A Founder Allele in SGCG Combining Missense Variant and Multi-Exon Duplication in Turkish Patients With Sarcoglycanopathy.

Abstract

Sarcoglycanopathies are autosomal recessive muscular dystrophies characterized by progressive muscle weakness and represent a major subset of limb-girdle muscular dystrophies (LGMDs). They result from pathogenic variants in sarcoglycan genes (SGCA, SGCB, SGCD, and SGCG), which encode subunits of a tetrameric transmembrane complex that stabilizes the dystrophin-associated glycoprotein complex. Among these, SGCG is commonly affected and is associated with LGMD2C/R5. Several founder variants in SGCG have been reported across different populations. Here, we describe a novel founder allele in the Turkish population, comprising a missense variant (c.392A>G, p.Lys131Arg) and a copy number gain (exon 1-4 duplication) that occurs in cis. Through an inductive screening strategy, we identified these linked variants in 11 individuals: five affected patients from four families and six unrelated incidental carriers. Haplotype analysis confirmed a shared genomic background supporting a founder effect. Affected individuals carried the allele in a homozygous or compound heterozygous state with other pathogenic SGCG variants. Molecular and histopathological investigations revealed that the duplicated allele results in mRNA decay and loss of SGCG protein expression. This study represents the first report of a disease-associated duplication in SGCG, highlighting a novel founder allele composed of two linked variants that contribute to sarcoglycanopathy in a specific population.