Auroneurodental Syndrome

Mendelian MONDO:0970998 Pathograph 56 Show in embeddings browser hereditary disease Neurodevelopmental Disorder

An autosomal recessive NAA80-associated syndrome reported in two brothers with progressive high-frequency sensorineural hearing impairment, craniofacial and dental abnormalities, developmental delay and mild proximal and axial muscle weakness. The reported p.Leu130Pro allele reduces NAA80 abundance and actin N-terminal acetylation in sampled cells. Patient-cell and knockout experiments show altered filament content, protrusions and migration, while separate zebrafish experiments support a hearing-related role. The routes to individual human organ manifestations remain incompletely resolved.

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Inheritance

Autosomal recessive HP:0000007

Both affected brothers are homozygous for NAA80 c.389T>C, p.(Leu130Pro); both parents are heterozygous and unaffected, and the two healthy siblings do not carry the variant in the homozygous state. A large run of homozygosity and shared parental geographic origin indicate distant consanguinity.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:34805998 SUPPORT PRIMARY RESULT Human Clinical

"We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant."

States the homozygous state in both affected individuals.

PMID:34805998 SUPPORT PRIMARY RESULT Human Clinical

"Both parents were heterozygous for this variant."

Unaffected heterozygous parents complete the recessive segregation argument.

Discussions and Knowledge Gaps

Which clinical manifestations are attributable to NAA80 in this single family?

KNOWLEDGE GAP gap_auroneurodental_clinical_attribution

Attached to

pathophysiology#Biallelic NAA80 Dysfunction

NAA80 reconstitution rescues the measured fibroblast abnormalities, but the brothers also share PLXNB1 p.Ser911Gly. Additional families and affected-tissue models are needed to distinguish the full NAA80 spectrum from possible additional genetic contributions. Neither the co-variant nor its absence in healthy siblings establishes a modifier mechanism.

How do the measured actin changes contribute to human organ manifestations?

KNOWLEDGE GAP gap_auroneurodental_tissue_routes

Attached to

pathophysiology#Reduced Actin N-Terminal Acetylation pathophysiology#Increased Cell Migration

Filament abundance, elongation, depolymerization, protrusion formation and migration are distinct results. Human inner-ear, neural, muscle and dental tissue mechanisms were not measured. The fish ear observations support a candidate sensory route, but acetylation and dynamics were not assayed in those F0 hair cells. No single fibroblast readout is established as the mediator of craniofacial, behavioral or brain-imaging abnormalities.

What does grossly normal behavior in stable knockout fish establish about muscle disease?

HUMAN MODEL MISMATCH gap_auroneurodental_muscle_model_scope

Attached to

phenotypes#Proximal muscle weakness phenotypes#Axial muscle weakness

Stable mutant fish lacked most detectable muscle actin acetylation but swam and fed normally under routine conditions. No force or endurance testing was performed. Species, allele severity and assay sensitivity preclude treating this as a stronger disproof of human hypomorphic myopathy, or assigning the human weakness to PLXNB1 by exclusion.

Is there a clinically meaningful residual NAA80 activity threshold?

KNOWLEDGE GAP gap_auroneurodental_activity_threshold

Attached to

pathophysiology#Reduced NAA80 Protein Abundance pathophysiology#Reduced Actin N-Terminal Acetylation

The human paper’s estimate of approximately 1–2% residual activity comes from a simplified kinetic model, not a patient enzyme assay. Proposed lethality below that range and asymptomatic status above it are unvalidated; viable zebrafish nulls further limit cross-species extrapolation. Strong-promoter rescue is not a therapeutic dose or clinical safety threshold.

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Pathophysiology

Biallelic NAA80 Dysfunction

The reported family carries homozygous NAA80 c.389T>C, p.(Leu130Pro), a hypomorphic allele with residual activity in expression assays. Molecular and cellular experiments support NAA80 dysfunction. Attribution of every clinical feature remains limited by one family and a co-segregating PLXNB1 variant.

NAA80 hgnc:30252

Genetic context NAA80 hgnc:30252 allele_type: MISSENSE variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

The reported p.Leu130Pro allele retains acetylation activity when expressed strongly in knockout HAP1 cells. This is functional evidence for a partial loss of function, without a validated human residual-activity or viability threshold.

Downstream

Reduced NAA80 Protein Abundance Mutant reconstitution reduces protein abundance relative to wild type across tested promoters.

High-frequency sensorineural hearing impairment Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Neurodevelopmental delay Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Hypotonia Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Feeding difficulties Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Fatigue Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Peripheral edema Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Vomiting Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Proximal muscle weakness Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Axial muscle weakness Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Gait ataxia Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Reduced cerebral white matter volume Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Lateral ventricle dilatation Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Self-injurious behavior Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Sleep apnea Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Loud snoring Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Chronic constipation Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Hypertelorism Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Low posterior hairline Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Highly arched eyebrow Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Protruding ear Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Low-set ears Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Narrow mouth Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Thin upper lip vermilion Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Retrognathia Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Ptosis Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Epicanthus Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Diastema Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Peg-shaped maxillary lateral incisors Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Tapered finger Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Reduced systolic function Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Disorganized implant of the toes Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Long philtrum Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Bulbous nose Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.

Sleep disturbance Observed in the affected brothers; the contribution of sensory, neurological or other factors remains unresolved.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant."

The clinical association is based on two affected brothers in one family.

Reduced NAA80 Protein Abundance

NAA80 protein is reduced in patient fibroblasts and after mutant reconstitution in HAP1 cells. Recombinant mutant protein is predominantly insoluble, consistent with predicted fold disruption. Mutant structure, folding kinetics and patient protein half-life were not directly measured.

Experimental models

Wild-type and p.Leu130Pro NAA80 reconstitution in HAP1 knockout cells CELL LINE Mutant NAA80 abundance is lower across the tested promoters.

Recombinant NAA80 p.Leu130Pro solubility assay OTHER Mutant recombinant protein preferentially partitions into the insoluble fraction.

Downstream

Reduced Actin N-Terminal Acetylation Lower available mutant enzyme contributes to incomplete actin acetylation; stronger mutant expression can restore the western-blot signal toward wild type.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters"

Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.

Reduced Actin N-Terminal Acetylation

N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.

protein-N-terminal amino-acid acetyltransferase activity GO:0004596 ↓ DECREASED

Experimental models

Patient fibroblasts and peripheral blood mononuclear cells PRIMARY CELL CULTURE N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.

Wild-type and p.Leu130Pro NAA80 reconstitution in HAP1 knockout cells CELL LINE Weak-promoter mutant expression incompletely restores actin acetylation; stronger expression can approach maximal signal.

CRISPR NAA80 knockout HAP1 cells CELL LINE Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.

Animal models

Stable naa80 5del/1in and 13del frameshift lines Zebrafish Zebrafish measures Muscle and heart samples show little to no detectable N-terminally acetylated actin in homozygotes.

Downstream

Slower Actin Filament Elongation Loss of acetylation slows elongation in purified seeded-filament assays.

Slower Actin Filament Depolymerization Loss of acetylation slows depolymerization in the purified-filament assay.

Increased Filamentous Actin Content NAA80 loss and wild-type rescue connect the modification defect with this cultured-cell phenotype; the intervening regulatory processes are incompletely resolved.

Increased Filopodia Formation NAA80 loss and wild-type rescue connect the modification defect with this cultured-cell phenotype; the intervening regulatory processes are incompletely resolved.

Increased Cell Migration NAA80 loss and wild-type rescue connect the modification defect with this cultured-cell phenotype; the intervening regulatory processes are incompletely resolved.

Reduced Inner-Ear Hair-Cell Bundles A proposed in-vivo extension of the acetylation mechanism: stable knockout muscle proteomics and separate F0 ear phenotyping support the model, but acetylation was not measured in the affected F0 ear cells.

Shortened Hair-Cell Stereocilia A proposed in-vivo extension of the acetylation mechanism: stable knockout muscle proteomics and separate F0 ear phenotyping support the model, but acetylation was not measured in the affected F0 ear cells.

Reduced Otolith Size A proposed in-vivo extension of the acetylation mechanism: stable knockout muscle proteomics and separate F0 ear phenotyping support the model, but acetylation was not measured in the affected F0 ear cells.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In healthy donors, ∼0.5% of beta and gamma-actins were not acetylated. However, for the NAA80 individuals, 25–65% of beta and gamma-actins were not acetylated, depending on the cell type and the type of cytoplasmic actin"

Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.

Slower Actin Filament Elongation

Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.

actin filament polymerization GO:0030041 ↓ DECREASED

Experimental models

Purified acetylated and nonacetylated beta/gamma-actin OTHER Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red)."

Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.

Slower Actin Filament Depolymerization

Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.

actin filament depolymerization GO:0030042 ↓ DECREASED

Experimental models

Purified acetylated and nonacetylated beta/gamma-actin OTHER Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red)."

The purified-filament assay measured slower depolymerization without acetylation.

Increased Filamentous Actin Content

Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.

actin cytoskeleton organization GO:0030036

Experimental models

Patient fibroblasts and peripheral blood mononuclear cells PRIMARY CELL CULTURE Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.

CRISPR NAA80 knockout HAP1 cells CELL LINE The measured globular-to-filamentous actin ratio decreased in knockout cells.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, NAA80 individual PBMCs and fibroblasts displayed increased phalloidin staining, corresponding with increased levels of polymerized actin"

Phalloidin fluorescence measures filamentous actin content, not polymerization flux.

Increased Filopodia Formation

Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.

Experimental models

Patient fibroblasts and peripheral blood mononuclear cells PRIMARY CELL CULTURE Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.

CRISPR NAA80 knockout HAP1 cells CELL LINE Knockout cells had more filopodia-like protrusions.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In NAA80 individual fibroblasts, increased filopodia counts were observed"

Filopodia were counted in fibroblasts from the elder brother; this was not a PBMC filopodia assay.

Increased Cell Migration

Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.

cell migration GO:0016477 ↑ INCREASED

Experimental models

Patient fibroblasts and peripheral blood mononuclear cells PRIMARY CELL CULTURE Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.

CRISPR NAA80 knockout HAP1 cells CELL LINE Directed and random migration increased in knockout cells.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Both fibroblasts and PBMCs of NAA80 individuals showed increased movement in response to chemotactic stimuli"

Boyden chamber assays measured migration in patient-derived cells.

Reduced Inner-Ear Hair-Cell Bundles

Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.

sensory hair cell CL:0000855

stereocilium bundle GO:0032421

Animal models

Transient F0 naa80 CRISPR targeting with two sgRNAs Zebrafish Zebrafish measures Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.

Downstream

High-frequency sensorineural hearing impairment The larval structural abnormality accompanies reduced acoustic responses and provides a candidate route relevant to hearing. It does not establish mediation, human cochlear pathology or high-frequency specificity.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls"

Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.

Shortened Hair-Cell Stereocilia

Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.

sensory hair cell CL:0000855

inner ear receptor cell stereocilium organization GO:0060122

Animal models

Transient F0 naa80 CRISPR targeting with two sgRNAs Zebrafish Zebrafish measures Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.

Downstream

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both number of hair cells per crista as well as stereocilia length reduced"

Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.

Reduced Otolith Size

Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.

Animal models

Transient F0 naa80 CRISPR targeting with two sgRNAs Zebrafish Zebrafish measures Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.

Downstream

High-frequency sensorineural hearing impairment Reduced otolith size accompanies the larval acoustic-response defect. Whether it mediates that response or informs the specific human cochlear lesion is unresolved.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"However, we observed a reduction in otolith size compared with controls following Cas9 protein injection"

Otolith size was reduced in F0 larvae compared with Cas9-injected controls.

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Pathograph

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

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Phenotypes

Cardiovascular 1

Reduced systolic function HP:0006673

Severity: MILD

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cardiac evaluation revealed mild systolic dysfunction, but no other abnormalities."

The cardiac finding in the elder brother, and the only cardiac measurement reported in either individual.

Digestive 3

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections."

Reports feeding difficulties in the elder brother.

Chronic constipation HP:0012450

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives."

Reports constipation severe enough to need laxatives.

Vomiting HP:0002013

Temporal: RECURRENT

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections."

Reports the vomiting among the elder brother's episodic features.

Ear 3

High-frequency sensorineural hearing impairment HP:0001757

Course: PROGRESSIVE

Show evidence (2 references)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"he was diagnosed with bilateral high-frequency sensorineural hearing loss of 40 dB at the age of five weeks"

The elder brother's audiological diagnosis and its age of detection.

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In addition, a bilateral sensorineural hearing loss of 70 dB, most prominent in the high frequency 3 kHz area, was detected."

The younger brother's hearing loss, with its severity and frequency profile.

Protruding ear HP:0000411

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers"

Reports protruding ears in the elder brother.

Low-set ears HP:0000369

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Reports low-set ears in the elder brother.

Eye 2

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips"

Confirms hypertelorism in the younger brother and states that the elder shares the pattern.

Ptosis HP:0000508

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Front view of proband 1.2 at the age of 7 years showing small upper lip, hypertelorism, abnormally shaped ears, ptosis and epicanthus fold."

Photographic documentation of ptosis in the elder brother.

Head and Neck 10

Low posterior hairline HP:0002162

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Lists the low posterior hairline as shared by both brothers.

Highly arched eyebrow HP:0002553

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Lists highly arched eyebrows as shared by both brothers.

Narrow mouth HP:0000160

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Lists the small mouth as shared by both brothers.

Thin upper lip vermilion HP:0000219

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Reports thin lips in the younger brother.

Retrognathia HP:0000278

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Lateral view of proband 1.2 showing retrognathia."

Photographic documentation of retrognathia in the elder brother.

Epicanthus HP:0000286

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Front view of proband 1.2 at the age of 7 years showing small upper lip, hypertelorism, abnormally shaped ears, ptosis and epicanthus fold."

Photographic documentation of the epicanthic fold.

Diastema HP:0000699

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Reports the diastema in the elder brother.

Peg-shaped maxillary lateral incisors HP:0006342

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Confirms the peg-shaped lateral incisors in both brothers.

Long philtrum HP:0000343

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Front view of proband 1.4 at the age of 1 year showing small upper lip, long philtrum, bulbous tip of the nose, ptosis, epicanthus fold, ocular hypertelorism, abnormally shaped ears."

Photographic documentation of the long philtrum in the younger brother.

Bulbous nose HP:0000414

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Front view of proband 1.4 at the age of 1 year showing small upper lip, long philtrum, bulbous tip of the nose, ptosis, epicanthus fold, ocular hypertelorism, abnormally shaped ears."

Photographic documentation of the bulbous nasal tip in the younger brother.

Limbs 2

Tapered finger HP:0001182

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Reports tapered fingers in the elder brother.

Disorganized implant of the toes Abnormal toe morphology HP:0001780

Coarse binding: source unspecified

The source does not specify overlapping, deviated or widely spaced toes, so a more specific morphology is not assigned.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Reports the toe finding in the elder brother.

Metabolism 1

Peripheral edema HP:0012398

Temporal: RECURRENT

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections."

Reports the swelling of the extremities among the elder brother's episodic features.

Musculoskeletal 3

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections."

Reports periodic hypotonia in the elder brother.

Proximal muscle weakness HP:0003701

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness."

States proximal weakness in both affected individuals.

Axial muscle weakness HP:0003327

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness."

States axial weakness in both affected individuals.

Nervous System 8

Neurodevelopmental delay HP:0012758

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall development was mildly delayed, with an estimated intelligence quotient of 79 at the age of three."

Quantifies the degree of delay in the elder brother.

Gait ataxia HP:0002066

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives."

Lists gait ataxia among the reported features.

Reduced cerebral white matter volume HP:0034295

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI revealed an enlarged right lateral ventricle system, a decreased amount of white matter volume and asymmetrical subcortical white matter lesions"

Reports the white matter findings on MRI.

Lateral ventricle dilatation HP:0006956

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI revealed an enlarged right lateral ventricle system, a decreased amount of white matter volume and asymmetrical subcortical white matter lesions"

Reports the ventricular enlargement on MRI.

Self-injurious behavior HP:0100716

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He had behavioural disturbances, including rage and auto-mutilation, triggered by either loud noises or visual images."

Reports the self-injurious behaviour and its sensory triggers.

Sleep apnea HP:0010535

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additionally, he has multiple obstructive and central apnoeas per night (not resulting in hypoxia)."

Reports both obstructive and central events, which is why the entry does not attribute the apnoea wholly to craniofacial structure.

Loud snoring HP:0025372

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives."

Lists loud snoring among the reported features.

Sleep disturbance HP:0002360

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives."

The clinical narrative reports difficulty sleeping.

Constitutional 1

Fatigue HP:0012378

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections."

Reports fatigue among the elder brother's ongoing symptoms.

🧬

Genetic Associations

NAA80 (Homozygous c.389T>C, p.(Leu130Pro) in the catalytic domain)

Gene: NAA80 hgnc:30252 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:34805998 SUPPORT PRIMARY RESULT Human Clinical

"We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant."

Identifies the allele and the number of affected individuals carrying it.

PMID:34805998 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Based on the molecular structure, we predicted and confirmed the NAA80 c.389T>C, p.(Leu130Pro) variant to result in protein destabilization, causing severely decreased NAA80 protein availability."

Functional evidence that the allele is deleterious, which is what carries the gene-disease assertion in a single family. INDIRECT because protein destabilization is a step short of the disease.

🗃️

External Assertions

OMIM auroneurodental syndrome record

OMIM disease record OMIM:620830

OMIM phenotype record corresponding to MONDO:0970998 and the NAA80-associated syndrome.

ClinVar NAA80 c.389T>C p.(Leu130Pro)

ClinVar variant classification VCV001301869

ClinVar reports aggregate Pathogenic/Likely pathogenic classification from two submissions, without assertion criteria provided. This external classification is not independent replication of the family report.

Checked 2026-09-21 at VCV001301869.6. The preferred transcript is NM_001200016.2:c.323T>C (p.Leu108Pro), whereas the paper uses c.389T>C (p.Leu130Pro). Both refer to GRCh37 chr3:g.50334572A>G. The submitting laboratory and OMIM cite the same original family; submission observation counts include relatives and functional assays and must not be counted as additional affected families.

💊

Medical Actions

Laxatives for constipation

Action: Laxatives for constipation Ontology label: Pharmacotherapy NCIT:C15986

Agent: Laxative NCIT:C29697

Platform: Other

The elder brother required laxatives for mild constipation. The report does not identify a drug, dose or quantified response.

Mechanism Target:

MODULATES Chronic constipation — Symptomatic support; no correction of NAA80 or actin acetylation is established.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives."

The original clinical report documents this symptomatic treatment.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives."

The original clinical report documents this symptomatic treatment.

Hearing aids and individualized hearing habilitation

Action: Hearing aids and individualized hearing habilitation Ontology label: Supportive Care NCIT:C15747

Platform: Device

General genetic-hearing-loss guidance supports audiologist-fitted hearing aids for mild-to-severe loss, guided by the individual’s hearing profile and communication goals. NAA80-specific aided outcomes have not been reported.

Mechanism Target:

MODULATES High-frequency sensorineural hearing impairment — Symptomatic support; no correction of NAA80 or actin acetylation is established.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."

General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."

General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.

Communication and early developmental support

Action: Supportive Care NCIT:C15747

Platform: Other

General pediatric hearing-loss care includes speech-language support, access to sign language according to family goals, and early intervention for assessed developmental needs. This is supportive guidance, not evidence of reversing the NAA80 developmental phenotype.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Referral to an early intervention program is recommended for access to occupational, physical, speech-language, and feeding therapy as well as specialized D/deaf and hard of hearing (DHH) services to support DHH identity development in the child and family."

General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.

Audiologic and multisystem follow-up

Action: Supportive Care NCIT:C15747

Platform: Other

Sequential audiologic assessment can document stability or progression. Additional specialty evaluation should respond to the child’s findings, including the reported apnea, developmental, motor and cardiac abnormalities; no syndrome-specific testing interval has been established.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Perform sequential audiologic examinations that: ... Document the stability or progression of the hearing loss;"

General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.

Cochlear implant assessment when hearing severity warrants

Action: Cochlear implant assessment when hearing severity warrants Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cochlear implantation is a general option for eligible children with severe-to-profound hearing loss, assessed by a specialist team. Neither implant use nor efficacy was reported in the founding NAA80 family, and it cannot be assumed from cell rescue.

Mechanism Target:

MODULATES High-frequency sensorineural hearing impairment — Symptomatic support; no correction of NAA80 or actin acetylation is established.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."

General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."

General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.

🔬

Diagnosis

Molecular testing and family segregation

The founding family was investigated with trio exome sequencing and Sanger segregation. Evaluation should consider the clinical pattern, allele interpretation and other segregating variants; homozygosity or a VUS alone is not diagnostic.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Sanger sequencing confirmed homozygosity for the same variant in NAA80: c.389T>C, p.(L130P) in proband 1.4, but not in healthy probands 1.1 and 1.3"

Segregation supports the familial association, alongside functional evidence.

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"The identification of variant(s) of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis."

General genetic-hearing-loss diagnostic interpretation.

Audiometry and clinical phenotyping

Age-appropriate audiologic testing establishes type, severity and frequency profile of hearing loss. Clinical examination assesses associated craniofacial, dental, developmental and neuromuscular findings; hearing loss alone does not distinguish NAA80 from other genetic causes.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Hearing status can be determined at any age and is tailored to the individual's ability to participate"

General age-appropriate hearing assessment guidance.

Research assessment of actin acetylation

Isotope-assisted mass spectrometry and patient-cell rescue provided functional support for the reported allele. These assays are research evidence, without established clinical sensitivity, specificity or diagnostic cutoffs.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.

📊

Prevalence

Individuals described in the founding NAA80 clinical report

Cases In Literature Ultra Rare

Two affected brothers in one family were reported. This case count provides neither an incidence nor a population prevalence estimate.

Show evidence (1 reference)

PMID:34805998 SUPPORT PRIMARY RESULT Human Clinical

"We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant."

States the number of reported individuals and that they are one family.

🧫

Experimental Models

Patient fibroblasts and peripheral blood mononuclear cells PRIMARY_CELL_CULTURE

Patient cells were compared with healthy-donor cells; control donor numbers varied by assay and could not be age- and sex-matched. Wild-type NAA80 rescue was performed in the elder brother’s fibroblasts. Technical replicates do not expand the number of patients.

Organism

human NCBITaxon:9606

Cell source

Skin fibroblasts from the elder brother; PBMCs from both brothers

Publication

PMID:34805998

Pathograph links

Reduced Actin N-Terminal Acetylation measures fidelity: high N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.

Limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.

Readouts

Fraction of unacetylated beta- and gamma-actin

Direction: INCREASED

Interpretation: N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.

Increased Filamentous Actin Content measures fidelity: high Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.

Limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.

Readouts

Phalloidin fluorescence

Direction: INCREASED

Interpretation: Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, NAA80 individual PBMCs and fibroblasts displayed increased phalloidin staining, corresponding with increased levels of polymerized actin"

Phalloidin fluorescence measures filamentous actin content, not polymerization flux.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Indeed, NAA80 individual PBMCs and fibroblasts displayed increased phalloidin staining, corresponding with increased levels of polymerized actin"

Phalloidin fluorescence measures filamentous actin content, not polymerization flux.

Increased Filopodia Formation measures fidelity: high Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.

Limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.

Readouts

Fibroblast filopodia count

Direction: INCREASED

Interpretation: Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In NAA80 individual fibroblasts, increased filopodia counts were observed"

Filopodia were counted in fibroblasts from the elder brother; this was not a PBMC filopodia assay.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In NAA80 individual fibroblasts, increased filopodia counts were observed"

Filopodia were counted in fibroblasts from the elder brother; this was not a PBMC filopodia assay.

Increased Cell Migration measures fidelity: high Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.

Limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.

Readouts

Chemotactic migration

Direction: INCREASED

Interpretation: Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Both fibroblasts and PBMCs of NAA80 individuals showed increased movement in response to chemotactic stimuli"

Boyden chamber assays measured migration in patient-derived cells.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Both fibroblasts and PBMCs of NAA80 individuals showed increased movement in response to chemotactic stimuli"

Boyden chamber assays measured migration in patient-derived cells.

Wild-type and p.Leu130Pro NAA80 reconstitution in HAP1 knockout cells CELL_LINE

Wild-type or patient-variant NAA80 was expressed with promoters of different strengths. Mutant protein levels were lower; stronger expression restored acetylated-actin signal. This separates reduced availability from complete catalytic inactivity, without measuring precise acetylation percentages or equal-concentration enzyme kinetics.

Organism

human NCBITaxon:9606

Publication

PMID:34805998

Pathograph links

Reduced NAA80 Protein Abundance measures fidelity: moderate Mutant NAA80 abundance is lower across the tested promoters.

Limitations: Engineered cell-line expression, not a patient protein-half-life measurement.

Readouts

NAA80 western-blot abundance

Direction: DECREASED

Interpretation: Mutant NAA80 abundance is lower across the tested promoters.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters"

Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters"

Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.

Reduced Actin N-Terminal Acetylation measures fidelity: moderate Weak-promoter mutant expression incompletely restores actin acetylation; stronger expression can approach maximal signal.

Limitations: Western blots are not precise quantification, and expression levels differ.

Readouts

Acetylated-actin western-blot signal

Direction: DECREASED

Interpretation: Weak-promoter mutant expression incompletely restores actin acetylation; stronger expression can approach maximal signal.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Use of the weakest promoter resulted in partial restoration of actin acetylation"

The experiment demonstrates residual activity under expression-dependent conditions.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Use of the weakest promoter resulted in partial restoration of actin acetylation"

The experiment demonstrates residual activity under expression-dependent conditions.

CRISPR NAA80 knockout HAP1 cells CELL_LINE

Two knockout clones were compared with control cells and reconstituted with wild-type or engineered catalytically inactive NAA80. The inactive construct carries W105F/R170Q/G173D/Y205F and is not the patient allele. Migration, protrusions, G/F-actin ratios and latrunculin recovery were measured.

Organism

human NCBITaxon:9606

Publication

PMID:29581253

Pathograph links

Reduced Actin N-Terminal Acetylation measures fidelity: moderate Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.

Limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.

Readouts

Acetylated beta/gamma-actin

Direction: ABOLISHED

Interpretation: Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Furthermore, both actin isoforms were 100% and 0% Nt-acetylated in control and NAA80 KO1 cells, respectively."

Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Furthermore, both actin isoforms were 100% and 0% Nt-acetylated in control and NAA80 KO1 cells, respectively."

Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.

Increased Filamentous Actin Content measures fidelity: moderate The measured globular-to-filamentous actin ratio decreased in knockout cells.

Limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.

Readouts

G/F-actin ratio

Direction: DECREASED

Interpretation: The measured globular-to-filamentous actin ratio decreased in knockout cells.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"from 0.73 in HAP1 control cells to 0.55 in NAA80 KO1 cells"

The measured globular-to-filamentous actin ratio decreased in knockout cells.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"from 0.73 in HAP1 control cells to 0.55 in NAA80 KO1 cells"

The measured globular-to-filamentous actin ratio decreased in knockout cells.

Increased Filopodia Formation measures fidelity: moderate Knockout cells had more filopodia-like protrusions.

Limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.

Readouts

Filopodia-like protrusion count

Direction: INCREASED

Interpretation: Knockout cells had more filopodia-like protrusions.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These cells showed an approximately fourfold increase in the number of filopodia-like structures, defined as phalloidin-stained protrusions with a length ≥0.5 µm"

Knockout cells had more filopodia-like protrusions.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These cells showed an approximately fourfold increase in the number of filopodia-like structures, defined as phalloidin-stained protrusions with a length ≥0.5 µm"

Knockout cells had more filopodia-like protrusions.

Increased Cell Migration measures fidelity: moderate Directed and random migration increased in knockout cells.

Limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.

Readouts

Cell migration

Direction: INCREASED

Interpretation: Directed and random migration increased in knockout cells.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Taken together these data demonstrate that cells deficient in actin Nt-acetylation have increased motility."

Directed and random migration increased in knockout cells.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Taken together these data demonstrate that cells deficient in actin Nt-acetylation have increased motility."

Directed and random migration increased in knockout cells.

Purified acetylated and nonacetylated beta/gamma-actin OTHER

Actin purified from control and NAA80-knockout HAP1 cells was tested in bulk pyrene assays, seeded elongation/depolymerization and assays with Arp2/3, mDia1/mDia2 and profilins. The effect depends on the reaction and actin-binding proteins.

Publication

PMID:29581253

Pathograph links

Slower Actin Filament Elongation measures fidelity: moderate Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.

Limitations: Cell-free preparations; unseeded polymerization and several nucleation conditions were unchanged.

Readouts

Seeded barbed-end elongation rate

Direction: DECREASED

Interpretation: Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red)."

Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red)."

Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.

Slower Actin Filament Depolymerization measures fidelity: moderate Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.

Limitations: Cell-free depolymerization does not establish the net tissue filament burden.

Readouts

Filament depolymerization rate

Direction: DECREASED

Interpretation: Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red)."

The purified-filament assay measured slower depolymerization without acetylation.

Show evidence (1 reference)

PMID:29581253 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red)."

The purified-filament assay measured slower depolymerization without acetylation.

Recombinant NAA80 p.Leu130Pro solubility assay OTHER

His-tagged wild-type and mutant human NAA80 were expressed in Escherichia coli and soluble versus sedimented fractions assessed by SDS-PAGE/western blot. The result is consistent with misfolding, without a mutant structural determination or degradation-rate assay.

Publication

PMID:34805998

Pathograph links

Reduced NAA80 Protein Abundance measures fidelity: moderate Mutant recombinant protein preferentially partitions into the insoluble fraction.

Limitations: Bacterial expression and solubility are proxies for folding-related availability, not patient-cell half-life.

Readouts

Soluble recombinant mutant NAA80 fraction

Direction: DECREASED

Interpretation: Mutant recombinant protein preferentially partitions into the insoluble fraction.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mutant protein was predominantly insoluble, contrasting with wild-type protein, which was essentially soluble, with only a very small proportion in the sediment"

Experimental solubility supports the structural prediction but does not directly determine mutant folding.

Show evidence (1 reference)

PMID:34805998 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mutant protein was predominantly insoluble, contrasting with wild-type protein, which was essentially soluble, with only a very small proportion in the sediment"

Experimental solubility supports the structural prediction but does not directly determine mutant folding.

🐁

Animal Models

Stable naa80 5del/1in and 13del frameshift lines Zebrafish Genetic

Stable frameshift lines supplied adult heart and skeletal-muscle proteomics and gross development/body-size observations. Homozygotes had little to no detectable acetylated actin peptides; one low-intensity acetylated peptide could reflect carryover or residual alternative activity. These were separate from the F0 ear experiments.

Species

Zebrafish

Genotype

Stable naa80 5del/1in and 13del frameshift lines

Publication

PMID:39384430

Pathograph links

Reduced Actin N-Terminal Acetylation measures fidelity: moderate Muscle and heart samples show little to no detectable N-terminally acetylated actin in homozygotes.

Limitations: Different tissues and species from patient fibroblasts; the method cannot estimate site occupancy. Gross behavior does not exclude stress-dependent or human muscle dysfunction.

Readouts

Acetylated actin peptide signal

Direction: DECREASED

Interpretation: Muscle and heart samples show little to no detectable N-terminally acetylated actin in homozygotes.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, in the naa80 −/− samples from both knockout lines, we found little to no detectable Nt-acetylated actin"

Adult stable-line proteomics supports the conserved enzyme-substrate relationship.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, in the naa80 −/− samples from both knockout lines, we found little to no detectable Nt-acetylated actin"

Adult stable-line proteomics supports the conserved enzyme-substrate relationship.

Routine swimming and feeding appeared comparable to controls; endurance, muscle force and stress testing were not performed. One line’s females failed to yield eggs, while 13del homozygous incrosses eventually produced viable larvae; universal infertility is not established.

Transient F0 naa80 CRISPR targeting with two sgRNAs Zebrafish Genetic

Five-day larvae generated by injection of Cas9 protein and two sgRNAs were compared with Cas9-injected controls. Reduced naa80 transcript, ear structural abnormalities and reduced acoustic startle were observed. These experiments do not directly quantify acetylation in F0 hair cells or provide Naa80 rescue.

Species

Zebrafish

Genotype

Transient F0 naa80 CRISPR targeting with two sgRNAs

Publication

PMID:39384430

Pathograph links

Reduced Inner-Ear Hair-Cell Bundles measures fidelity: moderate Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.

Limitations: F0 perturbation with no rescue or direct hair-cell acetylation/dynamics assay; relevance to human cochlear pathology is inferred.

Readouts

Lateral-crista hair-cell bundle count

Direction: DECREASED

Interpretation: Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls"

Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls"

Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.

Shortened Hair-Cell Stereocilia measures fidelity: moderate Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.

Limitations: F0 perturbation with no rescue or direct hair-cell acetylation/dynamics assay; relevance to human cochlear pathology is inferred.

Readouts

Lateral-crista stereocilia length

Direction: DECREASED

Interpretation: Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both number of hair cells per crista as well as stereocilia length reduced"

Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both number of hair cells per crista as well as stereocilia length reduced"

Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.

Reduced Otolith Size measures fidelity: moderate Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.

Limitations: F0 perturbation with no rescue or direct hair-cell acetylation/dynamics assay; relevance to human cochlear pathology is inferred.

Readouts

Otolith size

Direction: DECREASED

Interpretation: Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"However, we observed a reduction in otolith size compared with controls following Cas9 protein injection"

Otolith size was reduced in F0 larvae compared with Cas9-injected controls.

Show evidence (1 reference)

PMID:39384430 SUPPORT DIRECT PRIMARY RESULT Model Organism

"However, we observed a reduction in otolith size compared with controls following Cas9 protein injection"

Otolith size was reduced in F0 larvae compared with Cas9-injected controls.

The acoustic endpoint used 48 larvae per group and is a sensory-motor response, not a frequency-specific audiogram. Yo-Pro-1-positive cells were counted in lateral-line neuromasts (12 control/13 targeted larvae), not used as an inner-ear apoptosis assay. Stereocilia measurements are nested within three larvae per group.

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Source YAML

click to show

name: Auroneurodental Syndrome
creation_date: '2026-09-04T00:00:00Z'
category: Mendelian
description: An autosomal recessive NAA80-associated syndrome reported in two brothers with progressive high-frequency sensorineural hearing impairment, craniofacial and dental abnormalities, developmental delay and mild proximal and axial muscle weakness. The reported p.Leu130Pro allele reduces NAA80 abundance and actin N-terminal acetylation in sampled cells. Patient-cell and knockout experiments show altered filament content, protrusions and migration, while separate zebrafish experiments support a hearing-related role. The routes to individual human organ manifestations remain incompletely resolved.
disease_term:
  preferred_term: auroneurodental syndrome
  term:
    id: MONDO:0970998
    label: auroneurodental syndrome
parents:
- hereditary disease
- Neurodevelopmental Disorder
synonyms:
- NAA80-related syndrome
- AURDENS
notes: Clinical observations derive from two related individuals, so no phenotype-frequency bands or population prevalence are inferred. NAA80 functional evidence is substantial, but the co-segregating PLXNB1 variant leaves possible contributions to individual features unresolved. Cellular rescue is experimental and does not establish a clinical treatment. Search by NAA80 or OMIM 620830 to distinguish this disorder from FGF3-related labyrinthine aplasia-microtia-microdontia syndrome.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: Both affected brothers are homozygous for NAA80 c.389T>C, p.(Leu130Pro); both parents are heterozygous and unaffected, and the two healthy siblings do not carry the variant in the homozygous state. A large run of homozygosity and shared parental geographic origin indicate distant consanguinity.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant.
    explanation: States the homozygous state in both affected individuals.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both parents were heterozygous for this variant.
    explanation: Unaffected heterozygous parents complete the recessive segregation argument.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Biallelic NAA80 Dysfunction
  biological_scale: MOLECULAR
  description: The reported family carries homozygous NAA80 c.389T>C, p.(Leu130Pro), a hypomorphic allele with residual activity in expression assays. Molecular and cellular experiments support NAA80 dysfunction. Attribution of every clinical feature remains limited by one family and a co-segregating PLXNB1 variant.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant.
    explanation: The clinical association is based on two affected brothers in one family.
  genes:
  - preferred_term: NAA80
    term:
      id: hgnc:30252
      label: NAA80
  genetic_context:
    gene:
      preferred_term: NAA80
      term:
        id: hgnc:30252
        label: NAA80
    allele_type: MISSENSE
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: The reported p.Leu130Pro allele retains acetylation activity when expressed strongly in knockout HAP1 cells. This is functional evidence for a partial loss of function, without a validated human residual-activity or viability threshold.
  downstream:
  - target: Reduced NAA80 Protein Abundance
    causal_link_type: DIRECT
    description: Mutant reconstitution reduces protein abundance relative to wild type across tested promoters.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters
      explanation: Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.
  - target: High-frequency sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: he was diagnosed with bilateral high-frequency sensorineural hearing loss of 40 dB at the age of five weeks
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Neurodevelopmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Overall development was mildly delayed, with an estimated intelligence quotient of 79 at the age of three.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Peripheral edema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Vomiting
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Proximal muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Axial muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Gait ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Reduced cerebral white matter volume
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI revealed an enlarged right lateral ventricle system, a decreased amount of white matter volume and asymmetrical subcortical white matter lesions
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Lateral ventricle dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI revealed an enlarged right lateral ventricle system, a decreased amount of white matter volume and asymmetrical subcortical white matter lesions
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Self-injurious behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had behavioural disturbances, including rage and auto-mutilation, triggered by either loud noises or visual images.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Sleep apnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Additionally, he has multiple obstructive and central apnoeas per night (not resulting in hypoxia).
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Loud snoring
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Chronic constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Low posterior hairline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Highly arched eyebrow
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Protruding ear
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Narrow mouth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Thin upper lip vermilion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Retrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Lateral view of proband 1.2 showing retrognathia.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Front view of proband 1.2 at the age of 7 years showing small upper lip, hypertelorism, abnormally shaped ears, ptosis and epicanthus fold.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Epicanthus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Front view of proband 1.2 at the age of 7 years showing small upper lip, hypertelorism, abnormally shaped ears, ptosis and epicanthus fold.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Diastema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Peg-shaped maxillary lateral incisors
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Tapered finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Reduced systolic function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cardiac evaluation revealed mild systolic dysfunction, but no other abnormalities.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Disorganized implant of the toes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Long philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Front view of proband 1.4 at the age of 1 year showing small upper lip, long philtrum, bulbous tip of the nose, ptosis, epicanthus fold, ocular hypertelorism, abnormally shaped ears.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Bulbous nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype-associated manifestation in the reported family, with unresolved intermediates and no demonstrated tissue-specific actin mechanism.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Front view of proband 1.4 at the age of 1 year showing small upper lip, long philtrum, bulbous tip of the nose, ptosis, epicanthus fold, ocular hypertelorism, abnormally shaped ears.
      explanation: Observed in the reported NAA80 family; tissue-specific mediation and possible co-variant contributions remain unresolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Sleep disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in the affected brothers; the contribution of sensory, neurological or other factors remains unresolved.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
      explanation: Clinical association in the reported family, without a resolved biological route to sleep disturbance.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Reduced NAA80 Protein Abundance
  biological_scale: MOLECULAR
  description: NAA80 protein is reduced in patient fibroblasts and after mutant reconstitution in HAP1 cells. Recombinant mutant protein is predominantly insoluble, consistent with predicted fold disruption. Mutant structure, folding kinetics and patient protein half-life were not directly measured.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters
    explanation: Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.
  downstream:
  - target: Reduced Actin N-Terminal Acetylation
    causal_link_type: DIRECT
    description: Lower available mutant enzyme contributes to incomplete actin acetylation; stronger mutant expression can restore the western-blot signal toward wild type.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Use of the weakest promoter resulted in partial restoration of actin acetylation, as determined by western blotting with antibodies specific for the acetylated form of beta actin, while stronger promoters led to maximal or near maximal acetylation, indicating that the mutated protein still shows residual activity
      explanation: Expression-dependent rescue supports an abundance-related defect, but does not quantify catalytic activity at equal enzyme concentration.
- name: Reduced Actin N-Terminal Acetylation
  biological_scale: MOLECULAR
  description: N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.
  evidence:
  - &id002
    reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In healthy donors, ∼0.5% of beta and gamma-actins were not acetylated. However, for the NAA80 individuals, 25–65% of beta and gamma-actins were not acetylated, depending on the cell type and the type of cytoplasmic actin
    explanation: Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.
  molecular_functions:
  - preferred_term: protein-N-terminal amino-acid acetyltransferase activity
    term:
      id: GO:0004596
      label: protein-N-terminal amino-acid acetyltransferase activity
    modifier: DECREASED
  downstream:
  - target: Slower Actin Filament Elongation
    causal_link_type: DIRECT
    description: Loss of acetylation slows elongation in purified seeded-filament assays.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
      explanation: Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.
  - target: Slower Actin Filament Depolymerization
    causal_link_type: DIRECT
    description: Loss of acetylation slows depolymerization in the purified-filament assay.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
      explanation: The purified-filament assay measured slower depolymerization without acetylation.
  - target: Increased Filamentous Actin Content
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: NAA80 loss and wild-type rescue connect the modification defect with this cultured-cell phenotype; the intervening regulatory processes are incompletely resolved.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Expressing wild-type NAA80 with the SV40 promoter in NAA80 individual fibroblasts normalized phalloidin staining intensity
      explanation: Wild-type NAA80 rescue supports a cellular connection; it does not isolate each actin-dependent intermediate.
  - target: Increased Filopodia Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: NAA80 loss and wild-type rescue connect the modification defect with this cultured-cell phenotype; the intervening regulatory processes are incompletely resolved.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: The introduction of wild-type NAA80 protein with the SV40 promoter lowered filopodia counts to the level observed in healthy controls
      explanation: Wild-type NAA80 rescue supports a cellular connection; it does not isolate each actin-dependent intermediate.
  - target: Increased Cell Migration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: NAA80 loss and wild-type rescue connect the modification defect with this cultured-cell phenotype; the intervening regulatory processes are incompletely resolved.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: In fibroblasts, expression of NAA80 wild-type with the SV40 promoter protein lowered migration levels to the level observed in healthy controls
      explanation: Wild-type NAA80 rescue supports a cellular connection; it does not isolate each actin-dependent intermediate.
  - target: Reduced Inner-Ear Hair-Cell Bundles
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: 'A proposed in-vivo extension of the acetylation mechanism: stable knockout muscle proteomics and separate F0 ear phenotyping support the model, but acetylation was not measured in the affected F0 ear cells.'
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls
      explanation: Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.
  - target: Shortened Hair-Cell Stereocilia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: 'A proposed in-vivo extension of the acetylation mechanism: stable knockout muscle proteomics and separate F0 ear phenotyping support the model, but acetylation was not measured in the affected F0 ear cells.'
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: both number of hair cells per crista as well as stereocilia length reduced
      explanation: Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.
  - target: Reduced Otolith Size
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: 'A proposed in-vivo extension of the acetylation mechanism: stable knockout muscle proteomics and separate F0 ear phenotyping support the model, but acetylation was not measured in the affected F0 ear cells.'
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: However, we observed a reduction in otolith size compared with controls following Cas9 protein injection
      explanation: Otolith size was reduced in F0 larvae compared with Cas9-injected controls.
- name: Slower Actin Filament Elongation
  biological_scale: MOLECULAR
  description: Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.
  biological_processes:
  - preferred_term: actin filament polymerization
    term:
      id: GO:0030041
      label: actin filament polymerization
    modifier: DECREASED
  evidence:
  - reference: PMID:29581253
    reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
    explanation: Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.
- name: Slower Actin Filament Depolymerization
  biological_scale: MOLECULAR
  description: Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.
  biological_processes:
  - preferred_term: actin filament depolymerization
    term:
      id: GO:0030042
      label: actin filament depolymerization
    modifier: DECREASED
  evidence:
  - reference: PMID:29581253
    reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
    explanation: The purified-filament assay measured slower depolymerization without acetylation.
- name: Increased Filamentous Actin Content
  biological_scale: CELLULAR
  description: Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Indeed, NAA80 individual PBMCs and fibroblasts displayed increased phalloidin staining, corresponding with increased levels of polymerized actin
    explanation: Phalloidin fluorescence measures filamentous actin content, not polymerization flux.
- name: Increased Filopodia Formation
  biological_scale: CELLULAR
  description: Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In NAA80 individual fibroblasts, increased filopodia counts were observed
    explanation: Filopodia were counted in fibroblasts from the elder brother; this was not a PBMC filopodia assay.
- name: Increased Cell Migration
  biological_scale: CELLULAR
  description: Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.
  biological_processes:
  - preferred_term: cell migration
    term:
      id: GO:0016477
      label: cell migration
    modifier: INCREASED
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Both fibroblasts and PBMCs of NAA80 individuals showed increased movement in response to chemotactic stimuli
    explanation: Boyden chamber assays measured migration in patient-derived cells.
- name: Reduced Inner-Ear Hair-Cell Bundles
  biological_scale: CELLULAR
  description: Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.
  cellular_components:
  - preferred_term: stereocilium bundle
    term:
      id: GO:0032421
      label: stereocilium bundle
    modifier: DECREASED
  cell_types:
  - preferred_term: sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  evidence:
  - reference: PMID:39384430
    reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls
    explanation: Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.
  downstream:
  - target: High-frequency sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The larval structural abnormality accompanies reduced acoustic responses and provides a candidate route relevant to hearing. It does not establish mediation, human cochlear pathology or high-frequency specificity.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Moreover, the KOs demonstrated a reduced acoustic startle response compared with controls (Fig 6I), suggesting a hearing impairment.
      explanation: Acoustic startle is a sensory-motor proxy in larvae, not a human audiogram.
- name: Shortened Hair-Cell Stereocilia
  biological_scale: CELLULAR
  description: Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.
  biological_processes:
  - preferred_term: inner ear receptor cell stereocilium organization
    term:
      id: GO:0060122
      label: inner ear receptor cell stereocilium organization
  cell_types:
  - preferred_term: sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  evidence:
  - reference: PMID:39384430
    reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: both number of hair cells per crista as well as stereocilia length reduced
    explanation: Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.
  downstream:
  - target: High-frequency sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The larval structural abnormality accompanies reduced acoustic responses and provides a candidate route relevant to hearing. It does not establish mediation, human cochlear pathology or high-frequency specificity.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Moreover, the KOs demonstrated a reduced acoustic startle response compared with controls (Fig 6I), suggesting a hearing impairment.
      explanation: Acoustic startle is a sensory-motor proxy in larvae, not a human audiogram.
- name: Reduced Otolith Size
  biological_scale: TISSUE
  description: Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.
  evidence:
  - reference: PMID:39384430
    reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: However, we observed a reduction in otolith size compared with controls following Cas9 protein injection
    explanation: Otolith size was reduced in F0 larvae compared with Cas9-injected controls.
  downstream:
  - target: High-frequency sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced otolith size accompanies the larval acoustic-response defect. Whether it mediates that response or informs the specific human cochlear lesion is unresolved.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Moreover, the KOs demonstrated a reduced acoustic startle response compared with controls (Fig 6I), suggesting a hearing impairment.
      explanation: The coincident larval findings support a hypothesis rather than a resolved human mechanism.
phenotypes:
- name: High-frequency sensorineural hearing impairment
  category: Auditory
  description: Bilateral, progressive, high-frequency sensorineural hearing loss — 40 dB in the elder brother detected at five weeks of age, and 70 dB in the younger, most prominent around 3 kHz.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he was diagnosed with bilateral high-frequency sensorineural hearing loss of 40 dB at the age of five weeks
    explanation: The elder brother's audiological diagnosis and its age of detection.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, a bilateral sensorineural hearing loss of 70 dB, most prominent in the high frequency 3 kHz area, was detected.
    explanation: The younger brother's hearing loss, with its severity and frequency profile.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Neurodevelopmental delay
  category: Neurodevelopmental
  description: Overall development was mildly delayed in the elder brother, with an estimated IQ of 79 at age three. The clinical narrative does not establish a standardized global, multidomain assessment.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Overall development was mildly delayed, with an estimated intelligence quotient of 79 at the age of three.
    explanation: Quantifies the degree of delay in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Hypotonia
  category: Neuromuscular
  description: Periodic hypotonia in both brothers.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
    explanation: Reports periodic hypotonia in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Feeding difficulties
  category: Gastrointestinal
  description: Feeding difficulties reported in both brothers.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
    explanation: Reports feeding difficulties in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Fatigue
  category: Constitutional
  description: Fatigue reported alongside the periodic hypotonia.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
    explanation: Reports fatigue among the elder brother's ongoing symptoms.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Proximal muscle weakness
  category: Neuromuscular
  description: Mild proximal limb weakness in both brothers.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness.
    explanation: States proximal weakness in both affected individuals.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Axial muscle weakness
  category: Neuromuscular
  description: Mild axial weakness in both brothers.
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness.
    explanation: States axial weakness in both affected individuals.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Gait ataxia
  category: Neurological
  description: Reported among the elder brother's additional features.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
    explanation: Lists gait ataxia among the reported features.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Reduced cerebral white matter volume
  category: Neuroimaging
  description: Decreased white matter volume with asymmetrical subcortical white matter lesions on brain MRI.
  phenotype_term:
    preferred_term: Reduced cerebral white matter volume
    term:
      id: HP:0034295
      label: Reduced cerebral white matter volume
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI revealed an enlarged right lateral ventricle system, a decreased amount of white matter volume and asymmetrical subcortical white matter lesions
    explanation: Reports the white matter findings on MRI.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Lateral ventricle dilatation
  category: Neuroimaging
  description: An enlarged right lateral ventricle system on brain MRI.
  phenotype_term:
    preferred_term: Lateral ventricle dilatation
    term:
      id: HP:0006956
      label: Lateral ventricle dilatation
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI revealed an enlarged right lateral ventricle system, a decreased amount of white matter volume and asymmetrical subcortical white matter lesions
    explanation: Reports the ventricular enlargement on MRI.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Self-injurious behavior
  category: Behavioral
  description: Auto-mutilation as part of a behavioural disturbance triggered by loud noises or visual images.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had behavioural disturbances, including rage and auto-mutilation, triggered by either loud noises or visual images.
    explanation: Reports the self-injurious behaviour and its sensory triggers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Sleep apnea
  category: Respiratory
  description: Multiple obstructive and central apnoeas per night in the younger brother, without resulting hypoxia.
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, he has multiple obstructive and central apnoeas per night (not resulting in hypoxia).
    explanation: Reports both obstructive and central events, which is why the entry does not attribute the apnoea wholly to craniofacial structure.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Loud snoring
  category: Respiratory
  description: Loud snoring reported with sleeping difficulties.
  phenotype_term:
    preferred_term: Loud snoring
    term:
      id: HP:0025372
      label: Loud snoring
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
    explanation: Lists loud snoring among the reported features.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Chronic constipation
  category: Gastrointestinal
  description: Mild constipation requiring laxatives.
  phenotype_term:
    preferred_term: Chronic constipation
    term:
      id: HP:0012450
      label: Chronic constipation
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
    explanation: Reports constipation severe enough to need laxatives.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Hypertelorism
  category: Craniofacial
  description: Ocular hypertelorism in both brothers.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
    explanation: Confirms hypertelorism in the younger brother and states that the elder shares the pattern.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Low posterior hairline
  category: Craniofacial
  description: A low posterior hairline in both brothers.
  phenotype_term:
    preferred_term: Low posterior hairline
    term:
      id: HP:0002162
      label: Low posterior hairline
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
    explanation: Lists the low posterior hairline as shared by both brothers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Highly arched eyebrow
  category: Craniofacial
  description: Highly arched eyebrows in both brothers.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
    explanation: Lists highly arched eyebrows as shared by both brothers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Protruding ear
  category: Craniofacial
  description: Low-set protruding ears in both brothers.
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
    explanation: Reports protruding ears in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Low-set ears
  category: Craniofacial
  description: Low-set ears in both brothers.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
    explanation: Reports low-set ears in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Narrow mouth
  category: Craniofacial
  description: A small mouth in both brothers.
  phenotype_term:
    preferred_term: Narrow mouth
    term:
      id: HP:0000160
      label: Narrow mouth
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
    explanation: Lists the small mouth as shared by both brothers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Thin upper lip vermilion
  category: Craniofacial
  description: A small upper lip with thin lips.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
    explanation: Reports thin lips in the younger brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Retrognathia
  category: Craniofacial
  description: Retrognathia documented on lateral view in the elder brother.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lateral view of proband 1.2 showing retrognathia.
    explanation: Photographic documentation of retrognathia in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Ptosis
  category: Craniofacial
  description: Ptosis documented photographically in both brothers.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Front view of proband 1.2 at the age of 7 years showing small upper lip, hypertelorism, abnormally shaped ears, ptosis and epicanthus fold.
    explanation: Photographic documentation of ptosis in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Epicanthus
  category: Craniofacial
  description: Epicanthic folds documented photographically in both brothers.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Front view of proband 1.2 at the age of 7 years showing small upper lip, hypertelorism, abnormally shaped ears, ptosis and epicanthus fold.
    explanation: Photographic documentation of the epicanthic fold.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Diastema
  category: Dental
  description: A dental gap was reported and photographed in the elder brother.
  phenotype_term:
    preferred_term: Diastema
    term:
      id: HP:0000699
      label: Diastema
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
    explanation: Reports the diastema in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Peg-shaped maxillary lateral incisors
  category: Dental
  description: Peg-shaped lateral incisors were reported in both brothers and illustrated in the clinical photographs.
  phenotype_term:
    preferred_term: Peg-shaped maxillary lateral incisors
    term:
      id: HP:0006342
      label: Peg-shaped maxillary lateral incisors
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had similar dysmorphic features as proband 1.2, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, peg-shaped lateral incisors, small mouth and thin lips
    explanation: Confirms the peg-shaped lateral incisors in both brothers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Tapered finger
  category: Skeletal
  description: Tapered fingers noted on examination of the elder brother.
  phenotype_term:
    preferred_term: Tapered finger
    term:
      id: HP:0001182
      label: Tapered finger
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
    explanation: Reports tapered fingers in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Reduced systolic function
  category: Cardiovascular
  description: Mild systolic dysfunction was found in the elder brother, without other reported cardiac abnormalities. The chamber was unspecified, and the younger brother’s cardiac status was not reported.
  phenotype_term:
    preferred_term: Mild systolic dysfunction
    term:
      id: HP:0006673
      label: Reduced systolic function
    severity: MILD
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiac evaluation revealed mild systolic dysfunction, but no other abnormalities.
    explanation: The cardiac finding in the elder brother, and the only cardiac measurement reported in either individual.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Disorganized implant of the toes
  category: Skeletal
  description: Disorganized insertion of the toes, noted on examination of the elder brother in the same sentence that reports the tapered fingers.
  phenotype_term:
    preferred_term: Disorganized implant of the toes
    term:
      id: HP:0001780
      label: Abnormal toe morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Upon clinical examination, several dysmorphic features were noted, including hypertelorism, low posterior hair line, highly arched eyebrows, low-set protruding ears, small mouth, diastema, peg-shaped lateral incisors, disorganized implant of the toes and tapered fingers
    explanation: Reports the toe finding in the elder brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: The source does not specify overlapping, deviated or widely spaced toes, so a more specific morphology is not assigned.
- name: Long philtrum
  category: Craniofacial
  description: A long philtrum, documented photographically in the younger brother.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Front view of proband 1.4 at the age of 1 year showing small upper lip, long philtrum, bulbous tip of the nose, ptosis, epicanthus fold, ocular hypertelorism, abnormally shaped ears.
    explanation: Photographic documentation of the long philtrum in the younger brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Bulbous nose
  category: Craniofacial
  description: A bulbous nasal tip, documented photographically in the younger brother.
  phenotype_term:
    preferred_term: Bulbous nasal tip
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Front view of proband 1.4 at the age of 1 year showing small upper lip, long philtrum, bulbous tip of the nose, ptosis, epicanthus fold, ocular hypertelorism, abnormally shaped ears.
    explanation: Photographic documentation of the bulbous nasal tip in the younger brother.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Peripheral edema
  category: Constitutional
  description: Episodic swelling of the extremities in the elder brother, one of a group of intermittent features that the report says worsened during intercurrent infections. Reported in 1 of the 2 affected brothers.
  phenotype_term:
    preferred_term: Swelling of the extremities
    term:
      id: HP:0012398
      label: Peripheral edema
    temporality: RECURRENT
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
    explanation: Reports the swelling of the extremities among the elder brother's episodic features.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Vomiting
  category: Gastrointestinal
  description: Episodic vomiting in the elder brother, reported in the same group of intermittent features that worsened during intercurrent infections. Reported in 1 of the 2 affected brothers.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: RECURRENT
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the following years, proband 1.2 exhibited periodic hypotonia, feeding difficulties, fatigue, swelling of his extremities and vomiting, which worsened during infections.
    explanation: Reports the vomiting among the elder brother's episodic features.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Sleep disturbance
  category: Behavioral
  description: Sleeping difficulties were described in both brothers, separately from snoring and the younger brother’s mixed obstructive and central apnea.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
    explanation: The clinical narrative reports difficulty sleeping.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: NAA80
  gene_term:
    preferred_term: NAA80
    term:
      id: hgnc:30252
      label: NAA80
  relationship_type: CAUSATIVE
  association: Homozygous c.389T>C, p.(Leu130Pro) in the catalytic domain
  variant_origin: GERMLINE
  notes: One functionally studied NAA80 allele in one reported family. Both brothers also carry homozygous PLXNB1 p.Ser911Gly, which was absent in the healthy siblings. NAA80 rescue establishes its contribution to the measured fibroblast phenotypes, but does not exclude an additional clinical contribution from PLXNB1.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant.
    explanation: Identifies the allele and the number of affected individuals carrying it.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: Based on the molecular structure, we predicted and confirmed the NAA80 c.389T>C, p.(Leu130Pro) variant to result in protein destabilization, causing severely decreased NAA80 protein availability.
    explanation: Functional evidence that the allele is deleterious, which is what carries the gene-disease assertion in a single family. INDIRECT because protein destabilization is a step short of the disease.
    quote_role: PRIMARY_RESULT
prevalence:
- population: Individuals described in the founding NAA80 clinical report
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: Two affected brothers in one family were reported. This case count provides neither an incidence nor a population prevalence estimate.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant.
    explanation: States the number of reported individuals and that they are one family.
    quote_role: PRIMARY_RESULT
external_assertions:
- name: OMIM auroneurodental syndrome record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:620830
  url: https://omim.org/entry/620830
  description: OMIM phenotype record corresponding to MONDO:0970998 and the NAA80-associated syndrome.
- name: ClinVar NAA80 c.389T>C p.(Leu130Pro)
  source: ClinVar
  assertion_type: variant_classification
  external_id: VCV001301869
  url: https://www.ncbi.nlm.nih.gov/clinvar/variation/1301869/
  description: ClinVar reports aggregate Pathogenic/Likely pathogenic classification from two submissions, without assertion criteria provided. This external classification is not independent replication of the family report.
  notes: Checked 2026-09-21 at VCV001301869.6. The preferred transcript is NM_001200016.2:c.323T>C (p.Leu108Pro), whereas the paper uses c.389T>C (p.Leu130Pro). Both refer to GRCh37 chr3:g.50334572A>G. The submitting laboratory and OMIM cite the same original family; submission observation counts include relatives and functional assays and must not be counted as additional affected families.
experimental_models:
- name: Patient fibroblasts and peripheral blood mononuclear cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism: &id001
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Skin fibroblasts from the elder brother; PBMCs from both brothers
  publication: PMID:34805998
  description: Patient cells were compared with healthy-donor cells; control donor numbers varied by assay and could not be age- and sex-matched. Wild-type NAA80 rescue was performed in the elder brother’s fibroblasts. Technical replicates do not expand the number of patients.
  modeled_mechanisms:
  - target: Reduced Actin N-Terminal Acetylation
    relationship: MEASURES
    fidelity: HIGH
    description: N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.
    limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: In healthy donors, ∼0.5% of beta and gamma-actins were not acetylated. However, for the NAA80 individuals, 25–65% of beta and gamma-actins were not acetylated, depending on the cell type and the type of cytoplasmic actin
      explanation: Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.
    readouts:
    - name: Fraction of unacetylated beta- and gamma-actin
      target: Reduced Actin N-Terminal Acetylation
      direction: INCREASED
      interpretation: N-terminal acetylation of cytoplasmic beta- and gamma-actin is reduced in the sampled patient cells, with 25–65% unacetylated depending on cell type and actin isoform. Residual acetylation distinguishes this human allele from a complete knockout. Acetylation in human inner ear, brain and muscle was not measured.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: In healthy donors, ∼0.5% of beta and gamma-actins were not acetylated. However, for the NAA80 individuals, 25–65% of beta and gamma-actins were not acetylated, depending on the cell type and the type of cytoplasmic actin
        explanation: Isotope-assisted mass spectrometry quantified beta- and gamma-actin acetylation in the elder brother’s fibroblasts and both brothers’ PBMCs.
  - target: Increased Filamentous Actin Content
    relationship: MEASURES
    fidelity: HIGH
    description: Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.
    limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Indeed, NAA80 individual PBMCs and fibroblasts displayed increased phalloidin staining, corresponding with increased levels of polymerized actin
      explanation: Phalloidin fluorescence measures filamentous actin content, not polymerization flux.
    readouts:
    - name: Phalloidin fluorescence
      target: Increased Filamentous Actin Content
      direction: INCREASED
      interpretation: Patient fibroblasts and PBMCs have increased phalloidin-stained filamentous actin; wild-type NAA80 expression normalizes the fibroblast signal. HAP1 knockout cells show a lower globular-to-filamentous actin ratio. These abundance measurements do not show an increased instantaneous polymerization rate.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Indeed, NAA80 individual PBMCs and fibroblasts displayed increased phalloidin staining, corresponding with increased levels of polymerized actin
        explanation: Phalloidin fluorescence measures filamentous actin content, not polymerization flux.
  - target: Increased Filopodia Formation
    relationship: MEASURES
    fidelity: HIGH
    description: Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.
    limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: In NAA80 individual fibroblasts, increased filopodia counts were observed
      explanation: Filopodia were counted in fibroblasts from the elder brother; this was not a PBMC filopodia assay.
    readouts:
    - name: Fibroblast filopodia count
      target: Increased Filopodia Formation
      direction: INCREASED
      interpretation: Fibroblasts from the elder brother have increased filopodia counts that normalize after wild-type NAA80 expression. Knockout HAP1 cells independently show more and longer filopodia-like protrusions. A direct causal route from this cultured-cell phenotype to human neural or craniofacial malformations has not been demonstrated.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: In NAA80 individual fibroblasts, increased filopodia counts were observed
        explanation: Filopodia were counted in fibroblasts from the elder brother; this was not a PBMC filopodia assay.
  - target: Increased Cell Migration
    relationship: MEASURES
    fidelity: HIGH
    description: Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.
    limitations: One patient fibroblast line and two related PBMC donors; these are not inner-ear, neural, muscle or dental tissue.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Both fibroblasts and PBMCs of NAA80 individuals showed increased movement in response to chemotactic stimuli
      explanation: Boyden chamber assays measured migration in patient-derived cells.
    readouts:
    - name: Chemotactic migration
      target: Increased Cell Migration
      direction: INCREASED
      interpretation: Fibroblasts and PBMCs from affected individuals migrate more in chemotactic assays. Wild-type NAA80 expression rescues fibroblast migration; HAP1 knockout experiments also show increased directed and random migration. Migration was not measured in the patients’ developing neurons or craniofacial tissues.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Both fibroblasts and PBMCs of NAA80 individuals showed increased movement in response to chemotactic stimuli
        explanation: Boyden chamber assays measured migration in patient-derived cells.
- name: Wild-type and p.Leu130Pro NAA80 reconstitution in HAP1 knockout cells
  experimental_model_type: CELL_LINE
  organism: *id001
  publication: PMID:34805998
  description: Wild-type or patient-variant NAA80 was expressed with promoters of different strengths. Mutant protein levels were lower; stronger expression restored acetylated-actin signal. This separates reduced availability from complete catalytic inactivity, without measuring precise acetylation percentages or equal-concentration enzyme kinetics.
  modeled_mechanisms:
  - target: Reduced NAA80 Protein Abundance
    relationship: MEASURES
    fidelity: MODERATE
    description: Mutant NAA80 abundance is lower across the tested promoters.
    limitations: Engineered cell-line expression, not a patient protein-half-life measurement.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters
      explanation: Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.
    readouts:
    - name: NAA80 western-blot abundance
      target: Reduced NAA80 Protein Abundance
      direction: DECREASED
      interpretation: Mutant NAA80 abundance is lower across the tested promoters.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Lower protein levels of mutant NAA80 compared with healthy donors were observed with all promoters
        explanation: Promoter-matched reconstitution in NAA80-knockout HAP1 cells showed lower mutant protein abundance; patient fibroblasts also had reduced protein.
  - target: Reduced Actin N-Terminal Acetylation
    relationship: MEASURES
    fidelity: MODERATE
    description: Weak-promoter mutant expression incompletely restores actin acetylation; stronger expression can approach maximal signal.
    limitations: Western blots are not precise quantification, and expression levels differ.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Use of the weakest promoter resulted in partial restoration of actin acetylation
      explanation: The experiment demonstrates residual activity under expression-dependent conditions.
    readouts:
    - name: Acetylated-actin western-blot signal
      target: Reduced Actin N-Terminal Acetylation
      direction: DECREASED
      interpretation: Weak-promoter mutant expression incompletely restores actin acetylation; stronger expression can approach maximal signal.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Use of the weakest promoter resulted in partial restoration of actin acetylation
        explanation: The experiment demonstrates residual activity under expression-dependent conditions.
- name: CRISPR NAA80 knockout HAP1 cells
  experimental_model_type: CELL_LINE
  organism: *id001
  publication: PMID:29581253
  description: Two knockout clones were compared with control cells and reconstituted with wild-type or engineered catalytically inactive NAA80. The inactive construct carries W105F/R170Q/G173D/Y205F and is not the patient allele. Migration, protrusions, G/F-actin ratios and latrunculin recovery were measured.
  modeled_mechanisms:
  - target: Reduced Actin N-Terminal Acetylation
    relationship: MEASURES
    fidelity: MODERATE
    description: Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.
    limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Furthermore, both actin isoforms were 100% and 0% Nt-acetylated in control and NAA80 KO1 cells, respectively.
      explanation: Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.
    readouts:
    - name: Acetylated beta/gamma-actin
      target: Reduced Actin N-Terminal Acetylation
      direction: ABOLISHED
      interpretation: Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.
      evidence:
      - reference: PMID:29581253
        reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Furthermore, both actin isoforms were 100% and 0% Nt-acetylated in control and NAA80 KO1 cells, respectively.
        explanation: Proteomic analysis showed loss of beta/gamma-actin N-terminal acetylation.
  - target: Increased Filamentous Actin Content
    relationship: MEASURES
    fidelity: MODERATE
    description: The measured globular-to-filamentous actin ratio decreased in knockout cells.
    limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: from 0.73 in HAP1 control cells to 0.55 in NAA80 KO1 cells
      explanation: The measured globular-to-filamentous actin ratio decreased in knockout cells.
    readouts:
    - name: G/F-actin ratio
      target: Increased Filamentous Actin Content
      direction: DECREASED
      interpretation: The measured globular-to-filamentous actin ratio decreased in knockout cells.
      evidence:
      - reference: PMID:29581253
        reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: from 0.73 in HAP1 control cells to 0.55 in NAA80 KO1 cells
        explanation: The measured globular-to-filamentous actin ratio decreased in knockout cells.
  - target: Increased Filopodia Formation
    relationship: MEASURES
    fidelity: MODERATE
    description: Knockout cells had more filopodia-like protrusions.
    limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: These cells showed an approximately fourfold increase in the number of filopodia-like structures, defined as phalloidin-stained protrusions with a length ≥0.5 µm
      explanation: Knockout cells had more filopodia-like protrusions.
    readouts:
    - name: Filopodia-like protrusion count
      target: Increased Filopodia Formation
      direction: INCREASED
      interpretation: Knockout cells had more filopodia-like protrusions.
      evidence:
      - reference: PMID:29581253
        reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: These cells showed an approximately fourfold increase in the number of filopodia-like structures, defined as phalloidin-stained protrusions with a length ≥0.5 µm
        explanation: Knockout cells had more filopodia-like protrusions.
  - target: Increased Cell Migration
    relationship: MEASURES
    fidelity: MODERATE
    description: Directed and random migration increased in knockout cells.
    limitations: Complete knockout in a cell line, rather than the human hypomorphic allele or affected tissues.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Taken together these data demonstrate that cells deficient in actin Nt-acetylation have increased motility.
      explanation: Directed and random migration increased in knockout cells.
    readouts:
    - name: Cell migration
      target: Increased Cell Migration
      direction: INCREASED
      interpretation: Directed and random migration increased in knockout cells.
      evidence:
      - reference: PMID:29581253
        reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Taken together these data demonstrate that cells deficient in actin Nt-acetylation have increased motility.
        explanation: Directed and random migration increased in knockout cells.
- name: Purified acetylated and nonacetylated beta/gamma-actin
  experimental_model_type: OTHER
  publication: PMID:29581253
  description: Actin purified from control and NAA80-knockout HAP1 cells was tested in bulk pyrene assays, seeded elongation/depolymerization and assays with Arp2/3, mDia1/mDia2 and profilins. The effect depends on the reaction and actin-binding proteins.
  modeled_mechanisms:
  - target: Slower Actin Filament Elongation
    relationship: MEASURES
    fidelity: MODERATE
    description: Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.
    limitations: Cell-free preparations; unseeded polymerization and several nucleation conditions were unchanged.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
      explanation: Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.
    readouts:
    - name: Seeded barbed-end elongation rate
      target: Slower Actin Filament Elongation
      direction: DECREASED
      interpretation: Nonacetylated beta/gamma-actin purified from HAP1 knockout cells elongates more slowly in seeded barbed-end assays. Total unseeded polymerization, Arp2/3-driven assembly and mDia2-mediated assembly did not show the same difference; mDia1 and PFN1/PFN2 context matter. This is an in-vitro biochemical result, not a measured patient-tissue growth rate.
      evidence:
      - reference: PMID:29581253
        reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: The barbed-end elongation rate of β/γ-actin filament seeds is ∼2.2-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
        explanation: Purified acetylated versus nonacetylated beta/gamma-actin differed in seeded barbed-end elongation.
  - target: Slower Actin Filament Depolymerization
    relationship: MEASURES
    fidelity: MODERATE
    description: Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.
    limitations: Cell-free depolymerization does not establish the net tissue filament burden.
    evidence:
    - reference: PMID:29581253
      reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
      explanation: The purified-filament assay measured slower depolymerization without acetylation.
    readouts:
    - name: Filament depolymerization rate
      target: Slower Actin Filament Depolymerization
      direction: DECREASED
      interpretation: Purified nonacetylated actin filaments depolymerize more slowly than acetylated filaments. Both elongation and depolymerization change, so this result alone does not establish the net filament content or clinical effect in a tissue.
      evidence:
      - reference: PMID:29581253
        reference_title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: The depolymerization rate of β/γ-actin filament seeds is ∼1.7-fold faster for Ac-actin (blue) than for non–Ac-actin (red).
        explanation: The purified-filament assay measured slower depolymerization without acetylation.
- name: Recombinant NAA80 p.Leu130Pro solubility assay
  experimental_model_type: OTHER
  publication: PMID:34805998
  description: His-tagged wild-type and mutant human NAA80 were expressed in Escherichia coli and soluble versus sedimented fractions assessed by SDS-PAGE/western blot. The result is consistent with misfolding, without a mutant structural determination or degradation-rate assay.
  modeled_mechanisms:
  - target: Reduced NAA80 Protein Abundance
    relationship: MEASURES
    fidelity: MODERATE
    description: Mutant recombinant protein preferentially partitions into the insoluble fraction.
    limitations: Bacterial expression and solubility are proxies for folding-related availability, not patient-cell half-life.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Mutant protein was predominantly insoluble, contrasting with wild-type protein, which was essentially soluble, with only a very small proportion in the sediment
      explanation: Experimental solubility supports the structural prediction but does not directly determine mutant folding.
    readouts:
    - name: Soluble recombinant mutant NAA80 fraction
      target: Reduced NAA80 Protein Abundance
      direction: DECREASED
      interpretation: Mutant recombinant protein preferentially partitions into the insoluble fraction.
      evidence:
      - reference: PMID:34805998
        reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
        supports: SUPPORT
        evidence_source: IN_VITRO
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: Mutant protein was predominantly insoluble, contrasting with wild-type protein, which was essentially soluble, with only a very small proportion in the sediment
        explanation: Experimental solubility supports the structural prediction but does not directly determine mutant folding.
animal_models:
- species: Zebrafish
  genotype: Stable naa80 5del/1in and 13del frameshift lines
  category: Genetic
  publication: PMID:39384430
  description: Stable frameshift lines supplied adult heart and skeletal-muscle proteomics and gross development/body-size observations. Homozygotes had little to no detectable acetylated actin peptides; one low-intensity acetylated peptide could reflect carryover or residual alternative activity. These were separate from the F0 ear experiments.
  notes: Routine swimming and feeding appeared comparable to controls; endurance, muscle force and stress testing were not performed. One line’s females failed to yield eggs, while 13del homozygous incrosses eventually produced viable larvae; universal infertility is not established.
  modeled_mechanisms:
  - target: Reduced Actin N-Terminal Acetylation
    relationship: MEASURES
    fidelity: MODERATE
    description: Muscle and heart samples show little to no detectable N-terminally acetylated actin in homozygotes.
    limitations: Different tissues and species from patient fibroblasts; the method cannot estimate site occupancy. Gross behavior does not exclude stress-dependent or human muscle dysfunction.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: In contrast, in the naa80 −/− samples from both knockout lines, we found little to no detectable Nt-acetylated actin
      explanation: Adult stable-line proteomics supports the conserved enzyme-substrate relationship.
    readouts:
    - name: Acetylated actin peptide signal
      target: Reduced Actin N-Terminal Acetylation
      direction: DECREASED
      interpretation: Muscle and heart samples show little to no detectable N-terminally acetylated actin in homozygotes.
      evidence:
      - reference: PMID:39384430
        reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: In contrast, in the naa80 −/− samples from both knockout lines, we found little to no detectable Nt-acetylated actin
        explanation: Adult stable-line proteomics supports the conserved enzyme-substrate relationship.
- species: Zebrafish
  genotype: Transient F0 naa80 CRISPR targeting with two sgRNAs
  category: Genetic
  publication: PMID:39384430
  description: Five-day larvae generated by injection of Cas9 protein and two sgRNAs were compared with Cas9-injected controls. Reduced naa80 transcript, ear structural abnormalities and reduced acoustic startle were observed. These experiments do not directly quantify acetylation in F0 hair cells or provide Naa80 rescue.
  notes: The acoustic endpoint used 48 larvae per group and is a sensory-motor response, not a frequency-specific audiogram. Yo-Pro-1-positive cells were counted in lateral-line neuromasts (12 control/13 targeted larvae), not used as an inner-ear apoptosis assay. Stereocilia measurements are nested within three larvae per group.
  modeled_mechanisms:
  - target: Reduced Inner-Ear Hair-Cell Bundles
    relationship: MEASURES
    fidelity: MODERATE
    description: Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.
    limitations: F0 perturbation with no rescue or direct hair-cell acetylation/dynamics assay; relevance to human cochlear pathology is inferred.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls
      explanation: Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.
    readouts:
    - name: Lateral-crista hair-cell bundle count
      target: Reduced Inner-Ear Hair-Cell Bundles
      direction: DECREASED
      interpretation: Transient naa80-targeted F0 zebrafish larvae have fewer lateral-crista hair-cell bundles. This model-derived lesion is distinct from the lateral-line Yo-Pro-1 uptake readout and is not a demonstrated human cochlear cell-loss mechanism.
      evidence:
      - reference: PMID:39384430
        reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: KOs exhibited a fewer hair cell bundles in the lateral crista compared with controls
        explanation: Hair-cell bundles were imaged in separate transient F0 CRISPR larvae.
  - target: Shortened Hair-Cell Stereocilia
    relationship: MEASURES
    fidelity: MODERATE
    description: Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.
    limitations: F0 perturbation with no rescue or direct hair-cell acetylation/dynamics assay; relevance to human cochlear pathology is inferred.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: both number of hair cells per crista as well as stereocilia length reduced
      explanation: Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.
    readouts:
    - name: Lateral-crista stereocilia length
      target: Shortened Hair-Cell Stereocilia
      direction: DECREASED
      interpretation: Stereocilia in the lateral crista are shorter in transient F0 naa80 CRISPR larvae. Hair-cell actin acetylation and actin dynamics were not directly assayed, and no Naa80 rescue experiment was reported.
      evidence:
      - reference: PMID:39384430
        reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: both number of hair cells per crista as well as stereocilia length reduced
        explanation: Lateral-crista stereocilia were shorter in F0 larvae; 31 stereocilia from three larvae per group were measured.
  - target: Reduced Otolith Size
    relationship: MEASURES
    fidelity: MODERATE
    description: Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.
    limitations: F0 perturbation with no rescue or direct hair-cell acetylation/dynamics assay; relevance to human cochlear pathology is inferred.
    evidence:
    - reference: PMID:39384430
      reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: However, we observed a reduction in otolith size compared with controls following Cas9 protein injection
      explanation: Otolith size was reduced in F0 larvae compared with Cas9-injected controls.
    readouts:
    - name: Otolith size
      target: Reduced Otolith Size
      direction: DECREASED
      interpretation: Transient F0 naa80 CRISPR larvae have smaller otoliths. Otolith anatomy is a zebrafish model finding, without evidence that the human syndrome has the same lesion.
      evidence:
      - reference: PMID:39384430
        reference_title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        quote_role: PRIMARY_RESULT
        snippet: However, we observed a reduction in otolith size compared with controls following Cas9 protein injection
        explanation: Otolith size was reduced in F0 larvae compared with Cas9-injected controls.
discussions:
- discussion_id: gap_auroneurodental_clinical_attribution
  kind: KNOWLEDGE_GAP
  prompt: Which clinical manifestations are attributable to NAA80 in this single family?
  rationale: NAA80 reconstitution rescues the measured fibroblast abnormalities, but the brothers also share PLXNB1 p.Ser911Gly. Additional families and affected-tissue models are needed to distinguish the full NAA80 spectrum from possible additional genetic contributions. Neither the co-variant nor its absence in healthy siblings establishes a modifier mechanism.
  attaches_to:
  - pathophysiology#Biallelic NAA80 Dysfunction
- discussion_id: gap_auroneurodental_tissue_routes
  kind: KNOWLEDGE_GAP
  prompt: How do the measured actin changes contribute to human organ manifestations?
  rationale: Filament abundance, elongation, depolymerization, protrusion formation and migration are distinct results. Human inner-ear, neural, muscle and dental tissue mechanisms were not measured. The fish ear observations support a candidate sensory route, but acetylation and dynamics were not assayed in those F0 hair cells. No single fibroblast readout is established as the mediator of craniofacial, behavioral or brain-imaging abnormalities.
  attaches_to:
  - pathophysiology#Reduced Actin N-Terminal Acetylation
  - pathophysiology#Increased Cell Migration
- discussion_id: gap_auroneurodental_muscle_model_scope
  kind: HUMAN_MODEL_MISMATCH
  prompt: What does grossly normal behavior in stable knockout fish establish about muscle disease?
  rationale: Stable mutant fish lacked most detectable muscle actin acetylation but swam and fed normally under routine conditions. No force or endurance testing was performed. Species, allele severity and assay sensitivity preclude treating this as a stronger disproof of human hypomorphic myopathy, or assigning the human weakness to PLXNB1 by exclusion.
  attaches_to:
  - phenotypes#Proximal muscle weakness
  - phenotypes#Axial muscle weakness
- discussion_id: gap_auroneurodental_activity_threshold
  kind: KNOWLEDGE_GAP
  prompt: Is there a clinically meaningful residual NAA80 activity threshold?
  rationale: The human paper’s estimate of approximately 1–2% residual activity comes from a simplified kinetic model, not a patient enzyme assay. Proposed lethality below that range and asymptomatic status above it are unvalidated; viable zebrafish nulls further limit cross-species extrapolation. Strong-promoter rescue is not a therapeutic dose or clinical safety threshold.
  attaches_to:
  - pathophysiology#Reduced NAA80 Protein Abundance
  - pathophysiology#Reduced Actin N-Terminal Acetylation
references:
- reference: PMID:34805998
  title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
- reference: PMID:39384430
  title: Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.
- reference: PMID:29581253
  title: NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
treatments:
- name: Laxatives for constipation
  description: The elder brother required laxatives for mild constipation. The report does not identify a drug, dose or quantified response.
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
    explanation: The original clinical report documents this symptomatic treatment.
  target_mechanisms:
  - target: Chronic constipation
    treatment_effect: MODULATES
    description: Symptomatic support; no correction of NAA80 or actin acetylation is established.
    evidence:
    - reference: PMID:34805998
      reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Additional phenotypic features included sleeping difficulties, loud snoring, gait ataxia and mild constipation requiring laxatives.
      explanation: The original clinical report documents this symptomatic treatment.
  treatment_term:
    preferred_term: Laxatives for constipation
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Laxative
      term:
        id: NCIT:C29697
        label: Laxative
- name: Hearing aids and individualized hearing habilitation
  description: General genetic-hearing-loss guidance supports audiologist-fitted hearing aids for mild-to-severe loss, guided by the individual’s hearing profile and communication goals. NAA80-specific aided outcomes have not been reported.
  therapeutic_modality: DEVICE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss.
    explanation: General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.
  target_mechanisms:
  - target: High-frequency sensorineural hearing impairment
    treatment_effect: MODULATES
    description: Symptomatic support; no correction of NAA80 or actin acetylation is established.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
      reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss.
      explanation: General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.
  treatment_term:
    preferred_term: Hearing aids and individualized hearing habilitation
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Communication and early developmental support
  description: General pediatric hearing-loss care includes speech-language support, access to sign language according to family goals, and early intervention for assessed developmental needs. This is supportive guidance, not evidence of reversing the NAA80 developmental phenotype.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Referral to an early intervention program is recommended for access to occupational, physical, speech-language, and feeding therapy as well as specialized D/deaf and hard of hearing (DHH) services to support DHH identity development in the child and family.
    explanation: General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Audiologic and multisystem follow-up
  description: Sequential audiologic assessment can document stability or progression. Additional specialty evaluation should respond to the child’s findings, including the reported apnea, developmental, motor and cardiac abnormalities; no syndrome-specific testing interval has been established.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Perform sequential audiologic examinations that: ... Document the stability or progression of the hearing loss;'
    explanation: General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Cochlear implant assessment when hearing severity warrants
  description: Cochlear implantation is a general option for eligible children with severe-to-profound hearing loss, assessed by a specialist team. Neither implant use nor efficacy was reported in the founding NAA80 family, and it cannot be assumed from cell rescue.
  therapeutic_modality: SURGERY
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
    explanation: General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.
  target_mechanisms:
  - target: High-frequency sensorineural hearing impairment
    treatment_effect: MODULATES
    description: Symptomatic support; no correction of NAA80 or actin acetylation is established.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
      reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
      explanation: General hearing-loss guidance extrapolated to this syndrome; no NAA80-specific outcome study.
  treatment_term:
    preferred_term: Cochlear implant assessment when hearing severity warrants
    term:
      id: NCIT:C15329
      label: Surgical Procedure
diagnosis:
- name: Molecular testing and family segregation
  description: The founding family was investigated with trio exome sequencing and Sanger segregation. Evaluation should consider the clinical pattern, allele interpretation and other segregating variants; homozygosity or a VUS alone is not diagnostic.
  evidence:
  - reference: PMID:34805998
    reference_title: NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: 'Sanger sequencing confirmed homozygosity for the same variant in NAA80: c.389T>C, p.(L130P) in proband 1.4, but not in healthy probands 1.1 and 1.3'
    explanation: Segregation supports the familial association, alongside functional evidence.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: The identification of variant(s) of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis.
    explanation: General genetic-hearing-loss diagnostic interpretation.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
- name: Audiometry and clinical phenotyping
  description: Age-appropriate audiologic testing establishes type, severity and frequency profile of hearing loss. Clinical examination assesses associated craniofacial, dental, developmental and neuromuscular findings; hearing loss alone does not distinguish NAA80 from other genetic causes.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Hearing status can be determined at any age and is tailored to the individual's ability to participate
    explanation: General age-appropriate hearing assessment guidance.
- name: Research assessment of actin acetylation
  description: Isotope-assisted mass spectrometry and patient-cell rescue provided functional support for the reported allele. These assays are research evidence, without established clinical sensitivity, specificity or diagnostic cutoffs.
  evidence:
  - *id002

📚

References & Deep Research

References

PMID:34805998

NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay.

No top-level findings curated for this source.

PMID:39384430

Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish.

No top-level findings curated for this source.

PMID:29581253

NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/books/NBK1434/

Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

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