Workshop report

Diagnostic criteria for the limb-girdle muscular dystrophies: Report of the ENMC consortium on limbgirdle dystrophies

Limb-girdle muscular dystrophy (LGMD) is a term used for proximal muscles weakness mainly affecting arms, shoulders, legs and thighs. These patients have altered body posture due to weak muscles, and have difficulty in holding, standing or walking. Genetic causes of both autosomal dominant (LGMDD/LGMD1) and recessive (LGMDR/LGMD2) forms have been identified. We analyzed a consanguineous Pakhtun family from Khyber Pakhtunkhwa (KP), Pakistan. The disease started at early childhood (7–8 years). The phenotype worsened, and the patients had become completely wheelchair bound in teenages. Whole exome sequencing (WES) at 100× coverage on Illumina NovaSeq6000 platform followed by Sanger sequencing revealed a homozygous variant (c.610T > C; p.Ser204Pro) in the SGCB gene known for LGMDR4 phenotype. Structural protein prediction tools and molecular docking analyses showed critical structural changes in the binding interface and SGCB protein tunnel. To the best of our knowledge this is the first report of SGCB variant identified in a Pakistani family. Structural analysis of p.Ser204Pro substitution gives insight into SGCB pathogenicity causing LGMDR4 phenotype. WES analysis can be used as a first line tool in rare diseases molecular diagnostics. Encouraging premarital testing in the closest relatives of such patients may have positive impact on reduction of the recurrence risk in their subsequent generations.