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

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.

• 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

• 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)

1. 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.
2. The mutant protein results in dominant-negative disturbance of the sarcoglycan–sarcospan subcomplex of the DGC. The evidence comes from overexpression systems:
3. 2a. R97Q/R71T traffic normally to the membrane, and the DGC still assembles, but membrane stability under strain is reduced (PMID:26968544).
4. 2b. In transgenic mice, S151A is mislocalized to the nucleus, sequesters β/γ-SG, and mislocalizes lamin A/C and emerin (PMID:17164264).
5. 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)

6. 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).
7. 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.

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.

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

• Tsubata 2000, JCI · PMC381284
• ClinGen SGCD gene page · ClinGen CMD1L assertion
• GenCC SGCD · GenCC submission
• PanelApp DCM – SGCD
• Bauer 2009 EJHG
• Kawada 2002 PNAS (PMC117403)
• OMIM 601411 mirror
• GlyCosmos DOID:0110436

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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.