A novel splice site variant in the POPDC3 causes autosomal recessive limb‐girdle muscular dystrophy type 26

• Published in: Clinical genetics 2022-10, Vol.102 (4), p.345-349
• Main Authors: Zhang, Lin, Li, Wenwu, Weng, Yuting, Lin, Keqin, Huang, Kai, Ma, Shaohui, Chu, Jiayou, Yang, Zhaoqing, Zhang, Xiaochao, Sun, Hao
• Format: Article
• Language: English
• Subjects: Alternative splicing; c.486‐1G>A splice site variant; cDNA analysis; Genetic analysis; Genetic screening; LGMDR26; mRNA; Muscular dystrophy; Phenotypes; POPDC3
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14192

Limb‐Girdle muscular dystrophy (LGMD) is a group of muscle disorders with highly heterogeneous genetic patterns and clinical phenotypes, and this group includes multiple subtypes. Different LGMD subtypes have similar phenotypes and clinical overlaps, these subtypes are difficult to distinguish by clinical symptoms alone and can only be accurately diagnosed by analysis in combination with definitive genetic test results. Here, we report a female presenting features of LGMD. After analysis of whole‐exome sequencing data, a novel homozygous POPDC3 variant c.486‐1G>A (rs113419658) located in the acceptor splice site of intron 2 was identified in the proband. The variant effect on splicing were analyzed by genetic analysis based on cDNA synthesized by the patient's RNA. cDNA analysis indicated that the novel homozygous POPDC3 splice variant disrupted original acceptor splice site, which can cause a frameshift in the mRNA of the POPDC3 gene, thereby producing a truncated POPDC3 protein and ultimately affecting its normal function. POPDC3 variant was recently associated with recessive limb‐girdle muscular dystrophy type 26 (LGMDR26). Based on the above results, we hypothesize that this variant is probably a pathogenic variant, and expand the gene variant spectrum of POPDC3. A novel variation c.486‐1G>A in POPDC3 was found in a Chinese Limb‐Girdle muscular dystrophy pedigree. The variation alters the splicing form of POPDC3, truncates the protein encoded by this gene and causes disease.