🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant HP:0000006

The proposed mode is autosomal dominant, based on one three-carrier family and two apparently de novo sporadic cases. Penetrance is unproven. In an unrelated LGMD2F family, seven S151A carriers aged 3-64 years showed no clinical signs of cardiomyopathy, and ECG and echocardiography were normal in the four compound heterozygotes (the others had clinical examination only). R71T carriers showed a mild, late-onset phenotype. ClinGen evaluates the relationship under autosomal dominant inheritance and rates it Limited.

Autosomal dominant inheritance Penetrance: UNKNOWN

Show evidence (5 references)

CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z SUPPORT Other

ClinGen evaluates SGCD for this disease under autosomal dominant inheritance and classifies the relationship as Limited.

PMID:10974018 SUPPORT DIRECT Human Clinical

"In family FDCM no. 1100, three affected individuals were identified with abnormal SSCP conformers (Figure 2). None of the unaffected members of the family and none of the 200 control individuals had this abnormal conformer."

The only familial segregation offered for dominant transmission. Three affected carriers is a small number and gives no LOD score.

PMID:19259135 REFUTE DIRECT Human Clinical

"This finding calls into question the pathological relevance of this p.S151A sequence variant for causing familial autosomal-dominant DCM and thereby the existence of an autosomal-dominant mode of inheritance for the pathogenic mutations in the SGCD gene."

The authors' conclusion from an LGMD2F family in which S151A carriers, including compound heterozygotes, had no cardiomyopathy. It directly disputes dominant inheritance for SGCD.

+ 2 more references

?

Discussions and Knowledge Gaps

3

Do heterozygous SGCD variants cause Mendelian autosomal dominant DCM, or were the founding observations chance co-occurrences of rare variants with DCM?

CONTROVERSY OPEN cmd1l_does_sgcd_dominant_dcm_exist

Attached to

pathophysiology#Heterozygous SGCD Variant

Support comes from one three-carrier family, two apparently de novo sporadic children, one small Finnish family, and one splice variant of unreported phenotype. Against it are seven S151A carriers aged 3-64 years in an LGMD2F family who showed no clinical signs of cardiomyopathy, with normal ECG and echocardiography in the four compound heterozygotes (the others had clinical examination only); negative screens of 99 and 52 DCM patients, and a mild knock-in mouse. ClinGen rates the relationship Limited.

Proposed experiments

SGCD rare-variant burden in large DCM case-control data

exp_cmd1l_case_control_burden

Compare the burden of rare SGCD missense, in-frame and splice variants in DCM probands against population controls, stratified by variant class and protein domain. Collect cardiac phenotypes from heterozygous parents of LGMD2F patients as an internal penetrance check.

Show evidence (4 references)

PMID:19259135 SUPPORT DIRECT Human Clinical

"Comprehensive clinical and cardiac investigation in all of the compound heterozygous family members revealed no signs of cardiomyopathy or limb girdle muscular dystrophy."

The central counter-observation behind the controversy.

PMID:19259135 SUPPORT DIRECT Human Clinical

"Even the oldest family member carrying the mutation (pedigree no. II:4; 64 years old) did not show any clinical signs of DCM."

Absence of disease at an age when DCM would be expected.

PMID:23695275 SUPPORT DIRECT Model Organism

"So far, the role of mutations in the δ-sarcogylcan (Sgcd) gene in causing autosomal dominant dilated cardiomyopathy (DCM) remains inconclusive."

A later model study that also calls the question open.

+ 1 more reference

How informative are complete-loss and overexpression models for a disease attributed to one heterozygous SGCD allele?

HUMAN MODEL MISMATCH OPEN cmd1l_null_models_vs_heterozygous_disease

Attached to

pathophysiology#Cardiomyocyte Degeneration pathophysiology#Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization

The hamster, Sgcd-null mouse and SGCD-knockout pig are recessive nulls with skeletal myopathy, modeling LGMD R6 biology. The S151A transgenic mouse and fly overexpress the mutant, while the genotype-matched knock-in mouse shows only mild, subclinical change. The vascular mechanism of the null mouse is contradicted by normal coronaries in patients.

Proposed experiments

Isogenic heterozygous SGCD variants in human iPSC cardiomyocytes

exp_cmd1l_isogenic_ipsc_cardiomyocytes

Introduce S151A, p.Lys238del, R71T and a null allele heterozygously into one control iPSC line. Measure sarcoglycan localization, membrane permeability under cyclic stretch, and nuclear lamin A/C distribution against isogenic wild-type and heterozygous-null controls. This would separate a dominant-negative effect from haploinsufficiency and from overexpression artifacts.

Show evidence (4 references)

PMID:19259135 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Heydemann et al found up to sevenfold overexpression of the S151A sequence variant in hearts of their mice, which may suggest that rather the overall level of gene expression than the expression of the sequence variant has been responsible for the pathology in mice."

The dosage caveat for the transgenic evidence.

PMID:23695275 SUPPORT DIRECT Model Organism

"Heterozygous S151A knock-in mice developed a rather mild phenotype of cardiomyopathy."

The genotype-matched model diverges from the severe human founding family.

PMID:10974018 SUPPORT DIRECT Human Clinical

"Coronary angiography and echocardiography (transthoracic and in some cases transesophageal) identified normal coronary arteries in all patients with δ-sarcoglycan mutations, and no evidence of ischemia was found in the myocardium."

The human finding that contradicts the null-mouse vascular route.

+ 1 more reference

If heterozygous SGCD variants cause DCM, by what molecular mechanism, given that LGMD2F heterozygous carriers are not known to be affected?

KNOWLEDGE GAP OPEN cmd1l_dominant_negative_vs_haploinsufficiency

Attached to

pathophysiology#Dominant-Negative Disturbance of the Sarcoglycan Complex

A dominant-negative effect is proposed because heterozygous null carriers in LGMD2F families are not described as affected. The two overexpression systems disagree on the mechanism: normal trafficking with fragile membranes in one, nuclear sequestration in the other. A functionally confirmed canonical splice variant (c.4-1G>A), reclassified likely pathogenic in a cardiomyopathy cohort, is a likely loss-of-function allele. If it is causal, a dominant-negative-only mechanism does not explain it; its carrier's phenotype is not reported. A native-dosage S151A knock-in showed an intact sarcolemma, and S151A rescued Sgcd-null hearts. Systematic cardiac data on heterozygous LGMD2F relatives are lacking.

Show evidence (3 references)

PMID:10974018 SUPPORT INDIRECT Human Clinical

"Although heterozygotes within LGMD2F families have not been described to be affected, it is possible that cardiac evaluation overlooked cardiac pathology or the cardiac dysfunction had not become apparent at the time of evaluation"

The founding authors acknowledge the missing heterozygote cardiac data.

PMID:26968544 SUPPORT DIRECT In Vitro

"This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex."

This system shows normal trafficking, unlike the nuclear retention seen in transgenic mice.

PMID:36270459 SUPPORT INDIRECT Human Clinical

"Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were reclassified as likely pathogenic."

A likely loss-of-function SGCD allele classified likely pathogenic in a cardiomyopathy cohort; the carrier's phenotype and zygosity are not reported.

⚙

Pathophysiology

7

Heterozygous SGCD Variant

Mechanism confidence: Provisional

The proposed initiating lesion is a single germline SGCD missense or in-frame variant (S151A, p.Lys238del, R71T), plus one canonical splice variant. Delta-sarcoglycan is a sarcolemmal transmembrane glycoprotein of striated and smooth muscle that helps stabilize the sarcolemma. The causal status of every reported allele is uncertain: ClinGen rates the gene-disease relationship Limited, and the founding S151A allele was not associated with cardiac disease in an independent family.

cardiac muscle cell CL:0000746

SGCD hgnc:10807

Genetic context variant_origin: GERMLINE functional_impact_category: DOMINANT_NEGATIVE

The dominant-negative category is the authors' proposal, supported only by overexpression systems. Haploinsufficiency is not supported, because heterozygous relatives of LGMD2F patients have not been described as affected.

structural constituent of muscle GO:0008307 ⚠ ABNORMAL

sarcolemma GO:0042383

Downstream

Dominant-Negative Disturbance of the Sarcoglycan Complex Mutant delta-sarcoglycan, co-expressed with the wild-type protein, is proposed to interfere with sarcoglycan complex function. This is shown only where the mutant is overexpressed.

Show evidence (5 references)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Mutations affecting the secondary structure were identified in one family and two sporadic cases, whereas immunofluorescence analysis of myocardium from one of these patients demonstrated significant reduction in delta-sarcoglycan staining."

The founding report of heterozygous SGCD variants in DCM.

PMID:14564412 SUPPORT DIRECT Human Clinical

"We detected a novel mutation, Arg71Thr, in the delta-sarcoglycan gene in two members of a small DCM family."

A second, independent heterozygous allele in a small family.

PMID:8842738 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Its mRNA expression is abundant in striated and smooth muscles, with a main 8 kb transcript, encoding a predicted basic transmembrane glycoprotein of 290 amino acids."

The gene-identification paper's own expression result: SGCD mRNA is abundant in striated and smooth muscle and encodes a transmembrane glycoprotein.

+ 2 more references

Dominant-Negative Disturbance of the Sarcoglycan Complex

Mechanism confidence: Hypothetical

The proposed molecular effect is interference by the mutant protein with the sarcoglycan-sarcospan subcomplex of the dystrophin-glycoprotein complex. The two experimental systems disagree on how this happens. In rat cardiomyocytes, R97Q and R71T traffic normally and the complex assembles, but the membrane is fragile under strain. In transgenic mice, S151A is retained in the nucleus and sequesters beta- and gamma-sarcoglycan. Both systems overexpress the mutant, and R97Q was called a polymorphism in the founding report. In the one p.Lys238del explant, delta-sarcoglycan staining was reduced while alpha-, beta-, gamma-sarcoglycan and dystrophin staining was preserved.

cardiac muscle cell CL:0000746

sarcoglycan complex GO:0016012 dystrophin-associated glycoprotein complex GO:0016010

Downstream

Strain-Induced Cardiomyocyte Sarcolemmal Fragility

Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization

Show evidence (5 references)

PMID:26968544 SUPPORT DIRECT In Vitro

"This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex."

In this system the mutants assemble normally, so any dominant effect is functional rather than a loss of the complex.

PMID:26968544 SUPPORT DIRECT In Vitro

"Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan."

A variant-specific biochemical defect for the Finnish allele.

PMID:10974018 SUPPORT INDIRECT Human Clinical

"the staining for δ-sarcoglycan was significantly reduced in the patient with the ΔK238 mutation (Figure 4)."

The only patient myocardium examined showed reduced delta-sarcoglycan, while the other sarcoglycans stained normally. Reduced staining is not specific to a dominant-negative effect; it is equally compatible with reduced abundance of the mutant protein.

+ 2 more references

Strain-Induced Cardiomyocyte Sarcolemmal Fragility

Mechanism confidence: Hypothetical

Cardiomyocytes expressing mutant delta-sarcoglycan take up membrane-impermeant dye and develop contractures under cyclic stretch. This parallels the sarcolemmal instability that complete delta-sarcoglycan loss causes. It has not been measured in patient tissue or in patient-derived cardiomyocytes.

cardiac muscle cell CL:0000746

cellular response to mechanical stimulus GO:0071260 ⚠ ABNORMAL

sarcolemma GO:0042383

Animal models

Cardiomyopathic Syrian hamster (BIO14.6 and TO-2) Mesocricetus auratus partially recapitulates Cardiomyocytes take up Evans blue dye, a sign of sarcolemmal permeability, which gene transfer prevents.

Downstream

Cardiomyocyte Degeneration In complete-loss hamsters, restoring sarcolemmal integrity limits myocardial damage. Carrying this step over to the heterozygous human state is an inference.

Show evidence (3 references)

PMID:26968544 SUPPORT DIRECT In Vitro

"Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan."

The direct cellular readout of membrane fragility in adult rat cardiomyocytes.

PMID:17164264 SUPPORT INDIRECT BACKGROUND Model Organism

"Recessive mutations of delta-sarcoglycan that eliminate expression, and therefore function, lead to cardiomyopathy and muscular dystrophy by producing instability of the plasma membrane."

Background from the complete-loss setting. It shows that membrane instability is the established mechanism when the protein is absent, not that it occurs in heterozygous carriers.

PMID:23695275 REFUTE INDIRECT Model Organism

"The sarcolemmal membrane of 1–year-old heterozygous S151A knock-in mice is intact and cardiomyocytes show no morphological changes."

At native heterozygous dosage, S151A did not damage the sarcolemma by one year. This argues against membrane fragility as a consequence of the founding allele, although R97Q and R71T were not tested this way.

Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization

Mechanism confidence: Hypothetical

In transgenic mouse hearts overexpressing S151A from the alpha-myosin heavy chain promoter, delta-sarcoglycan accumulated in the nucleus, and lamin A/C and emerin were mislocalized throughout the nucleoplasm. Whether the transgenic DCM reflects the variant or its overexpression is disputed (see the human-model mismatch discussion). A heterozygous S151A knock-in at native dosage gave only a mild phenotype, and the finding has not been examined in patient myocardium.

cardiac muscle cell CL:0000746

nuclear envelope organization GO:0006998 ⚠ ABNORMAL

nuclear envelope GO:0005635

Animal models

Cardiac S151A delta-sarcoglycan transgenic mouse Mus musculus partially recapitulates Nuclear sequestration of the mutant and its partner sarcoglycans.

Downstream

Left Ventricular Dilatation and Systolic Dysfunction

Show evidence (1 reference)

PMID:17164264 SUPPORT DIRECT Model Organism

"Additionally, the nuclear-membrane-associated proteins, lamin A/C and emerin, were mislocalized throughout the nucleoplasm."

The nuclear-envelope phenotype in S151A transgenic cardiomyocytes.

Cardiomyocyte Degeneration

Mechanism confidence: Provisional

Loss of cardiomyocytes is the step proposed to precede replacement fibrosis and ventricular remodeling. Focal myocardial necrosis is the histological hallmark in Sgcd-null mice, a recessive model. In CMD1L the only tissue is one explanted S151A-family heart, which showed myocyte hypertrophy and moderate fibrosis without ischemia; myocyte loss itself was not described in it.

cardiac muscle cell CL:0000746

myocardium UBERON:0002349

Animal models

Sgcd-null mouse Mus musculus partially recapitulates Myocardial necrosis develops without delta-sarcoglycan.

Downstream

Replacement Myocardial Fibrosis Replacement fibrosis follows myocyte loss in DCM generally. In CMD1L the evidence is moderate fibrosis in one explanted heart; myocyte loss preceding it was not shown.

Left Ventricular Dilatation and Systolic Dysfunction Progressive myocyte loss is the general route to ventricular remodeling in DCM. In CMD1L the evidence is the co-occurrence of myocardial damage and left ventricular dilatation in one explanted heart.

Cardiomyocyte Hypertrophy

Show evidence (1 reference)

PMID:10481911 SUPPORT INDIRECT Model Organism

"We found that only Sgcd null mice developed cardiomyopathy with focal areas of necrosis as the histological hallmark in cardiac and skeletal muscle."

Myocardial necrosis under complete delta-sarcoglycan loss, a recessive model.

Replacement Myocardial Fibrosis

Mechanism confidence: Provisional

Cardiac fibroblasts deposit extracellular matrix where myocytes are lost. The one explanted S151A-family heart showed moderate fibrosis without ischemia, the histology of classic DCM.

fibroblast of cardiac tissue CL:0002548

extracellular matrix organization GO:0030198 ↑ INCREASED

myocardium UBERON:0002349

Downstream

Myocardial Fibrosis

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Gross and histopathologic examination of the explanted heart demonstrated features of classic DCM, including increased heart weight, left ventricular dilatation, histopathologic evidence of myocyte hypertrophy, and moderate fibrosis."

Human explant histology from the S151A family.

Left Ventricular Dilatation and Systolic Dysfunction

Mechanism confidence: Established

Affected members of the S151A family had severely dilated left ventricles with moderate to severe systolic dysfunction. One R71T carrier met DCM criteria, and the other had only slight dilatation with preserved systolic function. ESTABLISHED describes the clinical observation in reported carriers. It is not a claim that SGCD causes it.

cardiac muscle contraction GO:0060048 ↓ DECREASED

heart left ventricle UBERON:0002084

Animal models

Cardiomyopathic Syrian hamster (BIO14.6 and TO-2) Mesocricetus auratus partially recapitulates The TO-2 subline develops DCM, while BIO14.6 develops HCM from the same deletion.

Cardiac S151A delta-sarcoglycan transgenic mouse Mus musculus partially recapitulates The transgenic mice develop DCM.

Heterozygous S151A knock-in mouse Mus musculus fails to recapitulate The genotype-matched model did not develop systolic dysfunction by one year, only mild cardiac enlargement.

SGCD-knockout pig Sus scrofa partially recapitulates Systolic dysfunction and sudden death in a large-animal null.

Drosophila expressing human S151A delta-sarcoglycan Drosophila melanogaster partially recapitulates Chamber enlargement and systolic impairment in the fly heart tube.

Downstream

Congestive Heart Failure Severe systolic dysfunction leads to congestive heart failure. This is the general DCM course; the founding family shows the endpoint but does not isolate the step.

Sudden Cardiac Death Sudden death in DCM is generally arrhythmic and follows ventricular remodeling. The founding family shows the endpoint but does not isolate the step or the rhythm.

Dilated Cardiomyopathy

Left Ventricular Dilatation

Reduced Left Ventricular Ejection Fraction

Show evidence (2 references)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Echocardiographically, all affected individuals had severely dilated left ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction (ejection fractions < 35%)."

Ventricular dilatation and systolic dysfunction in the founding family.

PMID:14564412 SUPPORT DIRECT Human Clinical

"One of the mutation carriers fulfills diagnostic criteria for DCM and is also symptomatic. The other mutation carrier has slightly dilated left ventricle and well preserved systolic function."

A milder spectrum in the R71T family.

⬡

Pathograph

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

●

Phenotypes

8

Cardiovascular 7

Dilated Cardiomyopathy HP:0001644

Show evidence (2 references)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Echocardiographically, all affected individuals had severely dilated left ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction (ejection fractions < 35%)."

Dilated ventricles with systolic dysfunction in all affected members of the founding family.

PMID:14564412 SUPPORT DIRECT Human Clinical

"One of the mutation carriers fulfills diagnostic criteria for DCM and is also symptomatic. The other mutation carrier has slightly dilated left ventricle and well preserved systolic function."

One of the two R71T carriers met DCM criteria.

Left Ventricular Dilatation HP:4000141

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Echocardiographically, all affected individuals had severely dilated left ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction (ejection fractions < 35%)."

Severe left ventricular dilatation in all affected family members.

Reduced Left Ventricular Ejection Fraction HP:0012664

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Echocardiographically, all affected individuals had severely dilated left ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction (ejection fractions < 35%)."

Reduced ejection fraction in all affected family members.

Congestive Heart Failure HP:0001635

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"All affected individuals were symptomatic with evidence of congestive heart failure at young age"

Heart failure in the founding family.

Sudden Cardiac Death HP:0001645

Show evidence (2 references)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Note the severity of disease with early-onset CHF and sudden deaths in affected individuals."

Sudden deaths in the founding pedigree.

PMID:19259135 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Two of the patients died of sudden cardiac death at an early age (17–37 years) and the third patient required heart transplantation at the age of 21 years."

A secondary summary of the founding family's outcomes.

Myocardial Fibrosis HP:0001685

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Gross and histopathologic examination of the explanted heart demonstrated features of classic DCM, including increased heart weight, left ventricular dilatation, histopathologic evidence of myocyte hypertrophy, and moderate fibrosis."

Explant histology in patient III:7.

Cardiomyocyte Hypertrophy HP:0031319

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Gross and histopathologic examination of the explanted heart demonstrated features of classic DCM, including increased heart weight, left ventricular dilatation, histopathologic evidence of myocyte hypertrophy, and moderate fibrosis."

Explant histology in patient III:7.

Metabolism 1

Elevated Circulating Creatine Kinase Activity HP:0003236

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Creatine kinase (CK) was mildly elevated in this patient (Table 2), with the muscle isoform (CK-MM) entirely responsible for the elevation."

A single patient's CK finding.

🧬

Genetic Associations

1

SGCD

Gene: SGCD hgnc:10807 gene page variant_origin: GERMLINE

Show evidence (8 references)

CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z SUPPORT Other

The current expert-panel classification of this gene-disease pair.

PMID:10974018 SUPPORT DIRECT Human Clinical

"In two patients, a 3-bp deletion (either 710–712delAGA or 711–713delGAA) of δ-sarcoglycan exon 9p was identified (Figure 3) that deletes a codon encoding the amino acid lysine at position 238 (ΔK238); screening 200 control individuals, as well as the phenotypically normal parents of these..."

The two sporadic carriers and the absence of the deletion in their parents.

PMID:10974018 NO_EVIDENCE DIRECT Human Clinical

"In one case, a 290G→A transition in exon 4, which changes the arginine at codon 97 to glutamine (R97Q), was identified. This 290G→A transition was previously reported to be a polymorphism (45)."

The founding authors treated R97Q as a polymorphism. It is therefore not counted as a CMD1L allele, although Campbell et al. later tested it as a DCM mutant.

+ 5 more references

💊

Medical Actions

5

Guideline-directed heart failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Standard therapy for heart failure with reduced ejection fraction.

Mechanism Target:

Congestive Heart Failure — Supportive. It does not address the SGCD lesion.

Implantable cardioverter-defibrillator

Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

Considered for sudden-death prevention under general DCM criteria.

Mechanism Target:

Sudden Cardiac Death — Supportive. It addresses arrhythmic death only.

Heart transplantation

Action: Heart Transplantation NCIT:C15246

Platform: Surgery

Performed for end-stage disease in the founding family.

Mechanism Target:

Congestive Heart Failure — Replaces the failing heart.

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Cardiac transplantation was necessary in the 21-year-old son (III:7) of the proband (II:5) as seen in the pedigree (Figure 1)."

Transplantation in a CMD1L patient. This is a case report, not an outcome study.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling should convey that the SGCD-DCM relationship is Limited and contested.

Show evidence (1 reference)

CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z SUPPORT Other

Limited validity is the central fact counseling must communicate.

AAV delta-sarcoglycan gene transfer (preclinical, null models only)

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

AAV delivery of wild-type delta-sarcoglycan rescues cardiomyopathy in Sgcd-null mice and TO-2 hamsters.

Mechanism Target:

Strain-Induced Cardiomyocyte Sarcolemmal Fragility — Restores sarcolemmal integrity in null hamsters.

Show evidence (2 references)

PMID:19218289 SUPPORT INDIRECT Model Organism

"Left ventricular function remained stable in mice expressing Sgcd while it deteriorated in EGFP controls within 6 months, paralleled by increased expression of brain natriuretic peptide, a molecular marker of heart failure."

Rescue of a knockout mouse, which is not the human heterozygous genotype.

PMID:11805334 SUPPORT INDIRECT Model Organism

"The transgene preserved sarcolemmal permeability detected in situ by mutual exclusivity between cardiomyocytes taking up intravenously administered Evans blue dye and expressing the delta-SG transgene throughout life."

Rescue of sarcolemmal permeability in null TO-2 hamsters.

🔬

Diagnosis

3

Cardiac and neuromuscular clinical evaluation

The founding study evaluated patients by examination focused on the cardiac and neuromuscular systems, ECG, chest radiography and echocardiography, with catheterization and endomyocardial biopsy where clinically indicated. A normal neuromuscular examination and the absence of skeletal myopathy separate CMD1L from LGMD2F. CK may still be mildly elevated, as in one patient.

Show evidence (2 references)

PMID:10974018 SUPPORT DIRECT Human Clinical

"All patients were evaluated by physical examination (particularly focused in the cardiac and neuromuscular systems), chest radiography, electrocardiography, and echocardiography."

The clinical workup used in the founding cohort.

PMID:10974018 SUPPORT DIRECT Human Clinical

"No skeletal muscle disease occurred in any of these patients."

Absence of skeletal myopathy is part of the definition of this isolated DCM.

Genetic testing and variant interpretation

SGCD may appear on DCM multigene panels. Because gene-disease validity is Limited, and the founding allele did not cause disease in an independent family, a heterozygous SGCD variant should not on its own be taken as diagnostic. Functional splicing assays can resolve candidate splice variants.

Show evidence (2 references)

CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z SUPPORT Other

The Limited classification governs how a heterozygous SGCD finding is interpreted.

PMID:36270459 SUPPORT DIRECT Human Clinical

"Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were reclassified as likely pathogenic."

A minigene assay used to reclassify an SGCD splice variant in diagnostics.

Myocardial delta-sarcoglycan immunostaining

A research test. In the one explant examined, delta-sarcoglycan staining was reduced while the other sarcoglycans and dystrophin were preserved. It is not validated as a diagnostic test.

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"the staining for δ-sarcoglycan was significantly reduced in the patient with the ΔK238 mutation (Figure 4)."

The single tissue observation.

📈

Progression

3

Asymptomatic, physically active phase

Affected S151A-family members were athletic until heart failure or sudden death. The duration of this phase is not reported.

Show evidence (1 reference)

PMID:10974018 SUPPORT DIRECT Human Clinical

"All affected individuals remained athletic until their onset of heart failure or sudden death."

Describes the pre-symptomatic course.

Heart failure, transplantation or sudden death in the founding family

Age: childhood to young adulthood

Heart failure began at a young age. One son needed transplantation at 21. Bauer et al. summarize the two deaths as occurring at 17-37 years. The p.Lys238del carriers came from a pediatric series aged 3 days to 18 years.

Show evidence (2 references)

PMID:10974018 SUPPORT DIRECT Human Clinical

"Cardiac transplantation was necessary in the 21-year-old son (III:7) of the proband (II:5) as seen in the pedigree (Figure 1)."

Age at transplantation.

PMID:10974018 SUPPORT DIRECT Human Clinical

"Fifty patients ranging in age from 3 days to 18 years (mean, 9.5 years) with clinically apparent DCM presenting with heart failure and echocardiograms diagnostic for DCM were identified."

Age range of the sporadic series that included the two p.Lys238del carriers.

Mild, late-onset course in R71T carriers

The Finnish carriers had a milder phenotype with later onset.

Show evidence (1 reference)

PMID:14564412 SUPPORT DIRECT Human Clinical

"Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a late onset of the disease."

Variable expressivity across alleles or families.

📊

Prevalence

1

Published patients with heterozygous SGCD variants and DCM

Cases In Literature Ultra Rare

The cached primary reports describe the S151A family (three affected carriers), two sporadic p.Lys238del children and two R71T carriers in one Finnish family. A Dutch c.4-1G>A carrier is not counted, because no phenotype is reported. Across two cohort screens of 99 and 52 DCM patients, no causal SGCD variant was found apart from the single Finnish family. Sylvius et al. estimated SGCD variants at less than 1% of idiopathic DCM. ULTRA_RARE is a qualitative tier inferred from this handful of published cases; no population prevalence has been measured.

Show evidence (4 references)

PMID:12794684 SUPPORT DIRECT Human Clinical

"we could estimate the prevalence of delta-sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease."

A pooled estimate from published and new screening data.

PMID:12794684 SUPPORT DIRECT Human Clinical

"We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM."

Size of the negative French screen.

PMID:14564412 SUPPORT DIRECT Human Clinical

"All coding regions of the desmin and delta-sarcoglycan genes and the metavinculin-specific exon of the vinculin gene were screened in 52 DCM patients from eastern Finland by PCR-SSCP."

Size of the Finnish screen that yielded one R71T family.

+ 1 more reference

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1L:

Autosomal recessive limb-girdle muscular dystrophy type 2F (LGMD R6) Not Yet Curated MONDO:0011028

Overlapping Features Biallelic SGCD variants cause recessive LGMD with elevated CK and proximal weakness. Cardiac involvement varies. The CMD1L patients had no skeletal muscle disease, and the two conditions are curated separately (see Sarcoglycanopathy).

Show evidence (2 references)

PMID:19259135 SUPPORT DIRECT Human Clinical

"We identified a novel missense mutation in exon 6 (p.A131P) of the delta-sarcoglycan gene, which in a homozygous state leads to the clinical picture of a limb girdle muscular dystrophy."

The allelic recessive disorder.

PMID:10974018 SUPPORT INDIRECT BACKGROUND Human Clinical

"Thus, LGMD associated with sarcoglycan mutations appears to be inherited as a recessive disease."

The founding authors contrast recessive LGMD with the proposed dominant DCM.

Other sarcoglycanopathies (LGMD R3-R5) MONDO:0016140

Overlapping Features Alpha-, beta- and gamma-sarcoglycan deficiencies also cause recessive LGMD with possible cardiomyopathy. Skeletal myopathy and elevated CK point to these rather than isolated DCM.

Show evidence (1 reference)

PMID:19259135 SUPPORT INDIRECT BACKGROUND Human Clinical

"Patients with LGMD2C-F, in particular with β-sarcoglycan-deficient LGMD2E and δ-sarcoglycan-deficient LGMD2F, often develop a progressive and potentially fatal dilated cardiomyopathy (DCM) in association with muscular dystrophy."

Cardiomyopathy in the recessive sarcoglycanopathies, which also have muscular dystrophy.

Other genetic and acquired causes of dilated cardiomyopathy MONDO:0005021

Overlapping Features Most DCM has other genetic or acquired causes, including myocarditis, which was found on biopsy in part of the founding sporadic series. SGCD accounts for under 1% of idiopathic DCM.

Show evidence (1 reference)

PMID:12794684 SUPPORT DIRECT Human Clinical

"we could estimate the prevalence of delta-sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease."

Most idiopathic DCM is due to other causes.

🐁

Animal Models

6

Sgcd-null mouse

Complete delta-sarcoglycan loss causes cardiomyopathy with focal necrosis and muscular dystrophy, together with vascular smooth muscle sarcoglycan loss and coronary irregularities. It models the recessive null state, not a heterozygous dominant allele.

Species

Mus musculus

Genotype

Sgcd homozygous knockout

Publication

PMID:10481911

Pathograph links

Cardiomyocyte Degeneration partially recapitulates fidelity: low observes: tissue Myocardial necrosis develops without delta-sarcoglycan.

Limitations: This is a complete-loss genotype with skeletal muscle disease. The human CMD1L genotype is heterozygous without myopathy, so the model shows what loss of the protein can do, not what a heterozygous variant does. Necrosis in this mouse is driven at least partly by coronary vascular smooth muscle dysfunction, which a vasodilator prevents; CMD1L patients had normal coronary arteries and no ischemia.

Divergences from the human mechanism

cause unrepresented qualifying

The heterozygous missense or in-frame lesion of CMD1L is not encoded. Both alleles are null.

species mismatch qualifying

Necrosis was observed in mouse myocardium, so the finding is a cross-species inference for the human heart.

population mismatch qualifying

The null mouse's vascular route to necrosis belongs to the recessive state; patients with heterozygous variants showed normal coronaries and no ischemia.

Show evidence (1 reference)

PMID:10481911 SUPPORT DIRECT Model Organism

"We found that only Sgcd null mice developed cardiomyopathy with focal areas of necrosis as the histological hallmark in cardiac and skeletal muscle."

Necrotic cardiomyopathy in the null mouse.

Cardiomyopathic Syrian hamster (BIO14.6 and TO-2)

Inbred hypertrophic (BIO14.6) and dilated (TO-2) sublines share a deletion that abolishes delta-sarcoglycan. Cardiomyopathy and muscular dystrophy are inherited as an autosomal recessive trait. AAV delta-sarcoglycan restores sarcolemmal integrity and prolongs survival in TO-2.

Species

Mesocricetus auratus

Genotype

Homozygous Sgcd deletion of exon 1 and the promoter (natural null)

Publication

PMID:9391120

Pathograph links

Strain-Induced Cardiomyocyte Sarcolemmal Fragility partially recapitulates fidelity: low observes: cellular Cardiomyocytes take up Evans blue dye, a sign of sarcolemmal permeability, which gene transfer prevents.

Limitations: This is a recessive null. Membrane leak here reflects absent protein, not dominant-negative interference by a co-expressed mutant.

Divergences from the human mechanism

cause unrepresented qualifying

No heterozygous or missense allele. Both alleles lack delta-sarcoglycan.

species mismatch qualifying

Sarcolemmal leak was measured in hamster cardiomyocytes, so the finding is a cross-species inference for human myocardium.

Show evidence (1 reference)

PMID:11805334 SUPPORT DIRECT Model Organism

"The transgene preserved sarcolemmal permeability detected in situ by mutual exclusivity between cardiomyocytes taking up intravenously administered Evans blue dye and expressing the delta-SG transgene throughout life."

Sarcolemmal permeability in untreated TO-2 cardiomyocytes, reversed by the transgene.

Left Ventricular Dilatation and Systolic Dysfunction partially recapitulates fidelity: low observes: tissue The TO-2 subline develops DCM, while BIO14.6 develops HCM from the same deletion.

Limitations: A recessive null with muscular dystrophy. One deletion yields either HCM or DCM depending on subline.

Divergences from the human mechanism

cause unrepresented qualifying

Complete loss of delta-sarcoglycan from a homozygous deletion, rather than the heterozygous variant carried by CMD1L patients.

Show evidence (2 references)

PMID:9391120 SUPPORT DIRECT Model Organism

"This deletion included the major transcription initiation site, resulting in a deficiency of delta-SG transcripts with the consequent loss of delta-SG protein in all the CM hamsters"

Establishes the hamster as a complete-loss model.

+ 1 more reference

Cardiac S151A delta-sarcoglycan transgenic mouse

Cardiac overexpression of the founding human allele produces young-onset DCM with increased lethality, nuclear retention of delta-sarcoglycan, and mislocalized lamin A/C and emerin.

Species

Mus musculus

Genotype

alpha-MHC promoter-driven S151A delta-sarcoglycan transgene on a wild-type background

Publication

PMID:17164264

Pathograph links

Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization partially recapitulates fidelity: low observes: cellular Nuclear sequestration of the mutant and its partner sarcoglycans.

Limitations: Up to sevenfold overexpression (per Bauer et al.). The phenotype may reflect dosage rather than the variant, and a native-dosage knock-in was mild.

Divergences from the human mechanism

contested assumption qualifying

The model assumes that overexpressed mutant protein reflects the heterozygous state. Independent family and knock-in data dispute this.

species mismatch qualifying

Nuclear sequestration was seen in transgenic mouse cardiomyocytes, so the finding is a cross-species inference for human myocardium.

Show evidence (1 reference)

PMID:17164264 SUPPORT DIRECT Model Organism

"Instead of placement at the plasma membrane, delta-sarcoglycan was found in the nucleus of S151A delta-sarcoglycan cardiomyocytes. Retention of delta-sarcoglycan in the nucleus was accompanied by partial nuclear sequestration of beta- and gamma-sarcoglycan."

The mechanism observed in this transgenic line.

Left Ventricular Dilatation and Systolic Dysfunction partially recapitulates fidelity: low observes: tissue The transgenic mice develop DCM.

Limitations: The same overexpression caveat applies.

Divergences from the human mechanism

contested assumption qualifying

Overexpression rather than a heterozygous allele at native dosage.

Show evidence (1 reference)

PMID:17164264 SUPPORT DIRECT Model Organism

"Similar to the human delta-sarcoglycan gene mutation, S151A delta-sarcoglycan transgenic mice developed dilated cardiomyopathy at a young age with enhanced lethality."

The DCM phenotype of the transgenic line.

Heterozygous S151A knock-in mouse

The founding allele at native dosage gave only increased heart-to-body weight at one year, with preserved echocardiographic function and no histopathology. Crossing heterozygotes produced no homozygous S151A offspring, suggesting embryonic lethality of the homozygous genotype.

Species

Mus musculus

Genotype

Sgcd S151A/+ knock-in

Publication

PMID:23695275

Pathograph links

Left Ventricular Dilatation and Systolic Dysfunction fails to recapitulate fidelity: moderate observes: tissue The genotype-matched model did not develop systolic dysfunction by one year, only mild cardiac enlargement.

Limitations: Mouse lifespan and one-year follow-up may miss late disease. The authors read the result as a mild, subclinical phenotype rather than a strictly null one.

Divergences from the human mechanism

temporal scope qualifying

Follow-up ended at one year of age, so disease that develops later than that would not have been observed.

species mismatch qualifying

The native-dosage result comes from mouse heart, and the short mouse lifespan may not leave time for late disease to appear.

Show evidence (2 references)

PMID:23695275 SUPPORT DIRECT Model Organism

"Increased heart to body weight suggests cardiac enlargement in 1-year-old S151A knock-in mice. However, at this age cardiac function, assessed by echocardiography, is maintained and histopathology completely absent."

Function was preserved and histology was normal in the genotype-matched model.

+ 1 more reference

Show evidence (1 reference)

PMID:23695275 SUPPORT DIRECT Model Organism

"Crossing of heterozygous mice produced no homozygous offspring, suggesting that homozygous embryos died during embryogenesis."

Homozygous S151A appears embryonic lethal in mice.

SGCD-knockout pig

Loss of delta-sarcoglycan reduces the other sarcoglycans and causes systolic dysfunction, myocardial degeneration and sudden death.

Species

Sus scrofa

Genotype

SGCD homozygous knockout (TALEN, somatic cell nuclear transfer)

Publication

PMID:32060408

Pathograph links

Left Ventricular Dilatation and Systolic Dysfunction partially recapitulates fidelity: low observes: tissue Systolic dysfunction and sudden death in a large-animal null.

Limitations: This is a complete-loss model in which all sarcoglycans fall at both the cardiac and skeletal sarcolemma. That differs from the one human explant, where only delta-sarcoglycan was reduced.

Divergences from the human mechanism

cause unrepresented qualifying

A homozygous null in which every sarcoglycan falls, rather than the heterozygous variant carried by CMD1L patients.

Show evidence (1 reference)

PMID:32060408 SUPPORT DIRECT Model Organism

"Loss of δ-SG expression in the SGCD knockout pigs caused a concomitant reduction in the levels of α-, β-, and γ-SG in the cardiac and skeletal sarcolemma, resulting in systolic dysfunction, myocardial tissue degeneration, and sudden death."

The cardiac phenotype of the null pig.

Drosophila expressing human S151A delta-sarcoglycan

Inducible cardiac expression of human S151A gave enlarged cardiac chambers and impaired systolic function on optical coherence tomography, compared with flies expressing wild-type delta-sarcoglycan.

Species

Drosophila melanogaster

Genotype

Inducible cardiac transgene of human delta-sarcoglycan S151A

Publication

PMID:16432241

Pathograph links

Left Ventricular Dilatation and Systolic Dysfunction partially recapitulates fidelity: low observes: organism Chamber enlargement and systolic impairment in the fly heart tube.

Limitations: Overexpression of a human transgene in an invertebrate tubular heart. It does not reproduce human ventricular anatomy or native heterozygous dosage.

Divergences from the human mechanism

species mismatch qualifying

The Drosophila heart tube is not a mammalian ventricle.

contested assumption qualifying

Overexpression of the S151A allele, whose pathogenicity is disputed.

Show evidence (1 reference)

PMID:16432241 SUPPORT DIRECT Model Organism

"Compared to transgenic flies overexpressing wild-type deltasg, or the standard laboratory strain w(1118), Drosophila expressing deltasg(S151A) developed marked impairment of systolic function and significantly enlarged cardiac chambers."

The fly cardiac phenotype, controlled against wild-type overexpression.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1L
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: dilated cardiomyopathy 1L
  term:
    id: MONDO:0011702
    label: dilated cardiomyopathy 1L
synonyms:
- CMD1L
- cardiomyopathy, dilated, 1L
- cardiomyopathy, dilated, type 1L
- dilated cardiomyopathy type 1L
- SGCD familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in SGCD
description: >-
  Dilated cardiomyopathy 1L (CMD1L) is the proposed autosomal dominant, isolated
  dilated cardiomyopathy attributed to heterozygous variants in SGCD, which encodes
  delta-sarcoglycan, a transmembrane glycoprotein of the sarcoglycan subcomplex of
  the dystrophin-glycoprotein complex. The entity rests on one 2000 report: a
  heterozygous S151A missense variant in three affected relatives of one family with
  young-onset heart failure, transplantation and sudden death, and an in-frame
  deletion of lysine 238 in two sporadic pediatric patients, none with skeletal
  muscle disease. A small Finnish family carried R71T with a mild, late-onset course.
  The association is weak and contested. Cohort screens found SGCD variants to be a
  marginal cause of DCM. In a large family with recessive LGMD2F, S151A carriers,
  including compound heterozygotes, showed no clinical signs of cardiomyopathy, and
  echocardiography was normal in the four compound heterozygotes. A heterozygous S151A knock-in
  mouse showed only a mild, subclinical phenotype. ClinGen rates SGCD for this disease
  Limited (autosomal dominant). A dominant-negative mechanism has been proposed from
  overexpression studies in rat cardiomyocytes, transgenic mice and flies. The strong
  animal phenotypes (BIO14.6 and TO-2 hamsters, Sgcd-null mice, SGCD-knockout pigs)
  are complete-loss models of the separate recessive disorder. Biallelic SGCD loss
  causes limb-girdle muscular dystrophy R6 (LGMD2F), curated under Sarcoglycanopathy.
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
  Scope. This entry covers only the proposed heterozygous (autosomal dominant) isolated
  DCM. Recessive LGMD R6 / LGMD2F (MONDO:0011028) is curated in Sarcoglycanopathy and
  Autosomal Recessive Limb-Girdle Muscular Dystrophy, and its cardiac findings are not
  cited here as CMD1L facts.

  Case count, from the cached sources. Tsubata et al. (PMID:10974018) reported one
  family (FDCM no. 1100) in which three affected individuals carried S151A by SSCP,
  while the unaffected relatives tested did not. The text does not say how many
  relatives were tested by SSCP. CK was measured in five unaffected relatives (II:2,
  II:3, III:3, III:4 and III:5), all normal. Two of 50 sporadic pediatric DCM patients carried the
  in-frame deletion of lysine 238 (p.Lys238del), which was absent from their
  phenotypically normal parents and from 200 controls. That pattern suggests de novo
  occurrence, although parentage was not reported as confirmed. A third sporadic
  patient's R97Q was called a polymorphism by the authors. A fourth abnormal conformer,
  an intron 4 T>A change 38 nucleotides from the exon 5 boundary, was also found in 1 of
  200 controls and was judged a likely polymorphism. Bauer et al.
  (PMID:19259135) summarize the S151A family as two sudden deaths (ages 17-37 years)
  and one transplantation at 21 years. The Finnish screen (PMID:14564412) found one
  small family with two R71T carriers, one meeting DCM criteria and one with slight
  LV dilatation. A Dutch diagnostic cohort (PMID:36270459) reclassified SGCD
  c.4-1G>A as likely pathogenic after a minigene assay. The abstract does not report
  the carrier's phenotype, cardiomyopathy subtype, zygosity or the number of carriers,
  so this carrier is not counted among patients with DCM.

  ClinGen's Dilated Cardiomyopathy GCEP classification is Limited (2026-03-04,
  CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z),
  autosomal dominant, for exactly MONDO:0011702. It matches the committed ClinGen
  ingest table (kb/genes/ingest/clingen_gene_validity.tsv). An earlier version of the
  same assertion in the committed cache/clingen/gene_validity.csv, dated 2025-03-28,
  classified SGCD as No Known Disease Relationship for the umbrella term dilated
  cardiomyopathy (MONDO:0005021, AD). The 2026-03-04 Limited record for CMD1L is the
  current one. The Definitive SGCD record is for autosomal recessive LGMD
  (MONDO:0015152), a different disease, and is not used here. relationship_type is
  deliberately left unset.

  GeneReviews. `just check-genereviews --online` found no CMD1L- or SGCD-specific
  chapter. The disease-level Dilated Cardiomyopathy Overview (PMID:20301486) is tagged
  in references. Its cached record has only the chapter's purpose statement, so it is
  not quoted.

  Arrhythmia (HP:0011675) is not curated as a phenotype. None of the human CMD1L
  reports cited here (PMID:10974018, PMID:14564412, PMID:19259135) describes a rhythm
  disturbance in a carrier; the founding paper mentions conduction disease only for
  other DCM loci, and its sudden deaths are reported without a documented rhythm.

  Deep research. The report came from claude_code, after the falcon provider was not
  configured. Its quantitative ClinGen details (scored points, a case-control p value)
  and GenCC Disputed listing are not in any cached source here, so they are not
  curated.
inheritance:
- name: Autosomal dominant
  description: >-
    The proposed mode is autosomal dominant, based on one three-carrier family and two
    apparently de novo sporadic cases. Penetrance is unproven. In an unrelated LGMD2F
    family, seven S151A carriers aged 3-64 years showed no clinical signs of
    cardiomyopathy, and ECG and echocardiography were normal in the four compound
    heterozygotes (the others had clinical examination only). R71T carriers
    showed a mild, late-onset phenotype. ClinGen evaluates the relationship under
    autosomal dominant inheritance and rates it Limited.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: UNKNOWN
  evidence:
  - reference: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
    reference_title: "SGCD / dilated cardiomyopathy 1L (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SGCD | HGNC:10807 | dilated cardiomyopathy 1L | MONDO:0011702 | AD | Limited"
    explanation: >-
      ClinGen evaluates SGCD for this disease under autosomal dominant inheritance and
      classifies the relationship as Limited.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In family FDCM no. 1100, three affected individuals were identified with abnormal
      SSCP conformers (Figure 2). None of the unaffected members of the family and none
      of the 200 control individuals had this abnormal conformer.
    explanation: >-
      The only familial segregation offered for dominant transmission. Three affected
      carriers is a small number and gives no LOD score.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This finding calls into question the pathological relevance of this p.S151A
      sequence variant for causing familial autosomal-dominant DCM and thereby the
      existence of an autosomal-dominant mode of inheritance for the pathogenic mutations
      in the SGCD gene.
    explanation: >-
      The authors' conclusion from an LGMD2F family in which S151A carriers, including
      compound heterozygotes, had no cardiomyopathy. It directly disputes dominant
      inheritance for SGCD.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Comprehensive clinical examination of seven family members carrying the p.S151A
      sequence variant did not reveal any clinical signs of cardiomyopathy.
    explanation: >-
      Seven carriers aged 3-64 years without clinical cardiomyopathy argue against full
      penetrance of the founding allele. Only the compound heterozygotes had ECG and
      echocardiography.
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a
      late onset of the disease.
    explanation: Variable, milder expression in a second small family.
prevalence:
- population: Published patients with heterozygous SGCD variants and DCM
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The cached primary reports describe the S151A family (three affected carriers), two
    sporadic p.Lys238del children and two R71T carriers in one Finnish family. A Dutch
    c.4-1G>A carrier is not counted, because no phenotype is reported. Across two cohort screens of 99 and 52 DCM patients, no
    causal SGCD variant was found apart from the single Finnish family. Sylvius et al.
    estimated SGCD variants at less than 1% of idiopathic DCM. ULTRA_RARE is a
    qualitative tier inferred from this handful of published cases; no population
    prevalence has been measured.
  evidence:
  - reference: PMID:12794684
    reference_title: "Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      we could estimate the prevalence of delta-sarcoglycan gene mutations to be less
      than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only
      marginally implicated in the disease.
    explanation: A pooled estimate from published and new screening data.
  - reference: PMID:12794684
    reference_title: "Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We screened these two genes for mutations in 99 unrelated patients with sporadic or
      familial DCM.
    explanation: Size of the negative French screen.
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All coding regions of the desmin and delta-sarcoglycan genes and the
      metavinculin-specific exon of the vinculin gene were screened in 52 DCM patients
      from eastern Finland by PCR-SSCP.
    explanation: Size of the Finnish screen that yielded one R71T family.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Mutations affecting the secondary structure were identified in one family and two
      sporadic cases, whereas immunofluorescence analysis of myocardium from one of these
      patients demonstrated significant reduction in delta-sarcoglycan staining.
    explanation: The founding case series of one family and two sporadic patients.
pathophysiology:
- name: Heterozygous SGCD Variant
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: PROVISIONAL
  description: >-
    The proposed initiating lesion is a single germline SGCD missense or in-frame variant
    (S151A, p.Lys238del, R71T), plus one canonical splice variant. Delta-sarcoglycan is a
    sarcolemmal transmembrane glycoprotein of striated and smooth muscle that helps
    stabilize the sarcolemma. The causal status of every reported allele is uncertain:
    ClinGen rates the gene-disease relationship Limited, and the founding S151A allele
    was not associated with cardiac disease in an independent family.
  genes:
  - preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      The dominant-negative category is the authors' proposal, supported only by
      overexpression systems. Haploinsufficiency is not supported, because heterozygous
      relatives of LGMD2F patients have not been described as affected.
  molecular_functions:
  - preferred_term: structural constituent of muscle
    modifier: ABNORMAL
    term:
      id: GO:0008307
      label: structural constituent of muscle
  cellular_components:
  - preferred_term: sarcolemma
    term:
      id: GO:0042383
      label: sarcolemma
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Mutations affecting the secondary structure were identified in one family and two
      sporadic cases, whereas immunofluorescence analysis of myocardium from one of these
      patients demonstrated significant reduction in delta-sarcoglycan staining.
    explanation: The founding report of heterozygous SGCD variants in DCM.
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We detected a novel mutation, Arg71Thr, in the delta-sarcoglycan gene in two members
      of a small DCM family.
    explanation: A second, independent heterozygous allele in a small family.
  - reference: PMID:8842738
    reference_title: "Identification of a novel sarcoglycan gene at 5q33 encoding a sarcolemmal 35 kDa glycoprotein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: >-
      Its mRNA expression is abundant in striated and smooth muscles, with a main 8 kb
      transcript, encoding a predicted basic transmembrane glycoprotein of 290 amino
      acids.
    explanation: >-
      The gene-identification paper's own expression result: SGCD mRNA is abundant in
      striated and smooth muscle and encodes a transmembrane glycoprotein.
  - reference: PMID:9391120
    reference_title: "Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: >-
      We elucidated the molecular interaction of dystrophin-associated glycoproteins
      including delta-SG, by using an in vitro pull-down study and ligand overlay assay,
      which indicates the functional role of delta-SG in stabilizing sarcolemma.
    explanation: >-
      Supports the structural, sarcolemma-stabilizing molecular function bound on this
      node. The assay is in vitro and does not involve a human variant.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Our findings demonstrate that, even in the presence of a second disease-causing
      mutation, the p.S151A mutation in the delta-sarcoglycan gene does not result in
      cardiomyopathy.
    explanation: Independent family evidence against the founding allele being causal.
  downstream:
  - target: Dominant-Negative Disturbance of the Sarcoglycan Complex
    causal_link_type: DIRECT
    description: >-
      Mutant delta-sarcoglycan, co-expressed with the wild-type protein, is proposed to
      interfere with sarcoglycan complex function. This is shown only where the mutant is
      overexpressed.
    evidence:
    - reference: PMID:26968544
      reference_title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant
        negative effect on dystrophin-glycoprotein complex function leading to myocardial
        mechanical instability that may underlie the pathogenesis of
        δ-sarcoglycan-associated DCM.
      explanation: >-
        Adenoviral expression of R97Q or R71T in adult rat cardiomyocytes. The
        dominant-negative inference applies to the human heterozygous state only by
        extrapolation.
    - reference: PMID:17164264
      reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Therefore, the S151A delta-sarcoglycan gene mutation acts in a dominant negative
        manner to produce trafficking defects that disrupt nuclear localization of lamin
        A/C and emerin, thus linking together two common mechanisms of inherited
        cardiomyopathy.
      explanation: >-
        Conclusion drawn from transgenic mice overexpressing S151A from the alpha-MHC
        promoter, not from a heterozygous allele at its native dosage.
- name: Dominant-Negative Disturbance of the Sarcoglycan Complex
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The proposed molecular effect is interference by the mutant protein with the
    sarcoglycan-sarcospan subcomplex of the dystrophin-glycoprotein complex. The two
    experimental systems disagree on how this happens. In rat cardiomyocytes, R97Q and
    R71T traffic normally and the complex assembles, but the membrane is fragile under
    strain. In transgenic mice, S151A is retained in the nucleus and sequesters beta- and
    gamma-sarcoglycan. Both systems overexpress the mutant, and R97Q was called a
    polymorphism in the founding report. In the one p.Lys238del explant, delta-sarcoglycan
    staining was reduced while alpha-, beta-, gamma-sarcoglycan and dystrophin staining
    was preserved.
  protein_complexes:
  - preferred_term: sarcoglycan complex
    term:
      id: GO:0016012
      label: sarcoglycan complex
  - preferred_term: dystrophin-associated glycoprotein complex
    term:
      id: GO:0016010
      label: dystrophin-associated glycoprotein complex
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:26968544
    reference_title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in
      adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the
      plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex.
    explanation: >-
      In this system the mutants assemble normally, so any dominant effect is functional
      rather than a loss of the complex.
  - reference: PMID:26968544
    reference_title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that
      results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan.
    explanation: A variant-specific biochemical defect for the Finnish allele.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      the staining for δ-sarcoglycan was significantly reduced in the patient with the
      ΔK238 mutation (Figure 4).
    explanation: >-
      The only patient myocardium examined showed reduced delta-sarcoglycan, while the
      other sarcoglycans stained normally. Reduced staining is not specific to a
      dominant-negative effect; it is equally compatible with reduced abundance of the
      mutant protein.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      However, in the patients with DCM described in this report, we propose that
      dominant negative mutations in δ-sarcoglycan result in absent skeletal myopathy in
      the face of late-onset DCM.
    explanation: The dominant-negative hypothesis as first proposed, without functional data.
  - reference: PMID:23695275
    reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Myocardial expression of p.S151A cDNA, similar to intact Sgcd cDNA, restores cardiac
      function, although not being able to prevent myocardial histopathology in Sgcd-null
      mice completely.
    explanation: >-
      S151A delta-sarcoglycan restored cardiac function in Sgcd-null mice much as the
      wild-type protein did. A protein that can substitute for the wild type is unlikely
      to poison the complex, so the result argues against a dominant-negative effect of
      this allele.
  downstream:
  - target: Strain-Induced Cardiomyocyte Sarcolemmal Fragility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26968544
      reference_title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is
        sufficient to alter cardiac myocyte plasma membrane stability in the presence of
        mechanical strain.
      explanation: >-
        Mutant expression is sufficient to destabilize the membrane under strain, in
        rodent cells with wild-type protein present.
  - target: Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17164264
      reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Instead of placement at the plasma membrane, delta-sarcoglycan was found in the
        nucleus of S151A delta-sarcoglycan cardiomyocytes. Retention of delta-sarcoglycan
        in the nucleus was accompanied by partial nuclear sequestration of beta- and
        gamma-sarcoglycan.
      explanation: Mislocalized S151A pulls its partner sarcoglycans into the nucleus in transgenic hearts.
- name: Strain-Induced Cardiomyocyte Sarcolemmal Fragility
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Cardiomyocytes expressing mutant delta-sarcoglycan take up membrane-impermeant dye
    and develop contractures under cyclic stretch. This parallels the sarcolemmal
    instability that complete delta-sarcoglycan loss causes. It has not been measured in
    patient tissue or in patient-derived cardiomyocytes.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: sarcolemma
    term:
      id: GO:0042383
      label: sarcolemma
  biological_processes:
  - preferred_term: cellular response to mechanical stimulus
    modifier: ABNORMAL
    term:
      id: GO:0071260
      label: cellular response to mechanical stimulus
  evidence:
  - reference: PMID:26968544
    reference_title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q
      or R71T have increased cell-impermeant dye uptake and undergo contractures at
      greater frequencies than myocytes expressing normal δ-sarcoglycan.
    explanation: The direct cellular readout of membrane fragility in adult rat cardiomyocytes.
  - reference: PMID:17164264
    reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: >-
      Recessive mutations of delta-sarcoglycan that eliminate expression, and therefore
      function, lead to cardiomyopathy and muscular dystrophy by producing instability of
      the plasma membrane.
    explanation: >-
      Background from the complete-loss setting. It shows that membrane instability is
      the established mechanism when the protein is absent, not that it occurs in
      heterozygous carriers.
  - reference: PMID:23695275
    reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      The sarcolemmal membrane of 1–year-old heterozygous S151A knock-in mice is intact
      and cardiomyocytes show no morphological changes.
    explanation: >-
      At native heterozygous dosage, S151A did not damage the sarcolemma by one year. This
      argues against membrane fragility as a consequence of the founding allele, although
      R97Q and R71T were not tested this way.
  downstream:
  - target: Cardiomyocyte Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In complete-loss hamsters, restoring sarcolemmal integrity limits myocardial
      damage. Carrying this step over to the heterozygous human state is an inference.
    evidence:
    - reference: PMID:11805334
      reference_title: "Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        The persistent amelioration of sarcolemmal integrity improved wall thickness and
        the calcification score postmortem.
      explanation: >-
        In delta-sarcoglycan-null TO-2 hamsters, rescuing membrane integrity improves
        myocardial structure. This links the two nodes in a recessive null model only.
- name: Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In transgenic mouse hearts overexpressing S151A from the alpha-myosin heavy chain
    promoter, delta-sarcoglycan accumulated in the nucleus, and lamin A/C and emerin were
    mislocalized throughout the nucleoplasm. Whether the transgenic DCM reflects the
    variant or its overexpression is disputed (see the human-model mismatch
    discussion). A heterozygous S151A knock-in at native dosage gave only a mild
    phenotype, and the finding has not been examined in patient myocardium.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: nuclear envelope
    term:
      id: GO:0005635
      label: nuclear envelope
  biological_processes:
  - preferred_term: nuclear envelope organization
    modifier: ABNORMAL
    term:
      id: GO:0006998
      label: nuclear envelope organization
  evidence:
  - reference: PMID:17164264
    reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Additionally, the nuclear-membrane-associated proteins, lamin A/C and emerin, were
      mislocalized throughout the nucleoplasm.
    explanation: The nuclear-envelope phenotype in S151A transgenic cardiomyocytes.
  downstream:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17164264
      reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Similar to the human delta-sarcoglycan gene mutation, S151A delta-sarcoglycan
        transgenic mice developed dilated cardiomyopathy at a young age with enhanced
        lethality.
      explanation: >-
        The same overexpressing mice develop DCM. Co-occurrence in one model does not
        show that nuclear sequestration is the cause.
- name: Cardiomyocyte Degeneration
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Loss of cardiomyocytes is the step proposed to precede replacement fibrosis and
    ventricular remodeling. Focal myocardial necrosis is the histological hallmark in
    Sgcd-null mice, a recessive model. In CMD1L the only tissue is one explanted
    S151A-family heart, which showed myocyte hypertrophy and moderate fibrosis without
    ischemia; myocyte loss itself was not described in it.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:10481911
    reference_title: "Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      We found that only Sgcd null mice developed cardiomyopathy with focal areas of
      necrosis as the histological hallmark in cardiac and skeletal muscle.
    explanation: Myocardial necrosis under complete delta-sarcoglycan loss, a recessive model.
  downstream:
  - target: Replacement Myocardial Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Replacement fibrosis follows myocyte loss in DCM generally. In CMD1L the evidence
      is moderate fibrosis in one explanted heart; myocyte loss preceding it was not
      shown.
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Gross and histopathologic examination of the explanted heart demonstrated features
        of classic DCM, including increased heart weight, left ventricular dilatation,
        histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
      explanation: Moderate fibrosis in the explant; the preceding myocyte loss is inferred, not observed.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progressive myocyte loss is the general route to ventricular remodeling in DCM. In
      CMD1L the evidence is the co-occurrence of myocardial damage and left ventricular
      dilatation in one explanted heart.
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Gross and histopathologic examination of the explanted heart demonstrated features
        of classic DCM, including increased heart weight, left ventricular dilatation,
        histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
      explanation: Myocardial damage and left ventricular dilatation coexist in the explant; co-occurrence, not a demonstrated causal step.
  - target: Cardiomyocyte Hypertrophy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Gross and histopathologic examination of the explanted heart demonstrated features
        of classic DCM, including increased heart weight, left ventricular dilatation,
        histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
      explanation: Myocyte hypertrophy in the explanted heart.
- name: Replacement Myocardial Fibrosis
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Cardiac fibroblasts deposit extracellular matrix where myocytes are lost. The one
    explanted S151A-family heart showed moderate fibrosis without ischemia, the
    histology of classic DCM.
  cell_types:
  - preferred_term: fibroblast of cardiac tissue
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gross and histopathologic examination of the explanted heart demonstrated features
      of classic DCM, including increased heart weight, left ventricular dilatation,
      histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
    explanation: Human explant histology from the S151A family.
  downstream:
  - target: Myocardial Fibrosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Gross and histopathologic examination of the explanted heart demonstrated features
        of classic DCM, including increased heart weight, left ventricular dilatation,
        histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
      explanation: Moderate fibrosis in the explanted heart.
- name: Left Ventricular Dilatation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Affected members of the S151A family had severely dilated left ventricles with
    moderate to severe systolic dysfunction. One R71T carrier met DCM criteria, and the
    other had only slight dilatation with preserved systolic function. ESTABLISHED
    describes the clinical observation in reported carriers. It is not a claim that
    SGCD causes it.
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Echocardiographically, all affected individuals had severely dilated left
      ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
      (ejection fractions < 35%).
    explanation: Ventricular dilatation and systolic dysfunction in the founding family.
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      One of the mutation carriers fulfills diagnostic criteria for DCM and is also
      symptomatic. The other mutation carrier has slightly dilated left ventricle and well
      preserved systolic function.
    explanation: A milder spectrum in the R71T family.
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    description: >-
      Severe systolic dysfunction leads to congestive heart failure. This is the general
      DCM course; the founding family shows the endpoint but does not isolate the step.
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: Note the severity of disease with early-onset CHF and sudden deaths in affected individuals.
      explanation: Early-onset heart failure followed the ventricular disease in the founding family.
  - target: Sudden Cardiac Death
    causal_link_type: DIRECT
    description: >-
      Sudden death in DCM is generally arrhythmic and follows ventricular remodeling. The
      founding family shows the endpoint but does not isolate the step or the rhythm.
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: Note the severity of disease with early-onset CHF and sudden deaths in affected individuals.
      explanation: Sudden deaths followed the ventricular disease in the founding family.
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Echocardiographically, all affected individuals had severely dilated left
        ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
        (ejection fractions < 35%).
      explanation: Dilated ventricles with systolic dysfunction define DCM in the affected family members.
  - target: Left Ventricular Dilatation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Echocardiographically, all affected individuals had severely dilated left
        ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
        (ejection fractions < 35%).
      explanation: Severe left ventricular dilatation in all affected family members.
  - target: Reduced Left Ventricular Ejection Fraction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10974018
      reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Echocardiographically, all affected individuals had severely dilated left
        ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
        (ejection fractions < 35%).
      explanation: Ejection fractions below 35% in all affected family members.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    The defining feature. It was present in all affected S151A-family members and in the
    two sporadic p.Lys238del children, and was full-blown in one of two R71T carriers.
    Too few patients are reported to estimate a frequency.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Echocardiographically, all affected individuals had severely dilated left
      ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
      (ejection fractions < 35%).
    explanation: Dilated ventricles with systolic dysfunction in all affected members of the founding family.
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      One of the mutation carriers fulfills diagnostic criteria for DCM and is also
      symptomatic. The other mutation carrier has slightly dilated left ventricle and well
      preserved systolic function.
    explanation: One of the two R71T carriers met DCM criteria.
- name: Left Ventricular Dilatation
  category: Cardiovascular
  description: >-
    Severe in the S151A family and slight in the milder R71T carrier.
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Echocardiographically, all affected individuals had severely dilated left
      ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
      (ejection fractions < 35%).
    explanation: Severe left ventricular dilatation in all affected family members.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: >-
    Ejection fractions below 35% in the affected S151A-family members. Systolic function
    was well preserved in one R71T carrier.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Echocardiographically, all affected individuals had severely dilated left
      ventricular chambers (with Z scores > 4) and moderate to severe systolic dysfunction
      (ejection fractions < 35%).
    explanation: Reduced ejection fraction in all affected family members.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: Symptomatic heart failure at a young age in all affected members of the S151A family.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: All affected individuals were symptomatic with evidence of congestive heart failure at young age
    explanation: Heart failure in the founding family.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Sudden deaths occurred in the S151A family. Bauer et al. summarize them as two
    carriers dying at 17-37 years.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Note the severity of disease with early-onset CHF and sudden deaths in affected individuals.
    explanation: Sudden deaths in the founding pedigree.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Two of the patients died of sudden cardiac death at an early age (17–37 years) and
      the third patient required heart transplantation at the age of 21 years.
    explanation: A secondary summary of the founding family's outcomes.
- name: Myocardial Fibrosis
  category: Cardiovascular
  description: Moderate fibrosis in the one explanted S151A-family heart.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gross and histopathologic examination of the explanted heart demonstrated features
      of classic DCM, including increased heart weight, left ventricular dilatation,
      histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
    explanation: Explant histology in patient III:7.
- name: Cardiomyocyte Hypertrophy
  category: Cardiovascular
  description: Myocyte hypertrophy in the one explanted S151A-family heart.
  phenotype_term:
    preferred_term: Cardiomyocyte hypertrophy
    term:
      id: HP:0031319
      label: Cardiomyocyte hypertrophy
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gross and histopathologic examination of the explanted heart demonstrated features
      of classic DCM, including increased heart weight, left ventricular dilatation,
      histopathologic evidence of myocyte hypertrophy, and moderate fibrosis.
    explanation: Explant histology in patient III:7.
- name: Elevated Circulating Creatine Kinase Activity
  category: Musculoskeletal
  description: >-
    Mildly elevated CK, entirely of the muscle isoform, in the transplanted S151A-family
    member. Neuromuscular examination was normal. Other affected relatives had no CK
    measured before death, and the 50 sporadic patients had normal CK. This single
    observation is left unconnected because no source gives a mechanism for it in
    CMD1L.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Creatine kinase (CK) was mildly elevated in this patient (Table 2), with the muscle
      isoform (CK-MM) entirely responsible for the elevation.
    explanation: A single patient's CK finding.
genetic:
- name: SGCD
  gene_term:
    preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
  variant_origin: GERMLINE
  notes: >-
    relationship_type is left unset. ClinGen rates SGCD for MONDO:0011702 Limited, below
    the Definitive/Strong threshold that CAUSATIVE implies. The assertion (AD, Limited,
    2026-03-04) is for exactly MONDO:0011702 and matches the committed ClinGen ingest
    table. Reported heterozygous alleles: S151A
    (c.451T>G), contested by an independent family and a knock-in mouse; p.Lys238del
    (Tsubata's delta-K238, 710-712delAGA or 711-713delGAA), two sporadic children with
    unaffected parents and no functional data; R71T, one small Finnish family; and
    c.4-1G>A, reclassified likely pathogenic in a Dutch cardiomyopathy cohort, with no
    reported carrier phenotype or zygosity. A
    canonical splice variant would most likely act as loss of function, which sits
    uneasily with the proposed dominant-negative mechanism and with unaffected LGMD2F
    heterozygotes. A Chinese promoter-deletion plus p.Q283R haplotype associated with DCM
    risk is a susceptibility finding, not evidence for Mendelian CMD1L.
  gene_disease_validity:
  - validity_classification: LIMITED
    classified_by: CLINGEN
    external_id: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
    evidence:
    - reference: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
      reference_title: "SGCD / dilated cardiomyopathy 1L (Limited)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SGCD | HGNC:10807 | dilated cardiomyopathy 1L | MONDO:0011702 | AD | Limited"
      explanation: >-
        ClinGen's Dilated Cardiomyopathy GCEP classifies the autosomal dominant
        SGCD-CMD1L relationship as Limited (2026-03-04).
  evidence:
  - reference: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
    reference_title: "SGCD / dilated cardiomyopathy 1L (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SGCD | HGNC:10807 | dilated cardiomyopathy 1L | MONDO:0011702 | AD | Limited"
    explanation: The current expert-panel classification of this gene-disease pair.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In two patients, a 3-bp deletion (either 710–712delAGA or 711–713delGAA) of
      δ-sarcoglycan exon 9p was identified (Figure 3) that deletes a codon encoding the
      amino acid lysine at position 238 (ΔK238); screening 200 control individuals, as
      well as the phenotypically normal parents of these children, did not identify the
      same abnormality.
    explanation: The two sporadic carriers and the absence of the deletion in their parents.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In one case, a 290G→A transition in exon 4, which changes the arginine at codon 97
      to glutamine (R97Q), was identified. This 290G→A transition was previously reported
      to be a polymorphism (45).
    explanation: >-
      The founding authors treated R97Q as a polymorphism. It is therefore not counted as
      a CMD1L allele, although Campbell et al. later tested it as a DCM mutant.
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We detected a novel mutation, Arg71Thr, in the delta-sarcoglycan gene in two members
      of a small DCM family.
    explanation: The R71T family.
  - reference: PMID:36270459
    reference_title: "SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were
      reclassified as likely pathogenic.
    explanation: >-
      A functionally tested splice variant, likely pathogenic in a cardiomyopathy
      diagnostic cohort; no carrier phenotype or zygosity is reported. The
      abstract does not specify the carrier's cardiomyopathy subtype.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This finding questions the pathological relevance of this sequence variant for
      causing familial autosomal-dominant dilated cardiomyopathy and thereby the role of
      the delta-sarcoglycan gene in general as a disease-causing gene for
      autosomal-dominant dilated cardiomyopathy.
    explanation: The principal published challenge to the gene-disease relationship.
  - reference: PMID:12794684
    reference_title: "Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      New polymorphisms, as well as already described ones, were found in these two genes,
      but none appeared to be responsible for dilated cardiomyopathy.
    explanation: >-
      A negative screen of 99 DCM patients. It shows that causal SGCD variants are rare in
      DCM, not that heterozygous SGCD variants cannot cause it, so it neither supports nor
      refutes the gene-disease relationship.
  - reference: PMID:26720722
    reference_title: "A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Haplotype -_G consisting c.-100~-110 and A848G was associated with increased risk of
      DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM
    explanation: >-
      A single association study of common SGCD polymorphisms. It concerns susceptibility
      and provides no evidence for or against Mendelian CMD1L.
progression:
- phase: Asymptomatic, physically active phase
  notes: >-
    Affected S151A-family members were athletic until heart failure or sudden death. The
    duration of this phase is not reported.
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: All affected individuals remained athletic until their onset of heart failure or sudden death.
    explanation: Describes the pre-symptomatic course.
- phase: Heart failure, transplantation or sudden death in the founding family
  age_range: childhood to young adulthood
  notes: >-
    Heart failure began at a young age. One son needed transplantation at 21. Bauer et al.
    summarize the two deaths as occurring at 17-37 years. The p.Lys238del carriers came
    from a pediatric series aged 3 days to 18 years.
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Cardiac transplantation was necessary in the 21-year-old son (III:7) of the proband (II:5) as seen in the pedigree (Figure 1).
    explanation: Age at transplantation.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Fifty patients ranging in age from 3 days to 18 years (mean, 9.5 years) with
      clinically apparent DCM presenting with heart failure and echocardiograms diagnostic
      for DCM were identified.
    explanation: Age range of the sporadic series that included the two p.Lys238del carriers.
- phase: Mild, late-onset course in R71T carriers
  notes: The Finnish carriers had a milder phenotype with later onset.
  evidence:
  - reference: PMID:14564412
    reference_title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a
      late onset of the disease.
    explanation: Variable expressivity across alleles or families.
diagnosis:
- name: Cardiac and neuromuscular clinical evaluation
  description: >-
    The founding study evaluated patients by examination focused on the cardiac and
    neuromuscular systems, ECG, chest radiography and echocardiography, with
    catheterization and endomyocardial biopsy where clinically indicated. A normal
    neuromuscular examination and the absence of skeletal myopathy separate CMD1L from
    LGMD2F. CK may still be mildly elevated, as in one patient.
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All patients were evaluated by physical examination (particularly focused in the
      cardiac and neuromuscular systems), chest radiography, electrocardiography, and
      echocardiography.
    explanation: The clinical workup used in the founding cohort.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: No skeletal muscle disease occurred in any of these patients.
    explanation: Absence of skeletal myopathy is part of the definition of this isolated DCM.
- name: Genetic testing and variant interpretation
  description: >-
    SGCD may appear on DCM multigene panels. Because gene-disease validity is Limited,
    and the founding allele did not cause disease in an independent family, a heterozygous
    SGCD variant should not on its own be taken as diagnostic. Functional splicing assays
    can resolve candidate splice variants.
  evidence:
  - reference: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
    reference_title: "SGCD / dilated cardiomyopathy 1L (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SGCD | HGNC:10807 | dilated cardiomyopathy 1L | MONDO:0011702 | AD | Limited"
    explanation: The Limited classification governs how a heterozygous SGCD finding is interpreted.
  - reference: PMID:36270459
    reference_title: "SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were
      reclassified as likely pathogenic.
    explanation: A minigene assay used to reclassify an SGCD splice variant in diagnostics.
- name: Myocardial delta-sarcoglycan immunostaining
  description: >-
    A research test. In the one explant examined, delta-sarcoglycan staining was reduced
    while the other sarcoglycans and dystrophin were preserved. It is not validated as a
    diagnostic test.
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the staining for δ-sarcoglycan was significantly reduced in the patient with the
      ΔK238 mutation (Figure 4).
    explanation: The single tissue observation.
differential_diagnoses:
- name: Autosomal recessive limb-girdle muscular dystrophy type 2F (LGMD R6)
  description: >-
    Biallelic SGCD variants cause recessive LGMD with elevated CK and proximal
    weakness. Cardiac involvement varies. The CMD1L patients had no skeletal muscle
    disease, and the two conditions are curated separately (see Sarcoglycanopathy).
  disease_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2F
    term:
      id: MONDO:0011028
      label: autosomal recessive limb-girdle muscular dystrophy type 2F
  evidence:
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We identified a novel missense mutation in exon 6 (p.A131P) of the delta-sarcoglycan
      gene, which in a homozygous state leads to the clinical picture of a limb girdle
      muscular dystrophy.
    explanation: The allelic recessive disorder.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: Thus, LGMD associated with sarcoglycan mutations appears to be inherited as a recessive disease.
    explanation: The founding authors contrast recessive LGMD with the proposed dominant DCM.
- name: Other sarcoglycanopathies (LGMD R3-R5)
  description: >-
    Alpha-, beta- and gamma-sarcoglycan deficiencies also cause recessive LGMD with
    possible cardiomyopathy. Skeletal myopathy and elevated CK point to these rather
    than isolated DCM.
  disease_term:
    preferred_term: sarcoglycanopathy
    term:
      id: MONDO:0016140
      label: sarcoglycanopathy
  evidence:
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: >-
      Patients with LGMD2C-F, in particular with β-sarcoglycan-deficient LGMD2E and
      δ-sarcoglycan-deficient LGMD2F, often develop a progressive and potentially fatal
      dilated cardiomyopathy (DCM) in association with muscular dystrophy.
    explanation: Cardiomyopathy in the recessive sarcoglycanopathies, which also have muscular dystrophy.
- name: Other genetic and acquired causes of dilated cardiomyopathy
  description: >-
    Most DCM has other genetic or acquired causes, including myocarditis, which was found
    on biopsy in part of the founding sporadic series. SGCD accounts for under 1% of
    idiopathic DCM.
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  evidence:
  - reference: PMID:12794684
    reference_title: "Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      we could estimate the prevalence of delta-sarcoglycan gene mutations to be less
      than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only
      marginally implicated in the disease.
    explanation: Most idiopathic DCM is due to other causes.
treatments:
- name: Guideline-directed heart failure pharmacotherapy
  description: >-
    Standard therapy for heart failure with reduced ejection fraction.
  therapeutic_modality: SMALL_MOLECULE
  notes: >-
    No CMD1L- or SGCD-specific treatment data exist. This is generic DCM care, and no
    evidence item is attached.
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Supportive. It does not address the SGCD lesion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Implantable cardioverter-defibrillator
  description: >-
    Considered for sudden-death prevention under general DCM criteria.
  therapeutic_modality: DEVICE
  notes: >-
    No CMD1L-specific evidence exists. Sudden deaths in the founding family make the
    question relevant, but no source evaluates ICD use in SGCD carriers.
  target_mechanisms:
  - target: Sudden Cardiac Death
    description: Supportive. It addresses arrhythmic death only.
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
- name: Heart transplantation
  description: >-
    Performed for end-stage disease in the founding family.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Replaces the failing heart.
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Cardiac transplantation was necessary in the 21-year-old son (III:7) of the proband (II:5) as seen in the pedigree (Figure 1).
    explanation: Transplantation in a CMD1L patient. This is a case report, not an outcome study.
- name: Genetic counseling
  description: >-
    Counseling should convey that the SGCD-DCM relationship is Limited and contested.
  therapeutic_modality: BEHAVIORAL
  notes: >-
    No CMD1L-specific counseling studies exist. The evidence item supports only the
    uncertainty that counseling must convey.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
    reference_title: "SGCD / dilated cardiomyopathy 1L (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SGCD | HGNC:10807 | dilated cardiomyopathy 1L | MONDO:0011702 | AD | Limited"
    explanation: Limited validity is the central fact counseling must communicate.
- name: AAV delta-sarcoglycan gene transfer (preclinical, null models only)
  description: >-
    AAV delivery of wild-type delta-sarcoglycan rescues cardiomyopathy in Sgcd-null mice
    and TO-2 hamsters.
  therapeutic_modality: GENE_THERAPY
  notes: >-
    Preclinical only, and only in complete-loss models. Gene replacement has not been
    tested against a heterozygous dominant-negative allele, and it has not been used in
    humans with CMD1L.
  target_mechanisms:
  - target: Strain-Induced Cardiomyocyte Sarcolemmal Fragility
    description: Restores sarcolemmal integrity in null hamsters.
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:19218289
    reference_title: "Prevention of cardiomyopathy in delta-sarcoglycan knockout mice after systemic transfer of targeted adeno-associated viral vectors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Left ventricular function remained stable in mice expressing Sgcd while it
      deteriorated in EGFP controls within 6 months, paralleled by increased expression of
      brain natriuretic peptide, a molecular marker of heart failure.
    explanation: Rescue of a knockout mouse, which is not the human heterozygous genotype.
  - reference: PMID:11805334
    reference_title: "Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      The transgene preserved sarcolemmal permeability detected in situ by mutual
      exclusivity between cardiomyocytes taking up intravenously administered Evans blue
      dye and expressing the delta-SG transgene throughout life.
    explanation: Rescue of sarcolemmal permeability in null TO-2 hamsters.
animal_models:
- name: Sgcd-null mouse
  species: Mus musculus
  genotype: Sgcd homozygous knockout
  publication: PMID:10481911
  description: >-
    Complete delta-sarcoglycan loss causes cardiomyopathy with focal necrosis and
    muscular dystrophy, together with vascular smooth muscle sarcoglycan loss and
    coronary irregularities. It models the recessive null state, not a heterozygous
    dominant allele.
  modeled_mechanisms:
  - target: Cardiomyocyte Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Myocardial necrosis develops without delta-sarcoglycan.
    limitations: >-
      This is a complete-loss genotype with skeletal muscle disease. The human CMD1L
      genotype is heterozygous without myopathy, so the model shows what loss of the
      protein can do, not what a heterozygous variant does. Necrosis in this mouse is
      driven at least partly by coronary vascular smooth muscle dysfunction, which a
      vasodilator prevents; CMD1L patients had normal coronary arteries and no ischemia.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: The heterozygous missense or in-frame lesion of CMD1L is not encoded. Both alleles are null.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Necrosis was observed in mouse myocardium, so the finding is a cross-species inference for the human heart.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The null mouse's vascular route to necrosis belongs to the recessive state;
        patients with heterozygous variants showed normal coronaries and no ischemia.
    evidence:
    - reference: PMID:10481911
      reference_title: "Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        We found that only Sgcd null mice developed cardiomyopathy with focal areas of
        necrosis as the histological hallmark in cardiac and skeletal muscle.
      explanation: Necrotic cardiomyopathy in the null mouse.
- name: Cardiomyopathic Syrian hamster (BIO14.6 and TO-2)
  species: Mesocricetus auratus
  genotype: Homozygous Sgcd deletion of exon 1 and the promoter (natural null)
  publication: PMID:9391120
  description: >-
    Inbred hypertrophic (BIO14.6) and dilated (TO-2) sublines share a deletion that
    abolishes delta-sarcoglycan. Cardiomyopathy and muscular dystrophy are inherited as
    an autosomal recessive trait. AAV delta-sarcoglycan restores sarcolemmal integrity
    and prolongs survival in TO-2.
  modeled_mechanisms:
  - target: Strain-Induced Cardiomyocyte Sarcolemmal Fragility
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Cardiomyocytes take up Evans blue dye, a sign of sarcolemmal permeability, which
      gene transfer prevents.
    limitations: >-
      This is a recessive null. Membrane leak here reflects absent protein, not
      dominant-negative interference by a co-expressed mutant.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: No heterozygous or missense allele. Both alleles lack delta-sarcoglycan.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Sarcolemmal leak was measured in hamster cardiomyocytes, so the finding is a cross-species inference for human myocardium.
    evidence:
    - reference: PMID:11805334
      reference_title: "Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        The transgene preserved sarcolemmal permeability detected in situ by mutual
        exclusivity between cardiomyocytes taking up intravenously administered Evans
        blue dye and expressing the delta-SG transgene throughout life.
      explanation: Sarcolemmal permeability in untreated TO-2 cardiomyocytes, reversed by the transgene.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: The TO-2 subline develops DCM, while BIO14.6 develops HCM from the same deletion.
    limitations: >-
      A recessive null with muscular dystrophy. One deletion yields either HCM or DCM
      depending on subline.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: Complete loss of delta-sarcoglycan from a homozygous deletion, rather than the heterozygous variant carried by CMD1L patients.
    evidence:
    - reference: PMID:9391120
      reference_title: "Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        This deletion included the major transcription initiation site, resulting in a
        deficiency of delta-SG transcripts with the consequent loss of delta-SG protein in
        all the CM hamsters
      explanation: Establishes the hamster as a complete-loss model.
    - reference: PMID:9391120
      reference_title: "Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Syrian hamsters with CM are known to inherit both CM and muscular dystrophy as an
        autosomal recessive trait
      explanation: Recessive inheritance with skeletal disease, unlike CMD1L.
- name: Cardiac S151A delta-sarcoglycan transgenic mouse
  species: Mus musculus
  genotype: alpha-MHC promoter-driven S151A delta-sarcoglycan transgene on a wild-type background
  publication: PMID:17164264
  description: >-
    Cardiac overexpression of the founding human allele produces young-onset DCM with
    increased lethality, nuclear retention of delta-sarcoglycan, and mislocalized lamin
    A/C and emerin.
  modeled_mechanisms:
  - target: Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Nuclear sequestration of the mutant and its partner sarcoglycans.
    limitations: >-
      Up to sevenfold overexpression (per Bauer et al.). The phenotype may reflect dosage
      rather than the variant, and a native-dosage knock-in was mild.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: >-
        The model assumes that overexpressed mutant protein reflects the heterozygous
        state. Independent family and knock-in data dispute this.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Nuclear sequestration was seen in transgenic mouse cardiomyocytes, so the finding is a cross-species inference for human myocardium.
    evidence:
    - reference: PMID:17164264
      reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Instead of placement at the plasma membrane, delta-sarcoglycan was found in the
        nucleus of S151A delta-sarcoglycan cardiomyocytes. Retention of delta-sarcoglycan
        in the nucleus was accompanied by partial nuclear sequestration of beta- and
        gamma-sarcoglycan.
      explanation: The mechanism observed in this transgenic line.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: The transgenic mice develop DCM.
    limitations: The same overexpression caveat applies.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: Overexpression rather than a heterozygous allele at native dosage.
    evidence:
    - reference: PMID:17164264
      reference_title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Similar to the human delta-sarcoglycan gene mutation, S151A delta-sarcoglycan
        transgenic mice developed dilated cardiomyopathy at a young age with enhanced
        lethality.
      explanation: The DCM phenotype of the transgenic line.
- name: Heterozygous S151A knock-in mouse
  species: Mus musculus
  genotype: Sgcd S151A/+ knock-in
  publication: PMID:23695275
  description: >-
    The founding allele at native dosage gave only increased heart-to-body weight at one
    year, with preserved echocardiographic function and no histopathology. Crossing
    heterozygotes produced no homozygous S151A offspring, suggesting embryonic lethality
    of the homozygous genotype.
  evidence:
  - reference: PMID:23695275
    reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Crossing of heterozygous mice produced no homozygous offspring, suggesting that
      homozygous embryos died during embryogenesis.
    explanation: Homozygous S151A appears embryonic lethal in mice.
  modeled_mechanisms:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The genotype-matched model did not develop systolic dysfunction by one year, only
      mild cardiac enlargement.
    limitations: >-
      Mouse lifespan and one-year follow-up may miss late disease. The authors read the
      result as a mild, subclinical phenotype rather than a strictly null one.
    divergences:
    - divergence_type: TEMPORAL_SCOPE
      materiality: QUALIFYING
      description: Follow-up ended at one year of age, so disease that develops later than that would not have been observed.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: The native-dosage result comes from mouse heart, and the short mouse lifespan may not leave time for late disease to appear.
    evidence:
    - reference: PMID:23695275
      reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Increased heart to body weight suggests cardiac enlargement in 1-year-old S151A
        knock-in mice. However, at this age cardiac function, assessed by echocardiography,
        is maintained and histopathology completely absent.
      explanation: Function was preserved and histology was normal in the genotype-matched model.
    - reference: PMID:23695275
      reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Our results suggest that the p.S151A mutation causes a mild, subclinical phenotype
        of cardiomyopathy, which is prone to be overseen in patients carrying such sequence
        variants.
      explanation: The authors' own interpretation.
- name: SGCD-knockout pig
  species: Sus scrofa
  genotype: SGCD homozygous knockout (TALEN, somatic cell nuclear transfer)
  publication: PMID:32060408
  description: >-
    Loss of delta-sarcoglycan reduces the other sarcoglycans and causes systolic
    dysfunction, myocardial degeneration and sudden death.
  modeled_mechanisms:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Systolic dysfunction and sudden death in a large-animal null.
    limitations: >-
      This is a complete-loss model in which all sarcoglycans fall at both the cardiac
      and skeletal sarcolemma. That differs from the one human explant, where only
      delta-sarcoglycan was reduced.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: A homozygous null in which every sarcoglycan falls, rather than the heterozygous variant carried by CMD1L patients.
    evidence:
    - reference: PMID:32060408
      reference_title: "Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Loss of δ-SG expression in the SGCD knockout pigs caused a concomitant reduction in
        the levels of α-, β-, and γ-SG in the cardiac and skeletal sarcolemma, resulting in
        systolic dysfunction, myocardial tissue degeneration, and sudden death.
      explanation: The cardiac phenotype of the null pig.
- name: Drosophila expressing human S151A delta-sarcoglycan
  species: Drosophila melanogaster
  genotype: Inducible cardiac transgene of human delta-sarcoglycan S151A
  publication: PMID:16432241
  description: >-
    Inducible cardiac expression of human S151A gave enlarged cardiac chambers and
    impaired systolic function on optical coherence tomography, compared with flies
    expressing wild-type delta-sarcoglycan.
  modeled_mechanisms:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Chamber enlargement and systolic impairment in the fly heart tube.
    limitations: >-
      Overexpression of a human transgene in an invertebrate tubular heart. It does not
      reproduce human ventricular anatomy or native heterozygous dosage.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: The Drosophila heart tube is not a mammalian ventricle.
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: Overexpression of the S151A allele, whose pathogenicity is disputed.
    evidence:
    - reference: PMID:16432241
      reference_title: "Drosophila as a model for the identification of genes causing adult human heart disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Compared to transgenic flies overexpressing wild-type deltasg, or the standard
        laboratory strain w(1118), Drosophila expressing deltasg(S151A) developed marked
        impairment of systolic function and significantly enlarged cardiac chambers.
      explanation: The fly cardiac phenotype, controlled against wild-type overexpression.
discussions:
- discussion_id: cmd1l_does_sgcd_dominant_dcm_exist
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Do heterozygous SGCD variants cause Mendelian autosomal dominant DCM, or were the
    founding observations chance co-occurrences of rare variants with DCM?
  attaches_to:
  - pathophysiology#Heterozygous SGCD Variant
  rationale: >-
    Support comes from one three-carrier family, two apparently de novo sporadic
    children, one small Finnish family, and one splice variant of unreported phenotype.
    Against it are seven S151A carriers aged 3-64 years in an LGMD2F family who showed
    no clinical signs of cardiomyopathy, with normal ECG and echocardiography in the four
    compound heterozygotes (the others had clinical examination only); negative screens of 99 and 52 DCM patients, and a
    mild knock-in mouse. ClinGen rates the relationship Limited.
  evidence:
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Comprehensive clinical and cardiac investigation in all of the compound heterozygous
      family members revealed no signs of cardiomyopathy or limb girdle muscular
      dystrophy.
    explanation: The central counter-observation behind the controversy.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Even the oldest family member carrying the mutation (pedigree no. II:4; 64 years
      old) did not show any clinical signs of DCM.
    explanation: Absence of disease at an age when DCM would be expected.
  - reference: PMID:23695275
    reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      So far, the role of mutations in the δ-sarcogylcan (Sgcd) gene in causing autosomal
      dominant dilated cardiomyopathy (DCM) remains inconclusive.
    explanation: A later model study that also calls the question open.
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The other sequence variant (ΔK238) in the SGCD gene described by Tsubata et al was
      found in two patients with sporadic DCM but in the absence of clear functional data
      and cosegregation with the phenotype in an autosomal-dominant manner no final
      conclusion can be drawn.
    explanation: The sporadic cases are also unresolved.
  proposed_experiments:
  - experiment_id: exp_cmd1l_case_control_burden
    name: SGCD rare-variant burden in large DCM case-control data
    description: >-
      Compare the burden of rare SGCD missense, in-frame and splice variants in DCM
      probands against population controls, stratified by variant class and protein
      domain. Collect cardiac phenotypes from heterozygous parents of LGMD2F patients as
      an internal penetrance check.
- discussion_id: cmd1l_null_models_vs_heterozygous_disease
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    How informative are complete-loss and overexpression models for a disease attributed
    to one heterozygous SGCD allele?
  attaches_to:
  - pathophysiology#Cardiomyocyte Degeneration
  - pathophysiology#Nuclear Sequestration of Delta-Sarcoglycan with Lamin A/C Mislocalization
  rationale: >-
    The hamster, Sgcd-null mouse and SGCD-knockout pig are recessive nulls with skeletal
    myopathy, modeling LGMD R6 biology. The S151A transgenic mouse and fly overexpress
    the mutant, while the genotype-matched knock-in mouse shows only mild, subclinical
    change. The vascular mechanism of the null mouse is contradicted by normal coronaries
    in patients.
  evidence:
  - reference: PMID:19259135
    reference_title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Heydemann et al found up to sevenfold overexpression of the S151A sequence variant
      in hearts of their mice, which may suggest that rather the overall level of gene
      expression than the expression of the sequence variant has been responsible for
      the pathology in mice.
    explanation: The dosage caveat for the transgenic evidence.
  - reference: PMID:23695275
    reference_title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: Heterozygous S151A knock-in mice developed a rather mild phenotype of cardiomyopathy.
    explanation: The genotype-matched model diverges from the severe human founding family.
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Coronary angiography and echocardiography (transthoracic and in some cases
      transesophageal) identified normal coronary arteries in all patients with
      δ-sarcoglycan mutations, and no evidence of ischemia was found in the myocardium.
    explanation: The human finding that contradicts the null-mouse vascular route.
  - reference: PMID:10481911
    reference_title: "Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Our data indicate that disruption of the SG-SSPN complex in vascular smooth muscle
      perturbs vascular function, which initiates cardiomyopathy and exacerbates
      muscular dystrophy.
    explanation: >-
      In the null mouse, cardiomyopathy starts from vascular smooth muscle sarcoglycan
      loss, a mechanism not seen in CMD1L patients.
  proposed_experiments:
  - experiment_id: exp_cmd1l_isogenic_ipsc_cardiomyocytes
    name: Isogenic heterozygous SGCD variants in human iPSC cardiomyocytes
    description: >-
      Introduce S151A, p.Lys238del, R71T and a null allele heterozygously into one
      control iPSC line. Measure sarcoglycan localization, membrane permeability under
      cyclic stretch, and nuclear lamin A/C distribution against isogenic wild-type and
      heterozygous-null controls. This would separate a dominant-negative effect from
      haploinsufficiency and from overexpression artifacts.
- discussion_id: cmd1l_dominant_negative_vs_haploinsufficiency
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    If heterozygous SGCD variants cause DCM, by what molecular mechanism, given that
    LGMD2F heterozygous carriers are not known to be affected?
  attaches_to:
  - pathophysiology#Dominant-Negative Disturbance of the Sarcoglycan Complex
  rationale: >-
    A dominant-negative effect is proposed because heterozygous null carriers in LGMD2F
    families are not described as affected. The two overexpression systems disagree on
    the mechanism: normal trafficking with fragile membranes in one, nuclear
    sequestration in the other. A functionally confirmed canonical splice variant
    (c.4-1G>A), reclassified likely pathogenic in a cardiomyopathy cohort, is a likely
    loss-of-function allele. If it is causal, a dominant-negative-only mechanism does
    not explain it; its carrier's phenotype is not reported. A native-dosage S151A
    knock-in showed an intact sarcolemma, and S151A rescued Sgcd-null hearts. Systematic cardiac data on heterozygous LGMD2F relatives
    are lacking.
  evidence:
  - reference: PMID:10974018
    reference_title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Although heterozygotes within LGMD2F families have not been described to be
      affected, it is possible that cardiac evaluation overlooked cardiac pathology or the
      cardiac dysfunction had not become apparent at the time of evaluation
    explanation: The founding authors acknowledge the missing heterozygote cardiac data.
  - reference: PMID:26968544
    reference_title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in
      adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the
      plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex.
    explanation: This system shows normal trafficking, unlike the nuclear retention seen in transgenic mice.
  - reference: PMID:36270459
    reference_title: "SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were
      reclassified as likely pathogenic.
    explanation: >-
      A likely loss-of-function SGCD allele classified likely pathogenic in a
      cardiomyopathy cohort; the carrier's phenotype and zygosity are not reported.
references:
- reference: PMID:10974018
  title: "Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy."
- reference: PMID:19259135
  title: "Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?"
- reference: PMID:14564412
  title: "A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy."
- reference: PMID:12794684
  title: "Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy."
- reference: PMID:23695275
  title: "S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice."
- reference: PMID:26968544
  title: "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability."
- reference: PMID:17164264
  title: "Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes."
- reference: PMID:36270459
  title: "SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics."
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z
  title: "SGCD / dilated cardiomyopathy 1L (Limited)"

📚

References & Deep Research

References

10

PMID:10974018

Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy.

No top-level findings curated for this source.

PMID:19259135

Does delta-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?

No top-level findings curated for this source.

PMID:14564412

A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy.

No top-level findings curated for this source.

PMID:12794684

Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy.

No top-level findings curated for this source.

PMID:23695275

S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice.

No top-level findings curated for this source.

PMID:26968544

Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability.

No top-level findings curated for this source.

PMID:17164264

Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes.

No top-level findings curated for this source.

PMID:36270459

SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics.

No top-level findings curated for this source.

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z

SGCD / dilated cardiomyopathy 1L (Limited)

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Scope. This entry covers only the proposed heterozygous (autosomal dominant) isolated DCM. Recessive LGMD R6 / LGMD2F (MONDO:0011028) is curated in Sarcoglycanopathy and Autosomal Recessive Limb-Girdle Muscular Dystrophy, and its cardiac findings are not cited here as CMD1L facts. Case count, from the cached sources. Tsubata et al. (PMID:10974018) reported one family (FDCM no. 1100) in which three affected individuals carried S151A by SSCP, while the unaffected relatives tested did not. The text does not say how many relatives were tested by SSCP. CK was measured in five unaffected relatives (II:2, II:3, III:3, III:4 and III:5), all normal. Two of 50 sporadic pediatric DCM patients carried the in-frame deletion of lysine 238 (p.Lys238del), which was absent from their phenotypically normal parents and from 200 controls. That pattern suggests de novo occurrence, although parentage was not reported as confirmed. A third sporadic patient's R97Q was called a polymorphism by the authors. A fourth abnormal conformer, an intron 4 T>A change 38 nucleotides from the exon 5 boundary, was also found in 1 of 200 controls and was judged a likely polymorphism. Bauer et al. (PMID:19259135) summarize the S151A family as two sudden deaths (ages 17-37 years) and one transplantation at 21 years. The Finnish screen (PMID:14564412) found one small family with two R71T carriers, one meeting DCM criteria and one with slight LV dilatation. A Dutch diagnostic cohort (PMID:36270459) reclassified SGCD c.4-1G>A as likely pathogenic after a minigene assay. The abstract does not report the carrier's phenotype, cardiomyopathy subtype, zygosity or the number of carriers, so this carrier is not counted among patients with DCM. ClinGen's Dilated Cardiomyopathy GCEP classification is Limited (2026-03-04, CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z), autosomal dominant, for exactly MONDO:0011702. It matches the committed ClinGen ingest table (kb/genes/ingest/clingen_gene_validity.tsv). An earlier version of the same assertion in the committed cache/clingen/gene_validity.csv, dated 2025-03-28, classified SGCD as No Known Disease Relationship for the umbrella term dilated cardiomyopathy (MONDO:0005021, AD). The 2026-03-04 Limited record for CMD1L is the current one. The Definitive SGCD record is for autosomal recessive LGMD (MONDO:0015152), a different disease, and is not used here. relationship_type is deliberately left unset. GeneReviews. `just check-genereviews --online` found no CMD1L- or SGCD-specific chapter. The disease-level Dilated Cardiomyopathy Overview (PMID:20301486) is tagged in references. Its cached record has only the chapter's purpose statement, so it is not quoted. Arrhythmia (HP:0011675) is not curated as a phenotype. None of the human CMD1L reports cited here (PMID:10974018, PMID:14564412, PMID:19259135) describes a rhythm disturbance in a carrier; the founding paper mentions conduction disease only for other DCM loci, and its sudden deaths are reported without a documented rhythm. Deep research. The report came from claude_code, after the falcon provider was not configured. Its quantitative ClinGen details (scored points, a case-control p value) and GenCC Disputed listing are not in any cached source here, so they are not curated.

Create: Dilated_Cardiomyopathy_1L · 2026-10-08T20:50:17Z · View source

Created the CMD1L entry (heterozygous SGCD, MONDO:0011702) for claim issue #13734. Deep research: claude_code provider (falcon fallback, not configured); 20/20 references resolved. Curated as a weak, contested association: founding Tsubata 2000 report (PMID:10974018; one family with three affected S151A carriers, two sporadic pediatric p.Lys238del cases with unaffected non-carrier parents), Finnish R71T family (PMID:14564412; two carriers), Dutch c.4-1G>A reclassification (PMID:36270459), against negative screens (PMID:12794684, 99 patients; PMID:14564412, 52 patients), seven unaffected S151A carriers including four compound heterozygotes (PMID:19259135), and a mild heterozygous knock-in mouse (PMID:23695275). Dominant-negative mechanism recorded as HYPOTHETICAL from overexpression systems (PMID:26968544, PMID:17164264). Null models (Sgcd-null mouse PMID:10481911, BIO14.6/TO-2 hamster PMID:9391120 and PMID:11805334, SGCD-KO pig PMID:32060408) and S151A fly (PMID:16432241) recorded with CAUSE_UNREPRESENTED / CONTESTED_ASSUMPTION divergences; the knock-in is FAILS_TO_RECAPITULATE. ClinGen Limited (AD) assertion CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z cached via clingen-rebuild --csv-only (manifest not repinned; the assertion matches the committed kb/genes/ingest/clingen_gene_validity.tsv) and copied into gene_disease_validity; relationship_type left unset. GenCC Disputed listing and ClinGen point scores from the report were not curated because no cached source contains them. Validation: just validate clean; count-verified-snippets 95/95; check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-snippet-length, check-snippet-grading, check-retired-support-prose, check-coarse-phenotypes, check-gene-validity and gene-activity grounding (against origin/main) all OK; 7/8 phenotypes causally connected; check-genereviews --online: no SGCD-specific chapter, DCM Overview PMID:20301486 tagged. Review fixes (round 1): inheritance REFUTE now quotes Bauer's conclusion plus the seven-carrier clinical-examination sentence; carrier wording limited to clinical signs, with echo/ECG only in the four compound heterozygotes; removed the null-model coronary vascular node (point kept in the human-model mismatch discussion and as a POPULATION_MISMATCH divergence on the Sgcd-null mouse link); removed the knock-in REFUTE from the degeneration node and Bauer's dosage critique from the nuclear-sequestration node; added knock-in REFUTE items (intact sarcolemma; S151A rescue of Sgcd-null hearts, against a dominant-negative effect) and the homozygous S151A embryonic-lethality note; added evidence to all phenotype and HF edges; Sylvius screen set to NO_EVIDENCE; duplicate gene-level Finnish item removed; Dutch c.4-1G>A carrier no longer counted as a DCM patient; ClinGen notes now cite the committed ingest table and the earlier 2025-03-28 No Known Disease Relationship record for umbrella DCM from the committed cache/clingen/gene_validity.csv. Re-validated: 102/102 snippets, all gates OK, 7/8 phenotypes connected.

Claude Code ▸

Dilated Cardiomyopathy 1L (CMD1L; SGCD-related autosomal dominant DCM): research report

claude-haiku-5-5, claude-opus-5-5 11 citations 2026-10-08T16:25:38.412545

Still gathering sources; I'm checking for cached ClinGen SGCD records in the repo now.

Cached the key SGCD papers; now reading their titles and abstracts to pull exact quotes.

Mapped all cached papers to their PMIDs; doing one last check on the hamster gene-therapy paper and the cohort studies' SGCD results.

Dilated Cardiomyopathy 1L (CMD1L; SGCD-related autosomal dominant DCM): research report

Target: dilated cardiomyopathy 1L, MONDO:0011702 · Gene: SGCD (hgnc:10807) · Prepared: 2026-10-08

Key finding for curation. The link between monoallelic SGCD variants and dilated cardiomyopathy is weak and contested. - ClinGen (DCM GCEP) rates SGCD → "Dilated cardiomyopathy 1L" (AD) as Limited, evaluated 2026-03-04. Assertion: CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z. Human genetic evidence scored 0.25 of 12 points. - Ambry Genetics lists it on GenCC as Disputed Evidence (2023). - The founding variant, p.S151A, was found without cardiomyopathy in compound-heterozygous carriers (PMID:19259135). - Most of the support comes from SGCD-null animals (hamster, mouse, pig). Those animals model the recessive loss of the protein, not a heterozygous human state.

An entry should state this uncertainty openly: a gene_disease_validity block copied from ClinGen, plus a KNOWLEDGE_GAP / HUMAN_MODEL_MISMATCH discussion. A cleanly causal Mendelian claim would overstate the evidence.

One discrepancy is unresolved. A web-search summary said ClinGen had downgraded the gene to "No Known Disease Relationship" in March 2025. The live ClinGen page and GenCC both show Limited, dated 2026-03-04. I treated the live record as authoritative. Re-check it when the entry is written.

1. Disease information

Overview. CMD1L is a proposed autosomal dominant form of isolated dilated cardiomyopathy: left ventricular dilatation with systolic dysfunction and no skeletal muscle disease. It is attributed to heterozygous variants in SGCD, which encodes δ-sarcoglycan, part of the dystrophin–glycoprotein complex (DGC). The founding report described severe childhood or young-adult disease with heart failure, transplantation and sudden death (Tsubata et al. 2000, PMID:10974018).

"Mutations affecting the secondary structure were identified in one family and two sporadic cases, whereas immunofluorescence analysis of myocardium from one of these patients demonstrated significant reduction in delta-sarcoglycan staining. No skeletal muscle disease occurred in any of these patients." (PMID:10974018)

Identifiers

System	ID	Source checked
MONDO	MONDO:0011702 "dilated cardiomyopathy 1L"	`cache/mondo/terms.csv`
OMIM (phenotype)	606685	GenCC Ambry submission
OMIM (gene)	601411 (SGCD)	OMIM mirror
HGNC	hgnc:10807 (SGCD)	`cache/hgnc/terms.csv`
Orphanet	ORPHA:154 Familial isolated dilated cardiomyopathy (gene-level grouping)	GenCC
DOID	DOID:0110436	GlyCosmos page
MONDO parents	MONDO:0700335 familial isolated DCM; MONDO:0016144 qualitative or quantitative defects of delta-sarcoglycan	stub file

Synonyms (from the stub): CMD1L; cardiomyopathy, dilated, 1L; dilated cardiomyopathy type 1L; SGCD familial isolated dilated cardiomyopathy; familial isolated DCM caused by mutation in SGCD.

Data provenance. All of the evidence is aggregated, disease-level literature: case reports, small families and cohort screens. There are no EHR-derived data.

Allelic disorder. Biallelic SGCD loss causes autosomal recessive limb-girdle muscular dystrophy type 2F (LGMDR6; MONDO:0011028; OMIM 601287). ClinGen rates that link Definitive (2024-11-14).

2. Etiology

Causal factor (proposed): heterozygous germline SGCD missense or in-frame variants.
Founding variants: p.S151A (c.451T>G, exon 6) in one family, and p.ΔK238 (3-bp deletion in exon 9) in two sporadic cases (PMID:10974018).
Later variants: p.R71T in a Finnish family (PMID:14564412); a splice variant c.4-1G>A, functionally confirmed and reclassified as likely pathogenic (PMID:36270459).
Contribution to DCM is marginal. Sylvius et al. screened 99 DCM probands and found no causal variants (PMID:12794684):

"we could estimate the prevalence of delta-sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy"

The Finnish screen of 52 patients concluded the same (PMID:14564412):

"We conclude that the desmin and delta-sarcoglycan genes are not predominant disease-causing genes in patients with DCM in eastern Finland."

ClinGen's summary reports no enrichment of SGCD rare variants in a large case-control comparison (Mazzarotto et al. 2020, PMID:31983221; per ClinGen, p=0.74). That paper's abstract does not name SGCD, so cite the ClinGen record for this point. - Susceptibility haplotype (Chinese cohort): a promoter 11-bp deletion plus p.Q283R haplotype was associated with DCM (OR 17.27) (PMID:26720722). This is a single association study and should be modeled as RISK_FACTOR, not causative. - Environmental risk, protective factors, G×E: none reported specifically for CMD1L. General DCM modifiers (alcohol, cardiotoxic chemotherapy, myocarditis, pregnancy) are plausible but undocumented for SGCD.

3. Phenotypes

From the Tsubata families and sporadic cases (PMID:10974018), unless noted otherwise. HPO CURIEs were checked against cache/hp/terms.csv.

Phenotype	HPO	Onset / course	Notes
Dilated cardiomyopathy	HP:0001644	Childhood to young adult; progressive	Defining feature
Left ventricular dilatation	HP:4000141	—	Mild in R71T carriers (PMID:14564412)
Reduced LV ejection fraction / systolic function	HP:0012664 / HP:0006673	Progressive	—
Congestive heart failure	HP:0001635	Early onset in the S151A family	"early-onset CHF and sudden deaths"
Sudden cardiac death	HP:0001645	Young adults	S151A family; patients were "athletic until their onset of heart failure or sudden death"
Need for heart transplantation	(procedure; no HPO)	—	Transplanted at age 21 in the S151A family
Arrhythmia	HP:0011675	—	Not well characterized

Absent feature: no skeletal muscle disease. This contrasts with LGMD2F.
Variable expressivity: R71T carriers had "a relatively mild phenotype and a late onset of the disease" (PMID:14564412).
Frequencies: cannot be estimated. Fewer than 40 probands are reported worldwide; ClinGen counted about 33 across 11 publications.
Quality of life: there are no disease-specific data. General DCM/heart-failure QoL burden (NYHA class, KCCQ) applies.

4. Genetic and molecular information

Gene: SGCD at 5q33. It has 8 exons spanning at least 100 kb. The protein is a 290-aa, 35-kDa sarcolemmal transmembrane glycoprotein (PMID:8842738):

"Its mRNA expression is abundant in striated and smooth muscles, with a main 8 kb transcript, encoding a predicted basic transmembrane glycoprotein of 290 amino acids."

Variants

Variant	Type	Evidence	Status
p.S151A (c.451T>G)	Missense	Familial AD DCM (PMID:10974018)	Contested. Compound-heterozygous carriers with p.A131P had no cardiomyopathy (PMID:19259135). Knock-in mice showed only a mild, subclinical phenotype (PMID:23695275). ClinGen scored it 0.
p.ΔK238 (c.710_712del / 711_713del)	In-frame deletion	Two sporadic cases; absent from 200 controls and from unaffected parents, so presumed de novo; myocardial δ-SG reduced (PMID:10974018)	Scored 0 by ClinGen (population frequency)
p.R97Q (c.290G>A)	Missense	One sporadic case (PMID:10974018)	Uncertain
p.R71T	Missense; creates an ectopic N-glycosylation site	Finnish family, 2 carriers (PMID:14564412; PMID:26968544)	Uncertain
c.4-1G>A	Canonical splice	Minigene-confirmed; reclassified LP (PMID:36270459)	The only proband ClinGen scored (0.25 pts)

Constraint: gnomAD v4 pLI 0.05, LOEUF 0.88, DECIPHER %HI 4.64 (via ClinGen gene page). The gene is not constrained against loss of function, so haploinsufficiency is unlikely as the mechanism.
ClinGen dosage sensitivity: not curated.
Functional class: a dominant-negative mechanism is proposed (PMID:26968544; PMID:17164264). Germline origin.
Modifiers, epigenetics, chromosomal abnormalities: none reported.

5. Environmental information

There are no documented environmental, lifestyle or infectious triggers. Report this as "not available". A Left deliberately uncited. waiver is appropriate if an environmental section is added.

6. Mechanism and pathophysiology

Causal chain (inferred steps are marked)

A heterozygous SGCD missense or in-frame variant (germline) leads to a structurally abnormal δ-sarcoglycan that is co-expressed with the wild-type protein.
The mutant protein results in dominant-negative disturbance of the sarcoglycan–sarcospan subcomplex of the DGC. The evidence comes from overexpression systems:
2a. R97Q/R71T traffic normally to the membrane, and the DGC still assembles, but membrane stability under strain is reduced (PMID:26968544).
2b. In transgenic mice, S151A is mislocalized to the nucleus, sequesters β/γ-SG, and mislocalizes lamin A/C and emerin (PMID:17164264).
This leads to loss of sarcolemmal mechanical integrity during contraction (GO:0042383 sarcolemma; GO:0016012 sarcoglycan complex; GO:0016010 dystrophin-associated glycoprotein complex). The evidence:

"Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan." (PMID:26968544)
Membrane injury results in cardiomyocyte necrosis with replacement fibrosis. This step is extrapolated from null models, where focal necrosis is the histological hallmark (PMID:10481911). An additional branch, also from Sgcd-null mice: loss of the SG–SSPN complex in vascular smooth muscle causes coronary vasospasm and ischemic microinfarcts, and a vasodilator prevents the necrosis (PMID:10481911).
Progressive myocyte loss leads to LV dilatation and reduced systolic function (HP:0001644, HP:0012664). These in turn result in heart failure, arrhythmia and sudden death (HP:0001635, HP:0001645).

Upstream vs downstream. Steps 1–2 are molecular (the initiating lesion). Step 3 is cellular. Steps 4–5 are at the tissue and organism level.

Cell types: cardiac muscle cell (CL:0000746), ventricular cardiac muscle cell (CL:2000046), and vascular smooth muscle (null-model branch only).

GO process suggestions: plasma membrane repair (GO:0001778), cardiac muscle contraction (GO:0060048), programmed necrotic cell death (GO:0097300).

Caveat (HUMAN_MODEL_MISMATCH). Steps 4–5 are demonstrated only for complete δ-SG loss. In humans, heterozygous loss-of-function carriers (LGMD2F parents) are not known to develop DCM, and ΔK238 explant myocardium showed reduced δ-SG with preserved α/β/γ-SG. So a dominant-negative mechanism, not haploinsufficiency, has to carry the human claim, and it rests on overexpression systems.

Omics, single-cell, CRISPR screens: none specific to CMD1L.

7. Anatomical structures

Primary: heart (UBERON:0000948), myocardium (UBERON:0002349), heart left ventricle (UBERON:0002084). The cardiovascular system is the only system affected.
Spared: skeletal muscle tissue (UBERON:0001134). Sparing is the distinction from LGMD2F.
Subcellular: sarcolemma (GO:0042383), sarcoglycan complex (GO:0016012). In the S151A transgenic mouse, the nucleus/nuclear lamina is also involved (PMID:17164264).
Lateralization: global, bilateral ventricular disease, LV-predominant.

8. Temporal development

Onset: pediatric to young adult in the founding report. That screen covered patients aged 3 days to 18 years; deaths occurred at 17–37 years and transplantation at 21 (PMID:10974018; ages as summarized in PMID:19259135). Onset is late and mild in R71T carriers.
Onset pattern: insidious. Patients were asymptomatic and athletic until heart failure or sudden death.
Course: chronic and progressive. There are no remission data. No formal staging exists beyond generic ACC/AHA heart-failure stages A–D.

9. Inheritance and population

Inheritance: autosomal dominant (HP:0000006). Penetrance is incomplete or unproven, and expressivity is variable.
De novo cases: ΔK238 was absent in both unaffected parents (PMID:10974018).
Prevalence: unknown and ultra-rare. Suggested record: measure_type: CASES_IN_LITERATURE, about 33 probands per ClinGen. SGCD accounts for less than 1% of idiopathic DCM (PMID:12794684).
Populations: reports come from the USA (Tsubata), Finland (R71T), the Netherlands (c.4-1G>A) and China (risk haplotype). No founder effect is established.
Anticipation, mosaicism, consanguinity role, carrier frequency: not applicable or not reported.

10. Diagnostics

Clinical tests:
Echocardiography (LVEDD, LVEF)
Cardiac MRI with late gadolinium enhancement for fibrosis
ECG and Holter for arrhythmia
NT-proBNP
Creatine kinase, to exclude skeletal myopathy and sarcoglycanopathy
Pathology: myocardial immunofluorescence may show reduced δ-SG with preserved α/β/γ-SG and dystrophin (PMID:10974018). This is a research test.
Genetic testing: multigene DCM panel or exome sequencing. Given its Limited validity, an SGCD variant found in isolation should usually be reported as a VUS. Splice variants can be resolved with RNA or minigene assays (PMID:36270459).
Differential diagnosis:
TTN-truncating, LMNA, DSP, RBM20 and MYH7 DCM
LGMD2F and other sarcoglycanopathies (elevated CK, proximal weakness)
Dystrophinopathy cardiomyopathy
Myocarditis
Ischemic and toxic causes
Screening: cascade echocardiography and ECG for first-degree relatives, following general familial-DCM guidance. Predictive SGCD genotyping is not appropriate while validity is Limited.

11. Outcome and prognosis

There are no survival statistics. The founding family showed sudden death at a young age and transplantation at 21. The Finnish carriers had a mild course.
General DCM outcome data with genotype stratification exist (Escobar-Lopez 2021, PMID:34674813), but SGCD-specific outcomes are not reported.
Complications: heart failure, ventricular arrhythmia, sudden death, thromboembolism (generic).

12. Treatment

There is no disease-specific therapy. Management follows guideline-directed therapy for heart failure with reduced ejection fraction. NCIT CURIEs were checked against cache/ncit/terms.csv.

Treatment	NCIT action term	Notes
GDMT: ACEi/ARB/ARNI, β-blocker, MRA, SGLT2i	NCIT:C15986 Pharmacotherapy (+ `therapeutic_agent` CHEBI)	Not studied in CMD1L specifically
ICD for sudden-death prevention	— (device; see the CLAUDE.md device pattern)	Relevant given the SCD history
Heart transplantation	NCIT:C15289 Organ Transplantation	Performed in the founding family
Genetic counseling	NCIT:C15240 Genetic Counseling	Must convey uncertain validity
Supportive care	NCIT:C15747 Supportive Care	—
Gene therapy (preclinical only)	NCIT:C15238 Gene Therapy	AAV-δ-SG rescues Sgcd-null mice (PMID:19218289) and TO-2 hamsters (Kawada et al., PNAS 2002;99:901–906, doi:10.1073/pnas.022641799; PMID not verified)

From the mouse rescue study (PMID:19218289): "The aim of our study was to develop an approach for preventing cardiomyopathy in Sgcd-deficient mice by cardiac expression of the intact cDNA upon systemic delivery of adeno-associated viral (AAV) vectors."

In Sgcd-null mice, a vascular smooth-muscle relaxant (verapamil) prevented necrosis (PMID:10481911). This has not been tested in humans.

No clinical trials or pharmacogenomic data specific to CMD1L were identified.

13. Prevention

Primary prevention: none.
Secondary prevention: cascade cardiac screening of relatives.
Tertiary prevention: GDMT and ICD to prevent heart-failure progression and sudden death.
Counseling: 50% transmission risk if the variant is truly causal. Counseling must convey the Limited/Disputed validity.
Reproductive options: PGD or prenatal testing is not advisable without a pathogenic-classified variant.
Vaccination and public-health measures: not applicable.

14. Other species and natural disease

Syrian (cardiomyopathic) hamster, Mesocricetus auratus (NCBITaxon:10036), strains BIO14.6 (HCM-like) and TO-2 (DCM-like). These carry a naturally occurring homozygous deletion of Sgcd exon 1 and its promoter (PMID:9391120):

"Herein we show that both HCM and DCM hamsters share a common defect in a gene for delta-sarcoglycan (delta-SG)"
Inheritance mismatch: the hamster disease is recessive (null), unlike the proposed human AD disease.
Companion animals: no naturally occurring SGCD-DCM was found in OMIA searches as reported in the literature I reviewed.
Zoonotic potential: none.

15. Model organisms

NCBITaxon CURIEs were checked against the cache.

Model	Taxon	Genotype	Recapitulation	Ref
Sgcd-null mouse	NCBITaxon:10090	Homozygous KO	Cardiomyopathy and muscular dystrophy; focal necrosis; coronary vascular irregularities. Partial match: recessive and with skeletal disease.	PMID:10481911
α-MHC-S151A transgenic mouse	NCBITaxon:10090	Overexpressed S151A	DCM at a young age, increased lethality, nuclear δ-SG, lamin A/C and emerin mislocalized	PMID:17164264
S151A heterozygous knock-in mouse	NCBITaxon:10090	Physiological dosage	Only mild cardiac enlargement at 1 year; function preserved; no histopathology. This argues against strong pathogenicity.	PMID:23695275
SGCD-KO pig	NCBITaxon:9823	Homozygous KO	Systolic dysfunction, myocardial degeneration, sudden death; loss of α/β/γ-SG	PMID:32060408
Hamster BIO14.6 / TO-2	NCBITaxon:10036	Natural null	HCM and DCM sublines; rescued by AAV-δ-SG	PMID:9391120
Transgenic fly (human δ-SG S151A)	NCBITaxon:7227	Inducible overexpression	Enlarged chambers, impaired systolic function (OCT)	PMID:16432241
Adult rat cardiomyocytes (in vitro)	—	Adenoviral R97Q/R71T	Stretch-induced membrane fragility (dominant negative)	PMID:26968544

Suggested modeled_mechanisms fidelity. Null models should be PARTIALLY_RECAPITULATES (LOW–MODERATE fidelity). Record a POPULATION_MISMATCH or genotype divergence because the models are recessive null while the human disease is heterozygous dominant. The S151A knock-in arguably FAILS_TO_RECAPITULATE severe DCM.

Resources: MGI (Sgcd), IMSR, ZFIN (sgcd).

Notes for the curator

References cached. I fetched 18 references into references_cache/ with just fetch-reference; they are currently untracked:
Human genetics: 10974018, 14564412, 12794684, 19259135, 26720722, 36270459, 31983221, 33662488, 27532257
Gene identification and models: 8842738, 9391120, 10481911, 16432241, 17164264, 19218289, 23695275, 32060408, 26968544

Every quote above is copied from those cache files. Commit the ones the entry cites. Escobar-Lopez (PMID:34674813) and the Kawada hamster paper are not cached. - Not cached: the ClinGen CGGV record. Run just clingen-rebuild --id CGGV:assertion_59326e1b-5cc1-4dfe-8d67-3379aa305c40-2026-03-04T170000.000Z before citing it in gene_disease_validity. The local ClinGen pin may predate the 2026-03-04 assertion; repin if so. - No GeneReviews chapter is specific to CMD1L. The generic "Dilated Cardiomyopathy Overview" (NBK1309) is cached as a URL reference. - Lump/split. The ClinGen and Ambry verdicts bear on whether this should be a standalone DISEASE entry. An alternative is a subtype or notes on a familial-DCM entry; the current draft already exists, but surface the choice to the user.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	3
Quoted claims found in source	3
Quoted claims not found in source	0
References weighed for topical relevance	20
On topic	14
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	36
Resolved	34
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	14
Terms named correctly	6
Terms named as a different term	5
Terms whose name is worth a second look	3

Terms the report names something else

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

DOID:0110436 (4 mentions) - the report calls it "DOID"; DOID calls it dilated cardiomyopathy 1L
NCBITaxon:10036 (2 mentions) - the report calls it "Mesocricetus auratus", "Hamster BIO14.6 / TO-2"; NCBITaxon calls it Mesocricetus auratus
NCBITaxon:10090 (3 mentions) - the report calls it "Sgcd-null mouse", "α-MHC-S151A transgenic mouse", "S151A heterozygous knock-in mouse"; NCBITaxon calls it Mus musculus
NCBITaxon:9823 (1 mention) - the report calls it "SGCD-KO pig"; NCBITaxon calls it Sus scrofa
NCBITaxon:7227 (1 mention) - the report calls it "Transgenic fly (human δ-SG S151A)"; NCBITaxon calls it Drosophila melanogaster

Terms whose name is worth a second look

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

GO:0042383 (2 mentions) - the report calls it "Subcellular: sarcolemma"; GO calls it sarcolemma**
UBERON:0000948 (1 mention) - the report calls it "Primary: heart"; UBERON calls it heart**, and lists "branchial heart" among its other names
UBERON:0001134 (1 mention) - the report calls it "Spared: skeletal muscle tissue"; UBERON calls it skeletal muscle tissue**

Terms named inconsistently

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

NCBITaxon:10036 - called "Mesocricetus auratus", "Hamster BIO14.6 / TO-2"
NCBITaxon:10090 - called "Sgcd-null mouse", "α-MHC-S151A transgenic mouse", "S151A heterozygous knock-in mouse"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Dilated Cardiomyopathy 1L (CMD1L; SGCD-related autosomal dominant DCM): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Notes for the curator

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver