SGCD was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 1996 (Nigro et al., PMID: 8841194). At least eight variants (e.g. missense, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least eleven probands in seven publications (PMIDs: 8841194, 19259135, 20623375, 10838250, 10735275, 9832045, 30733730). Variants in this gene segregated with the disease in eight additional family members and many other heterozygous carriers. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is protein loss of function, with the loss or disruption of δ-sarcoglycan causing disruption and mislocalization of the sarcoglycan complex which causes destabilization of the sarcolemma and the resulting muscular phenotypes (PMID: 26709803). Of note, this gene has also been implicated in dilated cardiomyopathy which has been assessed separately.This gene-disease association is supported by two KO mouse models, expression studies, a partial mouse rescue, and intercellular protein interactions. The KO mouse models provide strong evidence by recapitulating the observed phenotypes in humans and a partial rescue in one was performed via restoring some of the wildtype SGCD functionality via embryonic stem cells. Expression evidence clearly links the protein to skeletal and cardiac muscle where phenotypes are observed. Finally, the protein physically interacts with all the other sarcoglycans which are all associated with AR LGMD when their function is affected. In summary, SGCD is definitively associated with autosomal recessive limb-girdle muscular dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on April 10, 2020 (SOP Version 7).
This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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