Format

Send to

Choose Destination
Hum Genomics. 2016 Sep 27;10(1):32.

A first-line diagnostic assay for limb-girdle muscular dystrophy and other myopathies.

Author information

1
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh, 11211, Kingdom of Saudi Arabia. dmonies@kfshrc.edu.sa.
2
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. dmonies@kfshrc.edu.sa.
3
Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
4
Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
5
Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh, 11211, Kingdom of Saudi Arabia.
6
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

Abstract

BACKGROUND:

Fifty random genetically unstudied families (limb-girdle muscular dystrophy (LGMD)/myopathy) were screened with a gene panel incorporating 759 OMIM genes associated with neurological disorders. Average coverage of the CDS and 10 bp flanking regions of genes was 99 %. All families were referred to the Neurosciences Clinic of King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Patients presented with muscle weakness affecting the pelvic and shoulder girdle. Muscle biopsy in all cases showed dystrophic or myopathic changes. Our main objective was to evaluate a neurological gene panel as a first-line diagnostic test for LGMD/myopathies.

RESULTS:

Our panel identified the mutation in 76 % of families (38/50; 11 novel). Thirty-four families had mutations in LGMD-related genes with four others having variants not typically associated with LGMD. The majority of cases had recessive inheritance with homoallelic pathogenic variants (97.4 %, 37/38), as expected considering the high rate of consanguinity in the study population. In one case, we detected a heterozygous mutation in DNAJB responsible for LGMD-1E. Our cohort included seven different subtypes of LGMD2. Mutations of DYSF were the most commonly identified cause of disease followed by that in CAPN3 and FKRP. Non-LGMD myopathies were due to mutations in genes associated with congenital disorder of glycosylation (ALG2), rigid spine muscular dystrophy 1 (SEPN1), inclusion body myopathy2/Nonaka myopathy (GNE), and neuropathy (WNK1). Whole exome sequencing (WES) of patients who remained undiagnosed with the neurological panel did not improve our diagnostic yield.

CONCLUSIONS:

Our neurological panel achieved a high clinical sensitivity (76 %) and is an effective first-line laboratory test in patients with LGMD and other myopathies. This sensitive, cost-effective, and rapid assay significantly assists clinical practice especially in these phenotypically and genetically heterogeneous disorders. Moreover, the application of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines applied in the classification of variant pathogenecity provides a clear interpretation for physicians on the relevance of such findings.

KEYWORDS:

LGMD; Myopaties; Neurological panel; Targeted resequencing

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center