Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Abstract

BackgroundDystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration.MethodsDeep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants.ResultsSuspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase.ConclusionsOverall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.Electronic supplementary materialThe online version of this article (10.1186/s13395-018-0170-1) contains supplementary material, which is available to authorized users.

The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease

“…The size of the gene panel for each study has varied from 10 in our study to 170 in the European/Middle Eastern study. The highest identification of variants (49%) was found with the largest panel [66,67]. For the United States sample with the 35-gene panel, the identification of variants was 27% [6].…”

“…The majority of variants identified in these other regional studies are similar and found within a limited set of genes in spite of diverse inclusion criteria and gene panels of varying size. In a study of 1001 European and Middle Eastern patients with undiagnosed limb-girdle muscle weakness and/or elevated serum CK activity, 20 genes of the 170-gene panel covered 80% of the patients for whom causal variants were found [66,67]. Seven of the 10 genes included in the current study panel were among these top 20 genes-CAPN3, DYSF, SGCG, SGCA, FKRP, ANO5, and GAA.…”

Novel mutations in DPM3 cause dystroglycanopathy with central nervous system involvement

“…The mutation in DPM3 , encoding dolichol‐phosphate‐mannose (DPM) synthase subunit 3, causes congenital disorders of glycosylation (CDG) type Io, also known as muscular dystrophy‐dystroglycanopathy (limb‐girdle) type C15 (MIM 612937). To date, only three mutations of DPM3 have been reported in five patients with muscular dystrophy, but without central nervous system (CNS) involvement . Herein, we describe a Chinese patient with hyperCKemia, developmental delay, epilepsy, and brain abnormality associated with novel mutations in DPM3 .…”

“…Mutations in DPM3 lead to deficient α‐dystroglycan, so it is classified into dystroglycanopathies, which represent a group of muscular dystrophies with a wide spectrum ranging from mild limb‐girdle muscular dystrophy to severe congenital muscular dystrophy with brain and eye abnormalities . Till date, only three mutations of DPM3 (NM_153471), c.254T>A (p.Leu85Ser), c.41T>C (p.Leu14Pro) and a deletion, have been reported in five patients . Mild and progressive limb‐girdle muscular dystrophy was present in four patients, and isolated hyperCKemia was reported in one patient.…”

N-glycosylated SGK196 suppresses the metastasis of basal-like breast cancer cells

“…Extensive glycosylation of α-DG is essential for its binding to extracellular matrix ligands [17][18][19] . Mutations of SGK196 can influence the biosynthesis of functional α-DG, causing a spectrum of congenital and limb-girdle muscular dystrophies [20][21][22][23] .…”