SGCD – Autosomal recessive limb-girdle muscular dystrophy

Delta-sarcoglycan, encoded by SGCD, is a critical component of the dystrophin–glycoprotein complex that maintains muscle membrane integrity. Biallelic pathogenic variants in SGCD underlie autosomal recessive limb-girdle muscular dystrophy type 2E. Patients typically present with proximal muscle weakness progressing to loss of ambulation and may exhibit variable cardiac involvement. Histopathology reveals a dystrophic muscle pattern, and immunofluorescence often shows reduced sarcoglycan staining at the sarcolemma. Cardiac screening can detect structural abnormalities even in subclinical cases, underscoring the need for multidisciplinary management.

In a Chinese cohort of 756 patients screened by next-generation sequencing, six unrelated LGMD2E probands were identified with biallelic SGCD variants, confirming autosomal recessive inheritance and expanding the mutation spectrum in this population (PMID:30764848). Onset ranged from childhood to adulthood, with all patients exhibiting progressive limb-girdle weakness and elevated serum creatine kinase. Muscle biopsies from affected individuals uniformly showed dystrophic changes, and sarcoglycan immunostaining confirmed delta-sarcoglycan deficiency. No clear genotype–phenotype correlations were observed specific to SGCD beyond the shared recessive pattern and clinical course.

The SGCD variant spectrum includes missense, nonsense, and splice-site changes, with c.451T>G (p.Ser151Ala) functionally characterized in an animal model. To date, no recurrent or founder alleles have been established in LGMD2E cohorts, and carrier frequency appears low consistent with disease rarity.

Functional validation of the p.Ser151Ala variant in a heterozygous knock-in mouse model demonstrated mild cardiomyopathy with preserved systolic function at one year of age. Cardiac-specific AAV-mediated transfer of p.Ser151Ala-mutated SGCD cDNA into SGCD-null mice partially restored cardiac function, supporting a loss-of-function mechanism (PMID:23695275). These findings align with human data showing variable cardiac involvement without early severe cardiomyopathy in LGMD2E patients.

Although the p.Ser151Ala allele shows incomplete penetrance for cardiac phenotypes in heterozygous carriers, there are no strong refutations of biallelic SGCD variants causing LGMD2E. Reports of asymptomatic carriers suggest potential modifying factors that influence expressivity.

Overall, the genetic and experimental evidence supports a moderate level of clinical validity for SGCD in autosomal recessive limb-girdle muscular dystrophy type 2E. Future studies with larger patient series, segregation analyses, and comprehensive functional assays will strengthen the association. Key take-home: Biallelic SGCD variants reliably diagnose LGMD2E, guiding genetic testing, cardiac surveillance, and management.

References

• Orphanet Journal of Rare Diseases • 2019 • Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients. PMID:30764848
• European Journal of Human Genetics • 2014 • S151A Δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice PMID:23695275

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