fibrillation, the general HCM management baseline recommends oral anticoagulation regardless of standard thromboembolic-risk algorithms. This is phenotype-directed care, not evidence of an ALPK3-specific drug effect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Atrial fibrillation
    description: Reduces thromboembolic risk associated with atrial fibrillation; does not restore sinus rhythm.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Oral anticoagulation regardless of standard algorithms to predict thromboembolic risk
    explanation: GeneReviews Table 4 recommendation for atrial fibrillation in HCM.
    quote_role: REVIEW_SYNTHESIS
- name: Cardiac follow-up and hydration advice
  description: >-
    For clinically established HCM with stable status, GeneReviews recommends echocardiography, ECG and ambulatory rhythm monitoring every one to two years, with earlier reassessment for new symptoms or cardiac events. Avoid dehydration. These are general HCM recommendations; severe pediatric ALPK3 disease requires individualized specialist follow-up.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'In those w/no change in clinical status ... no new cardiac events beginning at diagnosis (regardless of age): repeat every 1-2 yrs'
    explanation: GeneReviews Table 5 gives this interval for stable echocardiographic follow-up, with ECG and 48-hour ambulatory monitoring also every one to two years; new symptoms or events prompt reassessment.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Avoid dehydration; in general use caution to stay adequately hydrated, particularly when exercising or when insensible losses are increased.
    explanation: GeneReviews agents/circumstances-to-avoid baseline for HCM.
    quote_role: REVIEW_SYNTHESIS
- name: AAV-Delivered Full-Length ALPK3 Gene Replacement
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  description: >-
    Preclinical delivery of full-length human ALPK3 with AAV9 and a cardiac TNNT2 promoter prevented disease after neonatal treatment and reversed established dysfunction and hypertrophy after treatment of six-week-old homozygous W1538X mice. AAV6 delivery also restored force in ALPK3-mutant human cardiac organoids. The 5.8-kb vector exceeds conventional AAV capacity but produced full-length transcript and protein in the tested systems. Human efficacy, long-term safety and response in hearts with substantial pre-existing fibrosis remain unestablished.
  evidence:
  - reference: PMID:42618778
    reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: AAV9-TNNT2-ALPK3 delivery in 6-week-old mice was sufficient to fully rescue systolic function back to WT levels at all timepoints after treatment
    explanation: Adult treatment experiment in homozygous W1538X mice, followed to 18 weeks.
  - reference: PMID:42618778
    reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: treatment with AAV6-ALPK3 restored active force production to WT levels
    explanation: ALPK3-mutant human cardiac organoids provide a separate in vitro rescue system; these were not treated patients.
  target_mechanisms:
  - target: ALPK3 Loss of Function
    description: Replaces functional ALPK3 protein in deficient myocardium.
    evidence:
    - reference: PMID:42618778
      reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: AAV-ALPK3 prevented disease in neonatal Alpk3-mutant mice and reversed established pathology in adults
      explanation: Primary gene-replacement evidence supports ALPK3 deficiency as the upstream lesion.
  - target: Impaired Sarcomere Proteostasis
    description: Restores protein-quality-control activity in the truncation model.
    evidence:
    - reference: PMID:42618778
      reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In sum, truncating variants in Alpk3 impair both global and sarcomere-targeted proteostasis, and ALPK3 gene therapy directly rescues this phenotype.
      explanation: The study measured proteomic and proteasome-function rescue in treated mutant hearts.
- name: Disopyramide for symptomatic outflow obstruction
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    GeneReviews lists disopyramide as an option for symptomatic left ventricular outflow obstruction. Its use is phenotype-driven; this is general HCM guidance and does not establish an ALPK3-specific treatment response.
  treatment_term:
    preferred_term: Disopyramide therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: disopyramide
      term:
        id: NCIT:C61730
        label: Disopyramide
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Pharmacologic therapy to alleviate symptoms, incl beta-blockers as first-line therapy ... consideration of calcium channel blockers, disopyramide
    explanation: GeneReviews Table 4 places this option under symptomatic LVOTO.
- name: Septal reduction for persistent symptomatic obstruction
  therapeutic_modality: SURGERY
  description: >-
    Surgical septal myectomy or alcohol septal ablation may be considered for persistent symptomatic obstruction despite pharmacologic therapy, according to the general HCM baseline. Most reported ALPK3 cases are nonobstructive, so candidacy depends on demonstrated obstruction and symptoms.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Septal reduction therapy (alcohol septal ablation or myectomy) can be considered when symptoms persist despite pharmacologic therapy.
    explanation: General HCM treatment recommendation, not genotype-specific trial evidence.
- name: Liwen percutaneous intramyocardial radiofrequency ablation
  therapeutic_modality: SURGERY
  description: >-
    A single 2025 case report describes septal radiofrequency ablation in an 18-year-old with a pathogenic ALPK3 truncation and a trans missense variant of uncertain significance. At six months, septal thickness declined from 29 to 15 mm and exertional symptoms resolved. The uncontrolled observation does not establish durable benefit, prevention of sudden death or a biallelic genotype-specific response. The reported provoked LVOT gradient was 20 mmHg, with a separate intracavitary gradient of 31 mmHg.
  treatment_term:
    preferred_term: cardiac radiofrequency ablation
    term:
      id: NCIT:C170884
      label: Cardiac Radiofrequency Ablation
  evidence:
  - reference: PMID:41437994
    reference_title: "Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A), causing hypertrophic cardiomyopathy treated with the liwen procedure: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: septal thickness decreased from 29 mm to 15 mm
    explanation: Six-month imaging outcome after the reported Liwen intervention; the missense allele remained of uncertain significance.
  - reference: PMID:41437994
    reference_title: "Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A), causing hypertrophic cardiomyopathy treated with the liwen procedure: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: complete resolution of exertional symptoms, including chest tightness and dyspnea
    explanation: Single-patient symptom outcome, without a control group or long-term risk assessment.
- name: Heart-failure management for systolic dysfunction
  therapeutic_modality: OTHER
  description: >-
    Systolic dysfunction requires heart-failure management guided by ventricular function and clinical status, including careful volume management and consideration of advanced support when symptoms progress. General HCM symptom therapies require reassessment when pump function deteriorates.
  target_mechanisms:
  - target: Congestive heart failure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Guideline-based medical therapy for heart failure w/reduced ejection fraction
    explanation: GeneReviews Table 4 provides the systolic-dysfunction baseline.
animal_models:
- name: Alpk3 constitutive knockout mouse (C57BL/6J, Van Sligtenhorst line)
  species: Mouse
  genotype: Alpk3-/- (constitutive null, C57BL/6J background)
  publication: PMID:21441111
  description: >-
    Constitutive Alpk3-null mice develop a non-progressive cardiomyopathy with mixed
    hypertrophic and dilated features, reduced contractility, and abnormal intercalated
    discs with mild myofibrillar disarray. This is the first published Alpk3-null line and
    is distinct from the C57BL/6N line curated below; a later study judged this line
    inadequate as a model of the human neonatal disease and switched to the C57BL/6N line
    for that reason.
  evidence:
  - reference: PMID:21441111
    reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Alpk3 (-/-) mice were produced according to normal Mendelian ratios and appeared normal except for a nonprogressive cardiomyopathy that had features of both hypertrophic and dilated forms of cardiomyopathy."
    explanation: Establishes the model and its mixed hypertrophic/dilated cardiac phenotype.
  modeled_mechanisms:
  - target: Impaired Cardiomyocyte Contractility
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Ventricular contractility falls by about half on cardiac MRI.
    limitations: >-
      A constitutive germline null models the biallelic human genotype, not the
      heterozygous adult-onset disease that accounts for most human cases. The cardiomyopathy
      in this line is explicitly non-progressive and the mice survive; a later study
      reports that this line failed to recapitulate the rapidly progressive, often fatal
      neonatal disease seen in patients, and acquired a different Alpk3-null line instead.
    readouts:
    - name: Left ventricular septal and free wall contractility
      target: Impaired Cardiomyocyte Contractility
      direction: DECREASED
      interpretation: Direct functional correlate of the contractility node in this model.
      evidence:
      - reference: PMID:21441111
        reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Magnetic resonance imaging showed a 50% reduction in both septal and free wall LV contractility in Alpk3 (-/-) mice."
        explanation: Reports the measurement behind this readout.
    evidence:
    - reference: PMID:21441111
      reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cardiomyopathy developed in mice deficient for α-kinase 3 (ALPK3), a nuclear kinase previously implicated in the differentiation of cardiomyocytes."
      explanation: Establishes that loss of Alpk3 in mouse produces cardiomyopathy, so the model is informative for this node.
  - target: Sarcomere Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Mild myofibrillar disarray on light and electron microscopy.
    limitations: >-
      Disarray in this mouse line is mild. Human histopathology is variable, including neonatal and adult specimens without disarray.
    evidence:
    - reference: PMID:21441111
      reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"
      explanation: Reports the ultrastructural measurement behind this readout.
    readouts:
    - name: Cardiomyocyte ultrastructure
      target: Sarcomere Disorganization
      direction: ALTERED
      interpretation: Ultrastructural correlate of the disorganization node.
      evidence:
      - reference: PMID:21441111
        reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"
        explanation: Reports the ultrastructural measurement behind this readout.
  - target: Intercalated Disc Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Abnormal intercalated-disc architecture in the constitutive null mouse.
    limitations: >-
      Human evidence includes loss of selected junctional immunostaining in one neonatal sample; equivalent ultrastructure was not measured in that sample.
    evidence:
    - reference: PMID:21441111
      reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"
      explanation: Reports the ultrastructural measurement behind this readout.
    readouts:
    - name: Cardiomyocyte ultrastructure
      target: Intercalated Disc Remodeling
      direction: ALTERED
      interpretation: Intercalated-disc abnormalities observed by microscopy.
      evidence:
      - reference: PMID:21441111
        reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils"
        explanation: Reports the ultrastructural measurement behind this readout.
  - target: Reactive Interstitial Fibrosis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Interstitial fibrosis documented in human cohorts was absent in this mouse line under the reported conditions.
    limitations: >-
      The absence of spontaneous fibrosis limits this line for studying the human fibrotic phenotype. It does not establish that all Alpk3 models lack fibrosis or preclude other experimental injury contexts.
    evidence:
    - reference: PMID:21441111
      reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice"
      explanation: Directly reports the absence of the fibrotic phenotype in this model.
- name: Alpk3 K1420R kinase-dead knock-in mouse
  species: Mouse
  genotype: Alpk3 K1420R/K1420R (invariant catalytic lysine mutated to arginine)
  publication: PMID:38048395
  description: >-
    CRISPR knock-in mice carrying an arginine substitution at the predicted invariant catalytic lysine of the alpha-kinase domain. Homozygotes retain normal cardiac function and survival into adulthood, with unchanged cardiac SQSTM1 T269/S272 phosphorylation relative to total SQSTM1. Together with the negative in vitro kinase assay, these results support the pseudokinase interpretation under the tested conditions.
  evidence:
  - reference: PMID:38048395
    reference_title: "ALPK3 Functions as a Pseudokinase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we utilized CRISPR/Cas9 technology to generate knock-in mice in which the invariant K1420 of ALPK3 is mutated to arginine(R)"
    explanation: Describes the construction of the knock-in model used here.
  modeled_mechanisms:
  - target: Loss of M-Band Scaffolding
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The K1420R substitution does not reproduce the cardiomyopathy of the published null line. This is a negative functional comparison supporting a role for ALPK3 beyond putative kinase activity; M-band scaffold integrity was not directly established by the cardiac readout.
    limitations: >-
      Mutation of the equivalent lysine disables many other kinases, but absence of an ALPK3 kinase signal in the tested assay prevents direct demonstration of activity loss in this protein. Normal cardiac function in this model supports, but does not conclusively settle, the pseudokinase interpretation or resolve the conflicting SQSTM1 phosphorylation report.
    readouts:
    - name: Survival and cardiac function to adulthood
      target: Loss of M-Band Scaffolding
      direction: UNCHANGED
      interpretation: >-
        Homozygotes maintain normal survival and cardiac function into adulthood, in contrast to the previously published null line. The result supports a functional distinction between the K1420R substitution and removal of ALPK3 protein.
      evidence:
      - reference: PMID:38048395
        reference_title: "ALPK3 Functions as a Pseudokinase."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In contrast to the published Alpk3 null mutant mice2, the homozygous Alpk3 KR/KR mice did not exhibit premature mortality and maintained normal cardiac function into adulthood"
        explanation: Reports the survival and cardiac function measurement behind this readout.
    evidence:
    - reference: PMID:38048395
      reference_title: "ALPK3 Functions as a Pseudokinase."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In conclusion, our study presents compelling new evidence from both in vitro and in vivo experiments, supporting that ALPK3 functions as a pseudokinase."
      explanation: The study's conclusion, which is what makes this model informative about the nature of the scaffolding node.
- name: Alpk3 constitutive knockout mouse (C57BL/6N, MRC Harwell line)
  species: Mouse
  genotype: Alpk3-/- (constitutive null, C57BL/6N background, exon 3 deletion)
  publication: PMID:36321451
  description: >-
    A second, independently derived Alpk3-null line, acquired specifically because the earlier C57BL/6J null did not reproduce the human neonatal disease course. These mice are normal at birth and then develop a rapidly progressive cardiomyopathy in the first week with no survivors beyond 14 weeks, recapitulating the rapidly progressive neonatal presentation observed in some biallelic patients.
  evidence:
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A previous Alpk3-/- C57BL/6J mouse model14 failed to recapitulate the rapidly progressive and often fatal neonatal disease that is observed in human patients."
    explanation: States why a second line was needed, and distinguishes it from the C57BL/6J line curated above.
  modeled_mechanisms:
  - target: Ventricular Dilatation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Increased left ventricular cavity dimensions with severely depressed function,
      reproducing the dilated, hypocontractile presentation of biallelic human disease.
    limitations: >-
      A germline null models the biallelic genotype only. The human dilated phase
      characteristically remodels to hypertrophy in survivors; whether this line follows
      that trajectory is not established from the quoted result, and its mice die early.
    readouts:
    - name: Left ventricular cavity dimension and survival
      target: Ventricular Dilatation
      direction: INCREASED
      interpretation: Chamber-level correlate of the dilatation node, with early mortality.
      evidence:
      - reference: PMID:36321451
        reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "manifested a rapidly progressive cardiomyopathy in the first week of life that resulted in premature death (no survivors beyond 14 weeks)"
        explanation: Reports the survival measurement behind this readout.
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We therefore acquired and studied an alternative model, C57BL/6N Alpk3+/- mice (MRC Harwell Institute), that was created by deleting a region encompassing exon 3"
      explanation: Establishes the identity and derivation of the line, distinguishing it from the C57BL/6J null.
- name: Alpk3 K201X knock-in mouse
  species: Mouse
  genotype: Heterozygous or homozygous Alpk3 K201X on C57BL/6J background
  publication: PMID:40128237
  description: >-
    Patient-derived truncation model. Homozygotes develop ventricular dilatation, hypertrophy by mass and systolic dysfunction; heterozygotes lack overt baseline disease at three and six months but have an exaggerated hypertrophic response to chronic adrenergic stimulation. Mavacamten was tested in isolated cardiomyocytes only.
  evidence:
  - reference: PMID:40128237
    reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Homozygous Alpk3 K201X animals were viable and fertile, and showed no gross extra-cardiac abnormalities.
    explanation: The in vivo phenotype is cardiac and differs from severe human biallelic multisystem disease.
  modeled_mechanisms:
  - target: Abnormal Cardiomyocyte Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Elevated diastolic calcium and delayed relaxation in isolated ventricular cardiomyocytes.
    limitations: >-
      Cells are isolated and unloaded; ex vivo response does not establish systemic efficacy or clinical benefit.
    evidence:
    - reference: PMID:40128237
      reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Calcium transients from fura2 loaded cardiomyocytes showed dose-dependent increases in diastolic intracellular calcium
      explanation: Direct isolated-cell measurement in heterozygous and homozygous K201X mice.
  - target: Reduced Myosin Super-Relaxed State
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reduced SRX myosin occupancy in mutant cardiac tissue.
    limitations: >-
      The heterozygous mouse has no overt baseline cardiomyopathy at the ages studied, despite molecular abnormalities.
    evidence:
    - reference: PMID:40128237
      reference_title: An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Heterozygous and homozygous mice showed a significantly reduced proportion of myosin heads in the SRX state, compared to WT littermates
      explanation: Heterozygous and homozygous K201X mouse hearts showed a reduced proportion of myosin heads in the super-relaxed state. This molecular finding coexists with reduced whole-heart function in homozygotes and does not establish global hypercontractility in every ALPK3 genotype.
- name: Alpk3 exon-3 germline and adult inducible knockout mice
  species: Mouse
  genotype: Sox2-Cre germline deletion or tamoxifen-inducible cardiac deletion of floxed Alpk3 exon 3
  publication: PMID:40135575
  description: >-
    Germline loss produces early contractile impairment, ventricular dilatation and high neonatal mortality; survivors develop increased ventricular wall thickness. Induced loss in adult hearts produces dilated cardiomyopathy without a significant hypertrophic transition, separating developmental timing from the continuing need for ALPK3.
  evidence:
  - reference: PMID:40135575
    reference_title: α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In contrast, upon the loss of ALPK3 in the adult stage, icKO mice developed DCM without transitioning into LVH.
    explanation: Direct comparison of germline and adult-inducible loss.
  modeled_mechanisms:
  - target: Impaired Sarcomere Proteostasis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Thick-filament proteins accumulate in germline-knockout hearts.
    limitations: >-
      Coexpression experiments support an interaction with MuRF proteins, but do not by themselves prove the proposed turnover pathway.
    evidence:
    - reference: PMID:40135575
      reference_title: α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These data suggest that the loss of ALPK3 leads to selective dysregulation of thick filament protein homeostasis.
      explanation: Adult germline-knockout hearts accumulated thick-filament proteins without corresponding increases in their transcripts; the MuRF-dependent turnover mechanism remains a proposed explanation.
- name: Alpk3 W1538X knock-in mouse for gene replacement
  species: Mouse
  genotype: Homozygous Alpk3 W1538X on C57BL/6J background; models human ALPK3 W1765X
  publication: PMID:42618778
  description: >-
    Patient-variant model used for neonatal prevention and reversal of established cardiomyopathy with full-length human ALPK3 delivery. Adult mice received treatment at six weeks and were followed to 18 weeks.
  evidence:
  - reference: PMID:42618778
    reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We used Alpk3W1538X mice, which model a severe ALPK3-truncating variant, ALPK3W1765X, found in patients
    explanation: Specifies the mouse-to-human variant correspondence.
  modeled_mechanisms:
  - target: Impaired Cardiomyocyte Contractility
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Established systolic and diastolic dysfunction responds to ALPK3 replacement.
    limitations: >-
      Homozygous mice model severe recessive disease. Substantial interstitial fibrosis is absent, so rescue in fibrotic human myocardium remains uncertain.
    evidence:
    - reference: PMID:42618778
      reference_title: Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: AAV9-TNNT2-ALPK3 delivery in 6-week-old mice was sufficient to fully rescue systolic function back to WT levels at all timepoints after treatment
      explanation: Adult treatment experiment in homozygous W1538X mice, followed to 18 weeks.
experimental_models:
- name: ALPK3-null human stem cell-derived cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Cardiomyocytes differentiated from patient-derived iPSC carrying a homozygous ALPK3
    truncating variant and from gene-edited human ESC lines lacking ALPK3, used to define
    the ultrastructural and electrophysiological consequences of losing the protein in
    human cells.
  publication: PMID:27106955
  evidence:
  - reference: PMID:27106955
    reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that ALPK3-deficient cardiomyocytes derived from pluripotent stem cell models recapitulate the ultrastructural and electrophysiological defects observed in vivo."
    explanation: The authors' own statement that this model system reproduces the in vivo defects, which is what licenses its use here.
  modeled_mechanisms:
  - target: Sarcomere Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Disordered sarcomeres on electron microscopy in patient-derived and edited human cardiomyocytes.
    limitations: >-
      Stem cell-derived cardiomyocytes are immature relative to adult myocardium, and a
      monolayer culture cannot reproduce the chamber-level remodelling that defines the
      clinical phenotype.
    evidence:
    - reference: PMID:27106955
      reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
      explanation: Human pluripotent stem cell-derived cardiomyocytes model the sarcomeric ultrastructural abnormality.
    readouts:
    - name: Cardiomyocyte ultrastructure by electron microscopy
      target: Sarcomere Disorganization
      direction: ALTERED
      interpretation: Direct ultrastructural correlate of the node in human cells.
      evidence:
      - reference: PMID:27106955
        reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
        explanation: Reports the ultrastructural measurement behind this readout.
  - target: Intercalated Disc Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Abnormal intercalated discs on electron microscopy in ALPK3-deficient human cardiomyocytes.
    limitations: >-
      Stem cell-derived cardiomyocytes are immature relative to adult myocardium, and a
      monolayer culture cannot reproduce the chamber-level remodelling that defines the
      clinical phenotype.
    evidence:
    - reference: PMID:27106955
      reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
      explanation: The same cell systems also show abnormal intercalated discs.
    readouts:
    - name: Cardiomyocyte ultrastructure by electron microscopy
      target: Intercalated Disc Remodeling
      direction: ALTERED
      interpretation: Direct intercalated-disc ultrastructural readout in human cells.
      evidence:
      - reference: PMID:27106955
        reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs."
        explanation: Reports the ultrastructural measurement behind this readout.
  - target: Abnormal Cardiomyocyte Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Extended field potential duration and abnormal calcium handling in mutant contractile cultures.
    limitations: >-
      Field potential duration in an immature monolayer is not equivalent to the clinical
      QT interval, so the link to the repolarization phenotype is inferential.
    evidence:
    - reference: PMID:27106955
      reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Analysis of differentiated contractile cultures identified abnormal calcium handling as a potential feature of cardiomyocytes lacking ALPK3, providing functional insights into the molecular mechanisms underlying ALPK3-mediated cardiomyopathy."
      explanation: Supports treating this model as informative for the calcium-handling node.
    readouts:
    - name: Field potential duration and intracellular calcium transients
      target: Abnormal Cardiomyocyte Calcium Handling
      direction: ALTERED
      interpretation: Electrophysiological and calcium-handling correlate of the node.
      evidence:
      - reference: PMID:27106955
        reference_title: "ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures."
        explanation: Reports the multi-electrode array and calcium imaging measurements behind this readout.
- name: Isogenic ALPK3 iPSC-derived cardiomyocytes for M-band proteomics
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Isogenic human iPSC-derived cardiomyocytes carrying frameshift or engineered kinase-domain substitutions. Phosphoproteomics supports a pseudokinase interpretation in the tested systems, and imaging identifies altered myomesin localization. Residual protein differs by allele: the ins/del line has less than 5% of wild-type ALPK3, whereas the later del/del truncation retains approximately 39%.
  publication: PMID:36321451
  evidence:
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell-derived cardiomyocytes, mice, and human patient tissues."
    explanation: Describes the isogenic iPSC-cardiomyocyte system used here.
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: ALPK3del/del hiPSC-CMs had reduced ALPK3 protein expression (~39% WT), indicating that these cells produce a truncated ALPK3 protein with reduced stability
    explanation: Direct evidence that engineered truncations are not equivalent to complete protein absence.
  - reference: PMID:36321451
    reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: did not detect significant differences between WT, ALPK3ins/del, and ALPK3dIC/dIC hiPSC-CMs
    explanation: SarcTrack analysis of more than 40,000 sarcomeres per line found no significant contractility difference; later organoid experiments use a different model and assay.
  modeled_mechanisms:
  - target: Myomesin Mislocalization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: ALPK3 loss-of-function variants displaced MYOM1 and MYOM2 from the M-band and nuclear envelope.
    limitations: >-
      These immature monolayers had no significant contractility difference by SarcTrack despite molecular changes. Force-buffering impairment was inferred, not directly measured, and nuclear-envelope localization differs from endogenous-tagging studies.
    evidence:
    - reference: PMID:36321451
      reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover."
      explanation: Supports treating this model as informative for the myomesin mislocalization node.
    readouts:
    - name: Myomesin subcellular localization
      target: Myomesin Mislocalization
      direction: ALTERED
      interpretation: Direct correlate of the myomesin mislocalization node.
      evidence:
      - reference: PMID:36321451
        reference_title: "Pathogenesis of Cardiomyopathy Caused by Variants in ALPK3, an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function."
        explanation: Reports the localization measurement behind this readout.
- name: ALPK3-deficient human cardiac organoids
  experimental_model_type: ORGANOID
  description: >-
    Three-dimensional human cardiac organoids in which ALPK3 is disrupted, used to test
    whether loss of ALPK3 impairs force generation in a tissue-level human system rather
    than a monolayer.
  publication: PMID:39196058
  evidence:
  - reference: PMID:39196058
    reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant."
    explanation: Establishes that the organoid system reproduces the contractile deficit, alongside a mouse carrying a patient truncating allele.
  modeled_mechanisms:
  - target: Impaired Cardiomyocyte Contractility
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Contractility is impaired in ALPK3-deficient human cardiac organoids.
    limitations: >-
      Cardiac organoids remain developmentally immature and lack the loading conditions,
      vasculature and chronic time course under which the human ventricle remodels, so
      they report the cellular contractile deficit but not the hypertrophic or dilated
      chamber phenotype.
    evidence:
    - reference: PMID:39196058
      reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We demonstrate that ALPK3 is required to maintain a functional contractile apparatus in both hPSC-derived and mouse CMs."
      explanation: Supports treating this model as informative for the contractility node.
    readouts:
    - name: Organoid contractile force
      target: Impaired Cardiomyocyte Contractility
      direction: DECREASED
      interpretation: Tissue-level functional correlate of the contractility node in a human system.
      evidence:
      - reference: PMID:39196058
        reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant."
        explanation: Reports the contractility measurement behind this readout.
datasets:
- accession: geo:GSE215304
  title: Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle
  description: >-
    Transcriptomic profiling accompanying the study that localized ALPK3 to the sarcomeric
    M-band and defined the ALPK3-dependent phosphoproteome, using human pluripotent stem
    cell-derived cardiomyocytes carrying cardiomyopathic ALPK3 mutations.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 16
  publication: PMID:39196058
  notes: >-
    ALPK3-mutant human cardiomyocyte RNA sequencing accompanying PMID:39196058; interpretation is specific to the edited cellular system rather than a patient myocardial cohort.
discussions:
- discussion_id: alpk3_pseudokinase_controversy
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is ALPK3 a catalytically inactive scaffold, or a genuine kinase that phosphorylates
    SQSTM1 and other M-band proteins?
  attaches_to:
  - pathophysiology#Loss of M-Band Scaffolding
  rationale: >-
    ALPK3 catalytic activity remains disputed. One group reported no relevant activity in biochemical assays and normal adult hearts in mice carrying an invariant catalytic-lysine substitution. Another reported increased phosphorylation after recombinant-domain addition to deficient cardiomyocyte lysates and phosphorylation of SQSTM1; the lysate system does not exclude indirect kinase effects. The studies used different constructs and systems. Nuclear localization is also disputed: tagged overexpression supported a nuclear-envelope pool, whereas endogenous tagging localized ALPK3 to the M band without a nuclear signal. Shared M-band localization and protein-interaction findings support a structural role, but neither catalytic activity nor all downstream causal steps are settled.
  evidence:
  - reference: PMID:38048395
    reference_title: "ALPK3 Functions as a Pseudokinase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Recent studies present conflicting findings on ALPK3's kinase activity2,3."
    explanation: States the existence of the disagreement in the primary literature.
  - reference: PMID:39196058
    reference_title: "Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Finally, ALPK3 phosphorylates and is required for the sarcomeric localization of SQSTM1, an important transporter of polyubiquitinated proteins23,24."
    explanation: The claim of catalytic activity on a named substrate, which is the position opposing the pseudokinase conclusion.
  - reference: PMID:38048395
    reference_title: "ALPK3 Functions as a Pseudokinase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we investigated the phosphorylation status of the T269/S272 site of SQSTM1 by western blotting, but we did not observe a significant difference in T269/S272 phosphorylation to total SQSTM1 ratios between the hearts of the control mice and those carrying homozygous ALPK3KR/KR mutation"
    explanation: Directly contests the SQSTM1 substrate claim at the same residues, in vivo, which is the sharpest point of disagreement between the two positions.
- discussion_id: alpk3_risk_model_calibration
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the conventional hypertrophic cardiomyopathy sudden-death risk models perform
    adequately in ALPK3 truncating variant carriers?
  attaches_to:
  - phenotypes#Ventricular tachycardia
  - phenotypes#Cardiac arrest
  - treatments#Implantable Cardioverter-Defibrillator
  - phenotypes#Sudden cardiac death
  rationale: >-
    ALPK3-specific calibration of conventional HCM sudden-death risk models has not been established. Adult heterozygous cohorts document myocardial fibrosis and nonsustained ventricular tachycardia, but one major cohort observed no appropriate ICD shocks during follow-up. Separately, the biallelic case report by Jorholt et al. documents sudden cardiac death at age 12 despite previous surveillance without ventricular tachycardia or syncope. The pediatric event and adult cohort follow-up answer different questions and should not be combined into an unsupported incidence estimate. A later Swedish apical-HCM series did document an appropriate ICD discharge in an ALPK3 heterozygote. Thus the absence of shocks in the earlier cohort does not establish absence of risk across all heterozygous patients.
  evidence:
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+"
    explanation: Documents the dissociation the question turns on - wall thickness like sarcomere-negative patients, arrhythmia burden like sarcomere-positive ones.
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of arrhythmic events despite of the high proportion of ICD referrals, fibrosis and non-sustained ventricular tachycardia at baseline and follow-up did not allow modelling of SCD risk in patients with this particular genotype."
    explanation: The earlier cohort lacked events sufficient for genotype-specific sudden-death risk modeling. This does not negate the pediatric sudden death or the appropriate ICD therapies reported in other series.
  - reference: PMID:33076350
    reference_title: Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 12, the patient had no progression of chamber enlargement or reduction of contractility, but died due to sudden cardiac death (SCD) after 30 min of unsuccessful resuscitation.
    explanation: Case 1 had two reported ALPK3 frameshift variants and severe nonobstructive HCM. Sudden death occurred despite prior rhythm monitoring without documented ventricular tachycardia; a single case cannot establish incidence.
  - reference: PMID:40428316
    reference_title: Unravelling the Genotype of the Apical Variant of Hypertrophic Cardiomyopathy in a Swedish Cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The female patient with a wall thickness of 16 mm experienced an ICD discharge while running due to sustained VT, and a pathogenic variant in the non-sarcomeric ALPK3 gene was detected.
    explanation: The Swedish apical-HCM series documents an appropriate ICD discharge in the female ALPK3 carrier. The overall cohort event rates and aneurysm prevalence are not ALPK3-specific.
- discussion_id: alpk3_knockout_fibrosis_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does the original constitutive Alpk3 knockout mouse lack fibrosis reported in human ALPK3 cardiomyopathy?
  attaches_to:
  - pathophysiology#Reactive Interstitial Fibrosis
  rationale: >-
    The 2011 constitutive-null mouse reproduces contractile and ultrastructural abnormalities but lacks interstitial fibrosis and inflammation under the reported conditions. Human cohorts document fibrosis on imaging and histopathology, although it is not present in every patient. This limits the original line as a model of the human fibrotic phenotype; the observation should not be generalized to every Alpk3 mutant model.
  evidence:
  - reference: PMID:21441111
    reference_title: "Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice"
    explanation: The model-side half of the mismatch.
  - reference: PMID:34263907
    reference_title: "Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation."
    explanation: The human-side half of the mismatch.
- discussion_id: alpk3_mavacamten_safety
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the clinical benefit-risk balance of mavacamten in ALPK3 cardiomyopathy, particularly in patients with severe biallelic disease and systolic dysfunction?
  attaches_to:
  - treatments#Mavacamten
  rationale: >-
    The ALPK3-specific mavacamten experiment used isolated K201X mouse cardiomyocytes. Treatment improved relaxation in heterozygous cells but did not rescue homozygous relaxation and reduced fractional shortening. Many ALPK3 patients lack outflow obstruction, and severe biallelic disease can include systolic dysfunction. The balance of benefit and negative inotropy therefore requires clinical study; the ex vivo findings do not establish a genotype-specific treatment recommendation.
  evidence:
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although homozygous animals exhibited contractile dysfunction, they did not develop overt ventricular wall thickening, and treatment was restricted to ex vivo isolated cardiomyocytes."
    explanation: States the two limitations - no overt hypertrophy in the model and ex vivo-only treatment - that leave the question open.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41221624
    reference_title: "ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In heterozygous ALPK3 PTVs, hypertrophy is typically apical or concentric, LVOT obstruction is uncommon (~4% overall), and systolic function is preserved in most."
    explanation: Documents the mismatch between the ALPK3 phenotype and the approved indication for the drug.
    quote_role: REVIEW_SYNTHESIS
notes: >-
  Term scope: MONDO:0054838 corresponds to OMIM:618052 / CMH27, which some sources name "autosomal recessive familial hypertrophic cardiomyopathy-27". This entry deliberately spans both the biallelic recessive form and the numerically dominant heterozygous adult-onset form, because they are one gene-disease relationship with a zygosity-dependent presentation and the literature treats them together. MONDO's own label carries no inheritance restriction, so the term supports that scope. Note that both ClinGen assertions cited here are curated against MONDO:0005045 (the broad hypertrophic cardiomyopathy term), not against MONDO:0054838; that is ClinGen's practice, not a mismatch introduced here. The March 2025 GeneReviews Nonsyndromic Hypertrophic Cardiomyopathy Overview includes ALPK3 and supplies a general clinical, diagnostic, management and counseling baseline. Clinical frequencies and genotype-specific features are drawn from ALPK3 cohorts rather than transferred from HCM overall.
diagnosis:
- name: Echocardiography and cardiac MRI
  description: >-
    Echocardiography and, when needed, cardiac MRI establish the cardiac phenotype and assess ventricular thickness, function and fibrosis. The GeneReviews HCM criteria are unexplained maximum left ventricular wall thickness of at least 15 mm in adults, or 13–14 mm with a family history; pediatric interpretation uses body-size-adjusted measurements. These general HCM criteria do not exclude ALPK3 disease presenting with ventricular dilatation or systolic dysfunction before hypertrophy.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The diagnosis of HCM is most often established with noninvasive cardiac imaging, including echocardiography and/or cardiac MRI.
    explanation: General HCM diagnostic baseline, applicable to the hypertrophic presentation of ALPK3 cardiomyopathy.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If there is a family history of a clinical or molecular diagnosis of HCM, a maximum LV wall thickness ... 13-14 mm supports the diagnosis.
    explanation: GeneReviews explains the lower imaging threshold in a family with clinical or molecular HCM; this is not an ALPK3-specific criterion.
    quote_role: REVIEW_SYNTHESIS
- name: Molecular diagnosis and family segregation
  description: >-
    Use a cardiomyopathy multigene panel that includes ALPK3 and deletion/duplication analysis, or exome/genome sequencing when appropriate. Interpret the allele class, zygosity and family segregation together: one pathogenic truncating allele can cause dominant disease, whereas two damaging alleles can produce severe recessive disease. A variant of uncertain significance alone does not establish the diagnosis. Periodic reanalysis of unresolved sequencing can be useful when inheritance evidence or transcript annotation changes; segregation can reveal both affected and currently asymptomatic carriers. A contiguous deletion including ALPK3 can coexist with a damaging sequence variant on the other allele; copy-number analysis and sequencing therefore answer complementary questions.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: that also includes deletion/duplication analysis is recommended.
    explanation: In its molecular-testing section GeneReviews recommends a multigene panel including deletion/duplication analysis; ALPK3 is listed in its HCM gene table.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41645375
    reference_title: "[Genetic re-analysis of a Chinese pedigree affected with Hypertrophic cardiomyopathy due to a heterozygous truncating variant of ALPK3 gene and literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the mother exhibited severe obstructive HCM, while the brother was asymptomatic, suggesting incomplete or age-dependent penetrance within the family.
    explanation: The reported family was resolved by reanalysis after recognition of dominant ALPK3 disease. Transcript revision changed the original p.Pro720ThrfsTer53 annotation to NM_020778.5 p.Pro518ThrfsTer53; these describe the same reported allele.
  - reference: url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    reference_title: https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cardiac screening uncovered severe HCM.
    explanation: Full text of Grutters et al. (2023), PMID:37671554. In this child, cleft palate and contractures prompted genetic evaluation before cardiac symptoms; cardiac screening then identified severe concentric biventricular HCM.
mechanistic_hypotheses:
- hypothesis_group_id: alpk3_myomesin_force_buffering
  hypothesis_label: Myomesin mislocalization impairs force buffering
  status: EMERGING
  description: Myomesin mislocalization may impair sarcomere integrity and force buffering. The cellular localization phenotype is measured; its specific contribution to impaired contractility remains a mechanistic proposal and varies across ALPK3 models.
- hypothesis_group_id: alpk3_proteostasis_hypertrophy
  hypothesis_label: Impaired sarcomere protein turnover promotes hypertrophy
  status: EMERGING
  description: Dysregulated protein clearance is proposed to drive thick-filament accumulation and hypertrophic remodeling. Timing and phenotype vary across germline, adult-induced and truncation models, and direct mediation of hypertrophy by a specific turnover defect remains unresolved.

📚

References & Deep Research

References

14

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1768/

Nonsyndromic Hypertrophic Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

PMID:40128237

An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.

No top-level findings curated for this source.

PMID:40135575

α Protein Kinase 3 Is Essential for Neonatal and Adult Cardiac Function.

No top-level findings curated for this source.

PMID:41248220

A Novel miniALPK3 Gene Therapy for ALPK3-Associated Cardiomyopathy.

No top-level findings curated for this source.

PMID:42618778

Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy.

No top-level findings curated for this source.

url:https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf

https://repub.eur.nl/pub/127495/Repub_127495_O-A.pdf

No top-level findings curated for this source.

url:https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf

https://www.centogene.com/wp-content/uploads/2025/03/Publication_Almomani_R_Biallelic_truncating_mutations_in_ALPK3_cause_severe_pediatric_cardiomyopathy.pdf

No top-level findings curated for this source.

PMID:40447126

Whole-exome sequencing identifies novel truncating ALPK3 variants in a compound heterozygous state associated with pediatric hypertrophic cardiomyopathy and phenotypic heterogeneity.

No top-level findings curated for this source.

PMID:41645375

[Genetic re-analysis of a Chinese pedigree affected with Hypertrophic cardiomyopathy due to a heterozygous truncating variant of ALPK3 gene and literature review].

No top-level findings curated for this source.

PMID:40428316

Unravelling the Genotype of the Apical Variant of Hypertrophic Cardiomyopathy in a Swedish Cohort.

No top-level findings curated for this source.

url:https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf

https://pure.rug.nl/ws/files/915064722/Contiguous_Gene_Deletion_of_Chromosome_15q25.2q25.3_in_Biallelic_ALPK3-Related_Cardiomyopathy-_Novel_Insights_Into_Phenotypic_Presentation_and_Variant_Spectrum.pdf

No top-level findings curated for this source.

PMID:41437994

Novel compound heterozygous ALPK3 mutations (c.4234C>T and c.3491G>A), causing hypertrophic cardiomyopathy treated with the liwen procedure: case report.

No top-level findings curated for this source.

url:https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf

https://www.medrxiv.org/content/10.1101/2024.11.14.24317359v1.full.pdf

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Edit: ALPK3-Related Hypertrophic Cardiomyopathy - address pre-PR review; add deep-research report · 2026-09-01T13:23:46Z · View source

Second session on the same entry. Two inputs arrived after the initial commit: the --fallback deep-research report (openscientist, standing in for falcon after a 403) and a self-directed pre-PR red-team review. Both were acted on. Deep-research report, research/ALPK3-Related_Hypertrophic_Cardiomyopathy-deep-research-openscientist.md. Its own validation blocks were read first, per the skill. reference_validation: 23/23 verified, confabulation_rate 0.0, no unresolved identifiers, but only 15/23 assessed on topic - one of the off-topic citations is a paper on esophageal squamous cell carcinoma. term_validation: 43/44 resolved but 15 of 29 label checks mismatched, and needs_review is true. Most mismatches are table-cell artifacts rather than binding claims, but at least one is a genuine wrong binding that must not be copied: HP:0025169 is offered as 'LV aneurysm' when the ontology label is 'Left ventricular systolic dysfunction'. No term or claim was taken from the report. The report also states HGNC:17870 and 15q25.3 for ALPK3, both of which are wrong - the gene is hgnc:17574 (confirmed against the term cache and both ClinGen assertions) at 15q25.2 (per PMID:34263907). It corroborated the entry's structure - zygosity-dependent severity gradient, M-band scaffold, myomesin/MuRF/SQSTM1 proteostasis, 1-4 percent of adult HCM - but cited none of the four primary mechanism papers the entry rests on (PMID:36321451, PMID:39196058, PMID:38048395, PMID:34263907), so it added no claim the entry did not already carry better sourced. It is committed as a research input; nothing was curated from it. Review findings acted on. Overclaim removed: the entry and its genetic notes both said ALPK3 is the gene most often recovered from sarcomere-negative HCM re-analysis; PMID:41221624 says second or third in five of seven cohorts, behind cryptic-splice MYBPC3 and, in the French cohort, FLNC. Both statements corrected. Sudden cardiac death phenotype removed entirely. It had been asserted on the strength of an ICD referral rate. Re-reading every cached source, all sudden-death language is generic background about hypertrophic cardiomyopathy and no ALPK3-specific sudden death event is reported; the recorded deaths are heart-failure deaths. PMID:34263907 additionally reports no appropriate ICD shocks over 4.0 +/- 3.6 years and states that sudden-death risk could not be modelled in this genotype. That sentence is now cited on the risk-model discussion, the two sequelae edges were redirected, and the evidenced arrhythmic endpoint is cardiac arrest. Mouse lines de-conflated. PMID:36321451 states that the previously published C57BL/6J Alpk3-null line failed to recapitulate the rapidly progressive neonatal human disease, and that the authors acquired a separate C57BL/6N line (MRC Harwell, exon 3 deletion) with no survivors beyond 14 weeks. The entry had curated only the C57BL/6J line while contrasting the kinase-dead knock-in against 'the early mortality of the null', which is the other line. The curated line is now named by strain, carries the cited inadequacy in its limitations, the K1420R readout interpretation names which line it contrasts with, and the C57BL/6N line is added as its own animal model with a Ventricular Dilatation link. Disputed localization removed from structured form. The node was named Loss of M-Band and Nuclear Envelope Scaffolding and bound GO:0005635 while its own description called nuclear localization contested. Renamed to Loss of M-Band Scaffolding, GO:0005635 dropped, and the evidence explanation now says which half of the quoted sentence is relied on. PMID:38048395's finding that SQSTM1 T269/S272 phosphorylation is unchanged in K1420R hearts was added to the controversy discussion as the sharpest point of disagreement. Other corrections: fidelity HIGH downgraded to LOW on a FAILS_TO_RECAPITULATE link; apical and concentric hypertrophy frequencies dropped because both sources report the two patterns only as one combined figure; three ex vivo mavacamten evidence items regraded MODEL_ORGANISM to IN_VITRO; a biallelic-scoped LVOT statistic on the heterozygous hypertrophy node swapped for the heterozygous-scoped sentence from the same review; NCIT:C15289 Organ Transplantation replaced by the specific NCIT:C15246 Heart Transplantation, verified reachable from NCIT:C25218; two 'may cause' mechanism explanations and two flat pseudokinase assertions hedged to match the open controversy; Prolonged QT interval and Left ventricular noncompaction tagged subtype Biallelic; the two deliberately unconnected phenotypes now say in their descriptions why they are unconnected. A causal edge that had rested on a case report's introductory 'due to' gloss of another paper was made uncited with the reason recorded, since the primary source reports both findings without asserting causation. Additions: beta-blocker and non-dihydropyridine calcium channel blocker therapy (the reported standard of care, curated as such and not as disease-modifying) and cascade genetic testing with surveillance of carriers; a term-scope note recording that this entry deliberately spans both the recessive and dominant forms of CMH27 and that both ClinGen assertions are curated against MONDO:0005045 rather than MONDO:0054838; non-truncating alleles quantified in the genetic notes as an explicit unmodelled share. Grouping: two overclaims in the new member's differentiating_mechanisms were corrected. It is not the only member with a zygosity-dependent split - CMH4, CMH8 and CMH10 all curate a recessive biallelic arm - and the claim that it has the largest case share among sarcomere-negative probands is contradicted by the same source as the first finding, since MYBPC3 ranks ahead of it and is itself a member. Replaced with what is genuinely distinctive: the reverse direction of remodelling and the cardio-cranio-skeletal extracardiac branch. Review findings not acted on: the reviewer suggested binding NCIT:C174901 to the mavacamten therapeutic_agent. That was tried in the first session and fails term validation - NCIT classifies mavacamten under Inotropic Support, not under Pharmacologic Substance, so it is unreachable from either root of the ChemicalEntityTerm enum, and CHEBI has no mavacamten term in this build. The free-text preferred_term stands, with the reason recorded in the treatment notes. Moving the three histopathology findings into a histopathology block was left alone: they carry pathograph edges as phenotypes and moving them would break the chain for a presentational gain. Validation after changes: just validate passes with 112/112 snippets verified. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms and the online variant, and verify-datasets all pass; the whole-KB baseline gates and check-groupings were re-run. Compliance 90.3 percent, slightly below the previous 91.6 because the added causal edges and model links enlarge the denominator; uncited edges were left uncited rather than papered over with node-level citations.

Create: ALPK3-Related Hypertrophic Cardiomyopathy (CMH27) · 2026-09-01T13:03:20Z · View source

Curated MONDO:0054838 (cardiomyopathy, familial hypertrophic 27; ALPK3, hgnc:17574) as a new Disease entry, and added it as a member of the existing Familial_Hypertrophic_Cardiomyopathy grouping. The session was dispatched as /curate familial hypertrophic cardiomyopathy; that concept (MONDO:0024573) is already curated as a Grouping whose grouping_rationale argues explicitly against a third Disease entry at that level, and the umbrella MONDO:0005045 entry already exists, so the user was asked and chose CMH27 from the grouping's remaining stub series instead. stubs/Cardiomyopathy_Familial_Hypertrophic_27.yaml was deleted. Deep research: falcon was requested but returned HTTP 403 on authentication (EDISON_API_KEY present but rejected). The run was re-issued with --fallback rather than substituting a provider by hand, and fell back to openscientist; that run had not returned by the time this entry was committed, so the entry as committed was built entirely from PubMed-sourced primary literature and structured sources, not from a deep-research report. Anything the fallback report adds will be folded in as a follow-up EDIT. Content: zygosity-split has_subtypes (biallelic autosomal recessive paediatric-onset; heterozygous autosomal dominant adult-onset) with bound HP inheritance terms and both ClinGen assertions (CGGV AR Definitive, AD Strong). A twelve-node causal chain runs ALPK3 loss of function -> loss of M-band scaffolding -> myomesin mislocalization and impaired sarcomere proteostasis -> sarcomere and intercalated-disc disorganization -> calcium-handling and contractility defects -> ventricular dilatation -> hypertrophy -> reactive interstitial fibrosis, with a separate extracardiac striated-muscle and craniofacial branch off the trigger node. Two nodes declare conformance to cardiomyopathy_maladaptive_remodeling (Primary Cardiomyocyte Insult, Ventricular Remodeling). 22 phenotypes, 3 genetic case_fractions, 2 animal models (Alpk3-/- null; Alpk3 K1420R kinase-dead knock-in), 3 experimental models (patient/hESC iPSC-CM, isogenic iPSC-CM proteomics, cardiac organoid), 4 treatments, 4 discussions. Scientific judgement recorded rather than resolved: whether ALPK3 is a pseudokinase scaffold or a genuine kinase is contested in the primary literature (Agarwal 2022 PMID:36321451 and the K1420R knock-in PMID:38048395 versus McNamara PMID:39196058), as is nuclear-envelope localization. This is curated as a CONTROVERSY discussion plus a REFUTE evidence item against the nuclear-envelope half of the scaffolding node, and the top-level description was written to avoid asserting either side. A FAILS_TO_RECAPITULATE model link plus a HUMAN_MODEL_MISMATCH discussion record that the constitutive knockout mouse lacks the interstitial fibrosis that dominates the human phenotype. Datasets: scripts/discover_datasets.py returned 5 DIRECT and 5 GENE_ONLY candidates. All five DIRECT hits matched only the generic phrase 'cardiomyopathy familial hypertrophic' and are about sarcomere-gene HCM, a phospholamban-knockout mouse, and ABRA deficiency - textbook Named Entity Confusion. The single relevant accession, geo:GSE215304, was the one tagged GENE_ONLY. Only that accession was curated, the reasoning is recorded in its notes, and just verify-datasets resolves it. GeneReviews: no ALPK3-specific chapter exists. The nearest, PMID:20301725 (Nonsyndromic Hypertrophic Cardiomyopathy Overview), is tagged in the top-level references block, but its cached PubMed record is a book citation with no abstract text and no ALPK3 mention, so it backs no claim and was not usable as a phenotype baseline; this is recorded in the entry notes. Term bindings needing a judgement call: NCIT:C158080 and NCIT:C50032 were both rejected on verification (they are Deep Gray Matter and Limiter Device respectively) and replaced with NCIT:C174901 and NCIT:C93238/NCIT:C80435. NCIT:C174901 (Mavacamten) then failed the ChemicalEntityTerm dynamic enum because NCIT classifies it under Inotropic Support rather than Pharmacologic Substance, and CHEBI has no mavacamten term in this build, so therapeutic_agent was left as free-text preferred_term with the reason recorded in treatment notes rather than binding a wrong term. Validation: just validate passes (schema, terms, references) with 106/106 snippets verified against references_cache. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms and check-qualifier-terms-online, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-reference-titles, check-environmental-evidence and check-groupings all pass. just verify-datasets resolves the single accession. Compliance 89.6%. The grouping validates and both NECESSARY membership criteria are SATISFIED for the new member. No DOI-keyed evidence was used, so no --unskip-prefix run was needed.

OpenScientist ▸

ALPK3-Related Hypertrophic Cardiomyopathy: Comprehensive Disease Report

openscientist-autonomous 17 citations 2026-09-01T13:10:55.368346

ALPK3-Related Hypertrophic Cardiomyopathy: Comprehensive Disease Report

Summary

ALPK3-related hypertrophic cardiomyopathy (HCM) is a Mendelian sarcomeric/M-band cardiomyopathy caused by loss-of-function (LoF) variants in ALPK3 (alpha-protein kinase 3), located at chromosome 15q25.3 (HGNC:17870; NCBI Gene 57538; OMIM gene 617608; disease MIM 618052, CMH27). ALPK3 encodes a catalytically-dead atypical α-kinase that functions as a structural M-band scaffold of the cardiac sarcomere, anchoring myomesins (MYOM1/2), MuRF (muscle ring-finger) E3 ubiquitin ligases, and the autophagy adaptor SQSTM1/p62 to maintain thick-filament proteostasis. It is a distinctive disease because it exhibits a dose-dependent, zygosity-driven severity gradient: biallelic (recessive) LoF causes a severe, often lethal prenatal/pediatric cardiomyopathy with syndromic extracardiac features, whereas heterozygous (dominant) protein-truncating variants (ALPK3tv) cause an incompletely penetrant adult-onset HCM that accounts for roughly 1–4% of adult HCM.

The core mechanism is now well supported: ALPK3 loss displaces myomesins from the M-band, driving thick-filament protein aggregation, sarcomere and intercalated-disc disarray, abnormal calcium handling, and hypercontractility. In model systems, these defects were partially corrected by the myosin inhibitor mavacamten, and durable phenotypic rescue was achieved in global knockout mice using AAV-delivered ALPK3, establishing two genotype-directed therapeutic proof-of-concept fronts that remain preclinical. Clinically, the adult heterozygous phenotype has a characteristic morphology — apical/septal hypertrophy, apical aneurysm, right-ventricular involvement, and myocardial fibrosis — and ALPK3 has emerged as one of the leading (frequently the second most common) genotypes identified in apical HCM cohorts.

Management currently follows standard HCM guidelines (beta-blockers, disopyramide, septal reduction therapy, ICD for sudden-cardiac-death [SCD] prevention, and transplantation for end-stage disease), with cardiac MRI late gadolinium enhancement (LGE) serving as a key risk-stratification marker particularly relevant to the fibrosis- and aneurysm-prone ALPK3 phenotype. ALPK3 now carries established gene–disease validity for HCM with recognized dual (recessive and dominant) inheritance per the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.

1. Disease Information

Overview. ALPK3-related cardiomyopathy is an inherited cardiac muscle disease presenting predominantly as hypertrophic cardiomyopathy, but with a broad phenotypic spectrum that also includes dilated cardiomyopathy (DCM), a neonatal DCM-to-hypertrophy transition, and restrictive/mixed physiology. The disease exists as a spectrum defined by zygosity: severe recessive pediatric disease at one pole and penetrance-limited adult dominant HCM at the other.

Key identifiers.

Resource	Identifier
Gene symbol	ALPK3 (α-protein kinase 3; formerly MIDORI)
HGNC	HGNC:17870
NCBI Gene	57538
Cytogenetic locus	15q25.3
OMIM (gene)	617608
OMIM (disease)	618052 — Cardiomyopathy, familial hypertrophic, 27 (CMH27)
MONDO	Cardiomyopathy, familial hypertrophic, 27 (maps to OMIM 618052)
ICD-10	I42.1 (obstructive HCM) / I42.2 (other HCM)
ICD-11	BC43.0 (hypertrophic cardiomyopathy)
MeSH	D002312 (Cardiomyopathy, Hypertrophic)

Synonyms / alternative names: ALPK3 cardiomyopathy; ALPK3-related HCM; CMH27; alpha-kinase 3 cardiomyopathy; biallelic ALPK3 pediatric cardiomyopathy (recessive form); ALPK3tv HCM (heterozygous truncating-variant form).

Information source. Evidence is derived from aggregated disease-level and patient-level literature — systematic variant curations, multicentric cohorts (French, Swedish, Chinese), individual case reports, and functional model-organism/iPSC studies — rather than from a single EHR dataset.

2. Etiology

Primary causal factor: genetic. ALPK3-related cardiomyopathy is a monogenic disorder caused by loss-of-function variants in ALPK3. There is no established environmental or infectious cause. The disease displays a dose-dependent relationship between ALPK3 gene dosage and phenotype severity (Finding F001; Finding F007).

Genetic risk factors. - Biallelic LoF variants (homozygous or compound heterozygous nonsense, frameshift, or splice variants) → severe, often lethal, prenatal/early-onset cardiomyopathy with extracardiac involvement (recessive). - Heterozygous protein-truncating variants (nonsense/frameshift/splice) → adult-onset dominant HCM explaining ≈1–4% of adult HCM. - As stated in the integrative review (PMID: 41221624): "Biallelic loss-of-function variants lead to severe, often lethal cardiomyopathy with prenatal or early onset presentation and extracardiac involvement. Heterozygous protein-truncating variants, defined as nonsense or frameshift (resulting from insertion/deletion events or splicing mutations), explain ≈1% to 4% of adult hypertrophic cardiomyopathy."

Environmental / demographic risk factors. No specific toxic, occupational, or infectious triggers are established. Male predominance is reported among heterozygous ALPK3tv HCM patients, and age is a strong modifier given the late onset and age-dependent penetrance (PMID: 41645375). Consanguinity is an important contextual factor for the recessive form — the founding families were consanguineous (PMID: 26846950).

Protective factors. No specific genetic or environmental protective alleles are established for ALPK3 cardiomyopathy. The incomplete penetrance of heterozygous variants (~20% in the founding family; even lower in later cohorts) implies the existence of unidentified genetic/environmental modifiers that buffer disease expression.

Gene–environment interactions. Not specifically characterized. The variable expressivity within families carrying identical variants (e.g., a mother with severe obstructive HCM and an asymptomatic brother carrying the same variant; PMID: 41645375) points to modifier effects, but specific gene–environment interactions have not been mapped.

3. Phenotypes

ALPK3 cardiomyopathy has distinct cardiac and extracardiac phenotype clusters, with the extracardiac cluster largely confined to the biallelic (recessive) pediatric form.

Cardiac phenotypes

Phenotype	Type	HPO term (suggested)	Onset	Frequency / notes
Hypertrophic cardiomyopathy	Clinical sign	HP:0001639	Neonatal (biallelic) to adult (heterozygous)	Predominant phenotype; 26/31 adults in French cohort
Dilated cardiomyopathy / neonatal DCM	Clinical sign	HP:0001644	Neonatal	8/18 (44.4%; 95% CI 21.5–69.2%) biallelic live-borns had neonatal DCM transitioning to hypertrophy
Apical hypertrophy	Physical manifestation	HP:0001639 (apical variant)	Adult	Frequent in heterozygous ALPK3tv; ALPK3 a leading ApHCM genotype
Apical aneurysm	Physical manifestation	HP:0025169 (LV aneurysm)	Adult	~17.2% in ApHCM cohort
Right ventricular involvement	Physical manifestation	HP:0001707	Adult	Reported in heterozygous form
Myocardial fibrosis (LGE)	Laboratory/imaging	HP:0001637	Adult	Prominent; prognostically important
Left ventricular systolic dysfunction	Clinical sign	HP:0005162	Pediatric	E.g., patient 2, PMID 40447126
Restrictive physiology / hypertrabeculation	Clinical sign	HP:0001723	Adult	Overlap phenotype (PMID 36660067)
Atrial fibrillation	Clinical sign	HP:0005110	Adult	41.4% in ApHCM cohort
Non-sustained ventricular tachycardia	Clinical sign	HP:0004758	Adult	29.3% in ApHCM cohort
Sudden cardiac death / HCM-related events	Clinical outcome	HP:0001645	Any	36.2% had HCM-related events in ApHCM cohort

Extracardiac phenotypes (biallelic/recessive form — syndromic)

Phenotype	HPO term (suggested)	Notes
Facial dysmorphism	HP:0001999	Recurrent triad component
Cleft palate	HP:0000175	Reported in Tunisian case (PMID 30046096)
Pectus excavatum / carinatum	HP:0000767 / HP:0000768	Thoracic deformity
Scoliosis	HP:0002650	PMID 40447126
Joint contractures	HP:0002803	PMID 40447126
Short stature	HP:0004322	Multiple biallelic cases
Webbed neck	HP:0000465	PMID 40447126
Hand/foot skeletal deformities	HP:0001155 / HP:0001760	PMID 30046096

Onset, severity, progression: Biallelic disease is neonatal/prenatal-onset, severe, and often lethal (progressive; frequent early death). Heterozygous disease is adult-onset (delayed ~10 years vs. sarcomeric HCM), variable severity, slowly progressive with age-dependent penetrance. Quality-of-life impact ranges from catastrophic (perinatal heart failure, death, transplantation in the biallelic form) to variable in adults (exertional symptoms, arrhythmia burden, ICD, and SCD risk).

4. Genetic / Molecular Information

Causal gene. ALPK3 (HGNC:17870; NCBI Gene 57538; OMIM 617608), 15q25.3. Encodes alpha-protein kinase 3, an atypical α-kinase that is catalytically dead and functions structurally.

Pathogenic variant spectrum. The disease is driven overwhelmingly by truncating / loss-of-function variants: - Nonsense (e.g., p.Arg1173, p.Ser653) - Frameshift (e.g., c.1531_1532delAA p.Lys511Argfs12; c.109del p.R37Gfs72; c.2757dup p.T920Hfs14; c.3272del p.G1091Vfs43; c.1550dupC p.Pro518ThrfsTer53) - Splice-site variants - Contiguous gene deletion of 15q25.2q25.3 has been reported in a biallelic context (PMID 37671554) - Some missense variants (e.g., p.Arg1164Gln) appear in overlap/adult phenotypes (PMID 36660067)

Documented patient-level variants exceed 150 in systematic curation (156 variants; Finding F001).

Variant classification (ACMG/AMP). Truncating variants are generally classified Pathogenic / Likely Pathogenic; classification for heterozygotes was historically complicated because ALPK3 was initially annotated as autosomal recessive — re-analysis after dominant inheritance was established upgraded several variants (PMID 41645375). Bayesian/segregation evidence has supported Likely Pathogenic calls for recurrent truncating variants.

Allele frequency. Heterozygous ALPK3 truncating variants are rare but present in population databases (gnomAD); their appreciable heterozygous frequency combined with incomplete penetrance underlies the ~1–4% contribution to adult HCM.

Somatic vs. germline. All disease-associated variants are germline. No somatic mechanism is implicated.

Functional consequence. Loss of function (haploinsufficiency in heterozygotes; complete loss in biallelic patients) — loss of the M-band scaffolding function of ALPK3.

Modifier genes / epigenetics. No specific Mendelian modifier genes are established. Notably, microRNA-384-5p regulates the ALPK3 pathway in hypertrophy models (Finding F009): "miR-384-5p was notably decreased in cardiac hypertrophic tissues and cells, and overexpression of miR-384-5p could ameliorate pressure overload" (PMID: 35510648). This provides an epigenetic/post-transcriptional regulatory axis. Chromosomal abnormalities are limited to the reported 15q25 contiguous deletion.

5. Environmental Information

ALPK3 cardiomyopathy is a monogenic disease with no established environmental, lifestyle, or infectious etiology. No toxins, radiation, pollutants, dietary factors, or pathogens are implicated as causes or triggers. As with HCM generally, strenuous competitive exercise may modulate SCD risk and symptom burden, and standard HCM lifestyle counseling applies, but these are not ALPK3-specific causal factors. Age and male sex act as demographic modifiers of penetrance in the heterozygous form (see Section 2).

6. Mechanism / Pathophysiology

Ordered causal chain

Loss-of-function variant in ALPK3 (biallelic → complete loss; heterozygous → haploinsufficiency) leads to reduced/absent functional ALPK3 protein at the sarcomeric M-band.
Loss of ALPK3 results in failure of its scaffolding function — it can no longer anchor myomesins (MYOM1/2), MuRF E3 ubiquitin ligases, and SQSTM1/p62 at the M-band.
Displacement of myomesins and loss of the proteostasis hub leads to impaired thick-filament protein turnover and thick-filament protein aggregation.
Aggregation and scaffold failure result in disordered sarcomeres and intercalated discs (ultrastructural disarray).
Sarcomere disarray leads to abnormal calcium handling (elevated diastolic calcium) and altered myosin mechanochemistry — a reduced super-relaxed (SRX) myosin fraction, prolonged relaxation, and hypercontractility (demonstrated in the K201X knock-in mouse).
Reduced PKA phosphorylation of cardiac troponin I and impaired relaxation result in diastolic dysfunction and contractile impairment.
Chronic contractile/proteostatic stress leads to myocyte hypertrophy, myocardial fibrosis, and (in neonates) a dilated-to-hypertrophic transition → clinical HCM/DCM, apical aneurysm, arrhythmia, heart failure, and SCD risk.

Branch: In the neonatal biallelic context, the initial manifestation is often dilated cardiomyopathy that subsequently transitions to hypertrophy — a developmentally distinct branch, consistent with ALPK3's essential role in early cardiomyocyte differentiation (PMID: 26846950; PMID: 32480058).

Inferred vs. demonstrated: Steps 2–5 are directly demonstrated in iPSC-CM/ESC-CM models and mouse knock-ins (PMID 27106955, 40128237, 40135575). The downstream fibrosis/arrhythmia/SCD steps (step 7) are inferred from clinical cohorts and general HCM pathophysiology.

Supporting detail

Molecular pathways & protein dysfunction. ALPK3 is a catalytically-dead M-band scaffold (Finding F002): "ALPK3 lacks catalytic activity and maintains sarcomeric proteostasis by scaffolding MYOMs (myomesins), MuRF (muscle ring-finger protein) E3 ligases, and SQSTM1 (sequestosome-1)/p62. Loss of this scaffolding function displaces MYOMs, drives thick-filament protein aggregation, and precipitates severe contractile dysfunction" (PMID: 41221624). The relevant pathway is sarcomere/myofilament assembly and the ubiquitin–proteasome/autophagy quality-control system (MuRF ligases, p62). The founding study additionally described ALPK3 as a nuclear kinase essential for early cardiomyocyte differentiation (PMID: 26846950), and the α-kinase-3 mouse work supports a scaffold model recruiting machinery for thick-filament protein turnover (PMID: 40135575).

Cellular processes. Disrupted sarcomeric proteostasis, autophagy/protein turnover, and calcium homeostasis in cardiomyocytes. Ultrastructural evidence: "Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs" (PMID: 27106955).

Metabolic/biochemical abnormalities. Reduced SRX myosin fraction (an energy-conserving myosin state), elevated diastolic calcium, and reduced PKA-mediated troponin I phosphorylation — collectively producing hypercontractility and impaired relaxation (PMID: 40128237).

Tissue damage. Chronic myofibrillar stress → myocardial fibrosis (prominent LGE), apical aneurysm formation, and arrhythmogenic substrate.

Suggested ontology terms. - GO biological process: sarcomere organization (GO:0045214); myofibril assembly (GO:0030239); cardiac muscle hypertrophy (GO:0003300); regulation of protein catabolic process (GO:0042176); regulation of the force of heart contraction (GO:0002026); cardiac muscle cell differentiation (GO:0055007). - GO cellular component: M band (GO:0031430); sarcomere (GO:0030017); myofibril (GO:0030016); nucleus (GO:0005634). - CL cell types: cardiac muscle cell / cardiomyocyte (CL:0000746); regular cardiac myocyte (CL:0002098).

7. Anatomical Structures Affected

Organ level. Primary organ: the heart (UBERON:0000948), specifically the cardiac ventricles — left ventricle (UBERON:0002084) with frequent apex and interventricular septum involvement, and right ventricle (UBERON:0002080) in the heterozygous form. Secondary involvement: cardiac atria (atrial fibrillation), pulmonary/systemic circulation via heart failure. Body system: cardiovascular system (UBERON:0004535). In the biallelic syndromic form, additional systems affected: musculoskeletal system (skeleton, thoracic cage), craniofacial structures (palate), and skeletal/integumentary features (short stature, joint contractures).

Tissue and cell level. Cardiac (striated) muscle tissue (UBERON:0001133); target cell = cardiomyocyte (CL:0000746). Fibrosis reflects cardiac fibroblast (CL:0002548) activation and extracellular matrix expansion.

Subcellular level. The sarcomeric M-band (GO:0031430) is the primary locus of dysfunction, with secondary involvement of the sarcomere/myofibril (GO:0030017), and nucleus (GO:0005634, reflecting ALPK3's reported nuclear localization and differentiation role).

Localization / lateralization. Cardiac involvement is biventricular/bilateral with a characteristic apical predilection in heterozygotes; hypertrophy may be asymmetric (septal) or concentric/apical.

8. Temporal Development

Onset. - Biallelic (recessive): congenital/prenatal to neonatal/early-childhood onset; acute and severe. - Heterozygous (dominant): adult-onset, insidious/chronic; onset delayed by ~10 years relative to sarcomeric-gene-positive HCM (PMID: 41645375).

Progression. - Biallelic disease is rapidly progressive; three founding-cohort patients died of heart failure within the first week of life (PMID: 26846950). A characteristic neonatal DCM → ventricular hypertrophy transition occurs in ~44% of live-born biallelic patients (PMID: 32480058). - Heterozygous disease is slowly progressive/chronic-lifelong, with left ventricular wall thickness positively correlating with age (notably in female patients).

Patterns. Disease is progressive, not relapsing-remitting; no spontaneous remission. Critical windows: the perinatal period (biallelic lethality) and adult mid-life (penetrance onset in heterozygotes) represent the key vulnerability windows and — for preclinical gene/pharmacotherapy — potential intervention windows.

9. Inheritance and Population

Inheritance — dual. ALPK3 shows both recessive (biallelic) and dominant (heterozygous truncating) disease mechanisms, now formally recognized by ClinGen (Finding F010): "Existing genes were curated for new inheritance patterns where evidence existed" (PMID: 39971408). ALPK3 carries established (definitive/strong/moderate) gene–disease validity for HCM.

Penetrance & expressivity. Heterozygous penetrance is incomplete and age-dependent — ~20% (2 of 10 heterozygous family members) in the founding family (PMID: 26846950); later cohorts suggest even lower penetrance. Expressivity is variable, with identical variants producing severe obstructive HCM in one relative and no phenotype in another (PMID: 41645375).

Epidemiology. No ALPK3-specific prevalence figure exists. Contextually, HCM affects ~1 in 500 (PMID: 39971408; PMID: 39132495), and heterozygous ALPK3tv account for ~1–4% of adult HCM, giving a rough order-of-magnitude estimate. In apical HCM specifically, ALPK3 is over-represented: 28.6% of genotype-positive apical HCM in a Swedish cohort (2nd most common after MYH7) (PMID: 40428316).

Founder effects / consanguinity. The recessive form was first identified in consanguineous families via homozygosity mapping (PMID: 26846950); consanguinity elevates biallelic risk. No specific founder variants are broadly established.

Sex ratio. Male predominance among heterozygous ALPK3tv HCM patients (PMID: 41645375).

Carrier frequency. Heterozygous truncating ALPK3 variants are present at low frequency in gnomAD; precise carrier frequencies are population-dependent.

10. Diagnostics

Imaging (cornerstone). - Echocardiography — detects ventricular hypertrophy, apical morphology, systolic/diastolic dysfunction, outflow obstruction. - Cardiac MRI (CMR) with late gadolinium enhancement (LGE) — critical for detecting apical aneurysm, RV involvement, and fibrosis burden, all characteristic of ALPK3 HCM, and central to SCD risk stratification (Finding F006). "Late gadolinium enhancement (LGE) was present in 80% of patients and LGE% independently predi[cted events]" (PMID: 41759724). Combined markers stratify risk: "Patients with LVWT ≥30 mm and LGE ≥15% had a greater risk of SCD (subdistribution hazard ratio, 5.60; 95% confidence interval, 1.90-16.5, P = .002)" (PMID: 40317285).

Electrophysiology. ECG shows left ventricular hypertrophy patterns (more prevalent in ALPK3tv than sarcomeric HCM); Holter monitoring detects AF and NSVT.

Genetic testing (definitive for etiology). - Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are the primary discovery tools and identified nearly all reported variants. - HCM/cardiomyopathy gene panels should include ALPK3; historically ALPK3 was omitted or mis-annotated as recessive-only, causing missed diagnoses — periodic re-analysis/re-annotation is essential (PMID: 41645375). - Single-gene / targeted testing and cascade family testing for known variants; trio segregation (Sanger) to establish compound-heterozygous configuration in pediatric cases (PMID: 40447126). - Chromosomal microarray may be needed to detect contiguous 15q25 deletions (PMID 37671554).

Clinical criteria & differential diagnosis. Diagnosis follows standard HCM criteria (unexplained LV wall thickness ≥15 mm, or ≥13 mm with family history). Differential diagnosis includes sarcomeric HCM (MYH7, MYBPC3), infiltrative/storage cardiomyopathies (Fabry, amyloid), athlete's heart, and syndromic causes (RASopathies) — especially relevant given the extracardiac features of the biallelic form.

Screening. Cascade genetic and clinical (imaging) screening of at-risk relatives; prenatal/reproductive counseling for consanguineous families at risk of biallelic disease.

11. Outcome / Prognosis

Biallelic (recessive) form: Poor prognosis — severe, often lethal in utero, at birth, or in early childhood; heart transplantation, refractory heart failure, and cardiac arrest are reported outcomes; several founding-cohort neonates died within the first week of life (PMID: 26846950; PMID: 38356193).

Heterozygous (dominant) form: Variable, generally more favorable but with meaningful arrhythmic risk. In the apical HCM cohort where ALPK3 is prominent, 36.2% experienced HCM-related events, apical aneurysm occurred in 17.2%, AF in 41.4%, and NSVT in 29.3% (PMID: 40428316).

Prognostic factors. LV wall thickness, LGE burden/fibrosis, apical aneurysm, and NSVT are the principal risk markers for SCD. Guideline-based SCD risk algorithms have modest discriminatory power (AUC ~0.58–0.63; PMID: 39713197), and there is low inter-guideline agreement for primary-prevention ICD recommendations (Fleiss' kappa 0.340; PMID: 39557320) — reinforcing the value of CMR-LGE as an additional stratifier for the fibrosis-prone ALPK3 phenotype.

Complications. Heart failure, atrial and ventricular arrhythmias, thromboembolism (AF), apical aneurysm with thrombus, and sudden cardiac death.

12. Treatment

There is no ALPK3-specific approved therapy; management follows standard HCM guidelines, with genotype-directed therapies in preclinical development.

Pharmacotherapy (guideline HCM care; NCIT terms suggested). - Beta-adrenergic blockers (NCIT:C2496) — first-line for symptoms/obstruction. - Non-dihydropyridine calcium-channel blockers (e.g., verapamil). - Disopyramide — for obstruction. - Standard heart-failure therapy for the DCM/systolic-dysfunction phenotype. - Anticoagulation for AF.

Genotype-directed / advanced therapeutics (preclinical proof-of-concept; Finding F003). - Mavacamten (cardiac myosin inhibitor; NCIT:C171741) — "Contractile and calcium handling defects were partly corrected by treatment with mavacamten, a novel myosin inhibitor" (PMID: 40128237). Targets the hypercontractility/SRX defect central to ALPK3 pathophysiology. - AAV-based gene replacement therapy — "durable phenotypic rescue in global knockout mice using an adeno-associated virus" delivering ALPK3 (PMID: 41221624). Directly addresses the LoF mechanism. - miR-384-5p modulation — a candidate therapeutic axis based on amelioration of pressure-overload hypertrophy via the ALPK3 pathway (PMID: 35510648).

Surgical / interventional. - Septal reduction therapy — surgical septal myectomy (NCIT:C51899) or alcohol septal ablation for obstruction. - Implantable cardioverter-defibrillator (ICD) (NCIT:C50077) for primary/secondary SCD prevention, guided by CMR-LGE-informed risk stratification. - Heart transplantation (NCIT:C15328) for end-stage disease (used in severe pediatric/biallelic cases).

Supportive care. Symptom management, exercise counseling, arrhythmia management, and heart-failure supportive therapy.

13. Prevention

Primary prevention. Because ALPK3 cardiomyopathy is monogenic, primary prevention is reproductive/genetic: carrier identification, genetic counseling (especially for consanguineous couples at risk of biallelic disease), and reproductive options including preimplantation genetic testing (PGT) and prenatal diagnosis.

Secondary prevention. Cascade genetic testing and serial clinical/imaging surveillance of at-risk relatives to detect subclinical disease early — important given incomplete, age-dependent penetrance. Periodic re-analysis of previously "negative" HCM genetic tests to capture ALPK3 as knowledge of its dominant mechanism has matured (PMID: 41645375).

Tertiary prevention. Prevention of complications in diagnosed patients: ICD for SCD prevention (CMR-LGE-informed), anticoagulation for AF-related thromboembolism, heart-failure management, and activity modification.

Counseling. Genetic counseling should address dual inheritance — recessive risk in consanguineous unions and dominant, incompletely penetrant risk for offspring of heterozygotes.

No immunization or public-health/environmental prevention is applicable (non-infectious, non-environmental disease).

14. Other Species / Natural Disease

Taxonomy & orthologs. ALPK3 is highly conserved. Mouse Alpk3 (NCBI Gene 116904; Mus musculus, NCBI Taxon 10090) is the principal experimental ortholog. Human ALPK3 is NCBI Gene 57538 (Homo sapiens, NCBI Taxon 9606). The gene was originally described as Midori, a differentiation-associated cardiac gene.

Natural disease in other species. No well-characterized naturally occurring ALPK3 cardiomyopathy in companion animals or wildlife is documented in the reviewed literature (no OMIA entry established in this investigation). Disease knowledge derives from engineered rather than spontaneous animal models.

Comparative biology & conservation. The M-band scaffold function and requirement for cardiac function are evolutionarily conserved — mouse knockouts recapitulate neonatal and adult cardiac dysfunction (PMID: 40135575), supporting conserved disease mechanisms across mammals.

Transmission. Not applicable — genetic, non-zoonotic, non-transmissible.

15. Model Organisms

ALPK3 cardiomyopathy is supported by a robust set of complementary models spanning mouse and human cellular systems.

Model	Type	Key features	Reference
Alpk3 global knockout mouse	Mammalian, constitutive KO	Neonatal and adult cardiac dysfunction; scaffold model for thick-filament turnover; AAV-ALPK3 rescue	PMID: 40135575; PMID: 41221624
Inducible cardiac-specific Alpk3 KO	Mammalian, conditional	Dissects neonatal vs. adult requirement for ALPK3	PMID: 40135575
K201X (truncation) knock-in mouse	Mammalian, knock-in	Reduced SRX myosin, elevated diastolic Ca²⁺, reduced PKA-cTnI phosphorylation; partial mavacamten rescue	PMID: 40128237
Patient-derived iPSC-cardiomyocytes	In vitro, human	Disordered sarcomeres/intercalated discs; abnormal calcium handling	PMID: 27106955
ALPK3-mutant human ESC-derived CMs	In vitro, human	Establishes ALPK3 deficiency underlies familial cardiomyopathy	PMID: 27106955

Phenotype recapitulation. Models faithfully reproduce the core cellular phenotype (sarcomere disarray, thick-filament aggregation, calcium mishandling, hypercontractility) and the age-staged cardiac dysfunction. Limitations: models less completely capture the human syndromic extracardiac features (facial/skeletal/palate anomalies) and the age-dependent incomplete penetrance of the human heterozygous form. Applications: mechanism dissection (M-band proteostasis), developmental staging of ALPK3 requirement, and preclinical testing of mavacamten and AAV gene therapy.

Mechanistic Model / Interpretation

   ALPK3 loss-of-function variant
   (biallelic = complete loss | heterozygous = haploinsufficiency)
 |
 v
   Loss of catalytically-dead M-band SCAFFOLD
 |
 v
   Failure to anchor MYOM1/2 + MuRF E3 ligases + p62/SQSTM1
 |
 v
   Impaired thick-filament protein turnover -> AGGREGATION
 |
 v
   Sarcomere + intercalated-disc DISARRAY
 |
+--------+---------------------------+
v                                    v
  Ca2+ mishandling                   Reduced SRX myosin,
  (elevated diastolic Ca2+)          low PKA-cTnI phosphorylation
|                                    |
+----------------+-------------------+
         v
      HYPERCONTRACTILITY + impaired relaxation
         |
+----------------+----------------------------+
v (neonatal branch)                           v (adult branch)
  Dilated CM -> transition to                 Late-onset HCM: apical/septal
  hypertrophy; severe, often                  hypertrophy, apical aneurysm,
  lethal; +/- syndromic features              RV involvement, fibrosis
|                                            |
+----------------+---------------------------+
         v
Heart failure, arrhythmia (AF/NSVT), SCD risk
         |
      Rescue points: mavacamten (hypercontractility),
     AAV-ALPK3 (restores scaffold)

The unifying interpretation is that ALPK3 is a structural (not enzymatic) linchpin of M-band proteostasis, and disease severity scales with residual ALPK3 dosage. This single mechanism parsimoniously explains the entire clinical spectrum — from perinatal lethal recessive disease to penetrance-limited adult dominant HCM — and rationalizes two mechanistically distinct therapeutic strategies (myosin inhibition to relieve the downstream hypercontractile consequence; gene replacement to restore the upstream scaffold).

Evidence Base

PMID	Title (abbrev.)	Role in this report
26846950	Biallelic truncating mutations cause severe pediatric CM	Founding study: recessive causation, perinatal lethality, nuclear kinase role, ~20% heterozygote penetrance (F007)
41221624	ALPK3 Cardiomyopathy: Integrative Review	Zygosity–severity relationship, M-band scaffold mechanism, AAV/mavacamten proof-of-concept (F001, F002, F003, F004)
32480058	Expanding clinical/genetic spectrum	Neonatal DCM→hypertrophy transition (44.4%), adult heterozygous phenotypes (F001)
27106955	ALPK3-deficient iPSC/ESC cardiomyocytes	Ultrastructural disarray, abnormal calcium handling (F002)
40128237	ALPK3tv rescued by mavacamten	SRX/Ca²⁺ defects, partial mavacamten rescue (F003)
40135575	ALPK3 essential for neonatal/adult cardiac function	Mouse KO models, scaffold-for-turnover model (Sections 6, 15)
38356193	French multicentric cohort	31 adults heterozygous, HCM main phenotype (26/31), 15% apical/concentric (F004)
39606411 / 40469041	Heterozygous ALPK3tv late-onset HCM	Apical involvement and apical aneurysm signature (F004, F008)
30046096	Tunisian case, facio-thoraco-skeletal	Syndromic biallelic features, specific frameshift variant (F005)
40447126	Compound-het pediatric HCM	Novel truncating variants, extracardiac features (F005)
40428316	Swedish apical HCM cohort	ALPK3 = 2nd most common ApHCM genotype (28.6%), aneurysm 17.2% (F008)
41645375	Chinese pedigree re-analysis	Dominant inheritance, delayed onset, male predominance, re-annotation importance (Sections 2, 8, 10)
35510648	miR-384-5p protects via ALPK3	Post-transcriptional regulation of ALPK3 pathway (F009)
40317285	SCD prediction after myectomy	LVWT≥30 mm + LGE≥15% → HR 5.60 for SCD (F006)
41759724	Risk stratification / LGE	LGE independent SCD predictor (F006)
39713197	Guideline validation	Modest guideline discrimination (AUC 0.58–0.63) (Section 11)
39557320	Guideline agreement	Low inter-guideline ICD agreement (kappa 0.340) (Section 11)
39971408 / 39132495	ClinGen HCM gene reappraisal	Dual-inheritance curation, HCM ~1 in 500 (F010)
36660067	Overlapping adult-onset phenotype	Restrictive/overlap phenotype, missense variants (Sections 3, 4)
37671554	Contiguous 15q25 deletion	Structural-variant biallelic mechanism (Section 4)
33076350	HCM + skeletal muscle features	Skeletal muscle involvement (Section 3)

Limitations and Knowledge Gaps

No ALPK3-specific epidemiology. Prevalence/incidence are inferred from HCM-wide figures (~1 in 500) and the ~1–4% ALPK3 contribution; no direct registry estimate exists.
Penetrance uncertainty. The ~20% figure derives from a single founding family; population-scale penetrance of heterozygous ALPK3tv is likely lower and imprecisely quantified. Modifier genes and gene–environment interactions remain unidentified.
Therapies are preclinical. Mavacamten rescue and AAV gene therapy are shown only in mouse/iPSC models; no human trials specific to ALPK3 exist. Standard HCM management is extrapolated, not ALPK3-validated.
Mechanistic gaps. The relative contributions of ALPK3's nuclear (differentiation) role versus its cytoplasmic M-band scaffold role are not fully resolved, and how catalytic-dead α-kinase architecture confers scaffolding specificity is incompletely defined.
Extracardiac pathogenesis. The mechanism linking ALPK3 loss to craniofacial/skeletal malformations in the biallelic form is unexplained.
Variant interpretation. Historical mis-annotation of ALPK3 as recessive-only led to under-diagnosis; many gene panels and archived tests may still under-call ALPK3.
Model limitations. Animal/cellular models under-represent the syndromic extracardiac phenotype and age-dependent adult penetrance.

Proposed Follow-up Experiments / Actions

Population penetrance study. Leverage large biobanks (e.g., the biobank gene–disease association approach of PMID 41893039) to estimate age-specific penetrance and lifetime HCM risk for heterozygous ALPK3 truncating variants.
Prospective natural-history registry. Establish an ALPK3-specific longitudinal registry capturing apical aneurysm incidence, arrhythmia burden, LGE progression, and SCD to build an ALPK3-tailored risk model (given weak performance of generic guidelines).
Clinical translation of genotype-directed therapy. Advance AAV-ALPK3 gene replacement and evaluate mavacamten in ALPK3tv patients via biomarker-driven early-phase trials; define the therapeutic window (neonatal vs. adult).
Modifier discovery. GWAS/whole-genome and multi-omics analysis of penetrant vs. non-penetrant heterozygous carriers to identify genetic/epigenetic modifiers (including the miR-384-5p axis).
Structural biology. Determine the ALPK3 M-band interactome structure (with MYOM, MuRF, p62) via cryo-EM/AlphaFold-guided modeling to rationalize truncating-variant effects and design stabilizing therapeutics.
Panel/curation updates. Ensure all clinical HCM gene panels include ALPK3 with dual-inheritance interpretation, and systematically re-analyze archived "gene-negative" HCM cases.
Mechanism of extracardiac disease. Use conditional/humanized models to dissect the developmental basis of the syndromic facio-thoraco-skeletal features in biallelic disease.

Report compiled from 5 investigation iterations, 10 confirmed findings, and 24 reviewed papers. Evidence types: human clinical cohorts and case reports, model-organism (mouse) studies, in vitro human iPSC/ESC-cardiomyocyte studies, and expert-panel gene curation.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	23
Resolved	23
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	23
On topic	15
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	44
Resolved	43
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	29
Terms named correctly	8
Terms named as a different term	15
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001639 (2 mentions) - the report calls it "Clinical sign", "apical variant"; HP calls it Hypertrophic cardiomyopathy
HP:0001644 (1 mention) - the report calls it "Clinical sign"; HP calls it Dilated cardiomyopathy
HP:0025169 (1 mention) - the report calls it "LV aneurysm"; HP calls it Left ventricular systolic dysfunction
HP:0001707 (1 mention) - the report calls it "Physical manifestation"; HP calls it Abnormal right ventricle morphology
HP:0001637 (1 mention) - the report calls it "Laboratory/imaging"; HP calls it Abnormal myocardium morphology
HP:0005162 (1 mention) - the report calls it "Clinical sign"; HP calls it Abnormal left ventricular function
HP:0001723 (1 mention) - the report calls it "Clinical sign"; HP calls it Restrictive cardiomyopathy
HP:0005110 (1 mention) - the report calls it "Clinical sign"; HP calls it Atrial fibrillation
HP:0004758 (1 mention) - the report calls it "Clinical sign"; HP calls it Effort-induced polymorphic ventricular tachycardia
HP:0001645 (1 mention) - the report calls it "Clinical outcome"; HP calls it Sudden cardiac death
GO:0031430 (2 mentions) - the report calls it "GO cellular component: M band", "sarcomeric M-band"; GO calls it M band
NCIT:C2496 (1 mention) - the report calls it "Beta-adrenergic blockers"; NCIT calls it Anti-VEGF Monoclonal Antibody
NCIT:C51899 (1 mention) - the report calls it "septal myectomy", "Septal reduction therapy — surgical septal myectomy"; NCIT calls it Radical Cystoprostatectomy
NCIT:C50077 (1 mention) - the report calls it "Implantable cardioverter-defibrillator (ICD)"; NCIT calls it Motor Device
NCIT:C15328 (1 mention) - the report calls it "Heart transplantation"; NCIT calls it Splenectomy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002803 (1 mention) - the report calls it "Joint contractures"; HP calls it Congenital contracture, and lists "congenital contractures" among its other names
GO:0045214 (1 mention) - the report calls it "GO biological process: sarcomere organization"; GO calls it sarcomere organization
GO:0030017 (2 mentions) - the report calls it "sarcomere/myofibril"; GO calls it sarcomere
CL:0000746 (2 mentions) - the report calls it "CL cell types: cardiac muscle cell / cardiomyocyte", "cardiomyocyte"; CL calls it cardiac muscle cell
UBERON:0001133 (1 mention) - the report calls it "Cardiac (striated) muscle tissue"; UBERON calls it cardiac muscle tissue, and lists "cardiac muscle muscle tissue" among its other names
CL:0002548 (1 mention) - the report calls it "cardiac fibroblast"; CL calls it fibroblast of cardiac tissue, and lists "cardiac fibroblast" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0001639 - called "Clinical sign", "apical variant"
GO:0031430 - called "GO cellular component: M band", "sarcomeric M-band"
CL:0000746 - called "CL cell types: cardiac muscle cell / cardiomyocyte", "cardiomyocyte"
NCIT:C51899 - called "septal myectomy", "Septal reduction therapy — surgical septal myectomy"

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References

Deep Research

ALPK3-Related Hypertrophic Cardiomyopathy: Comprehensive Disease Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

Cardiac phenotypes

Extracardiac phenotypes (biallelic/recessive form — syndromic)

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Supporting detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

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Proposed Follow-up Experiments / Actions

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Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently