Impact of next‐generation sequencing panels in the evaluation of limb‐girdle muscular dystrophies

Abstract

Introduction Limb‐girdle muscular dystrophy (LGMD) is the fourth most common muscular dystrophy, with progressive proximal muscle weakness. However, a large number of neuromuscular conditions are similarly presented. Because of this, the use of high‐throughput methods such as next‐generation sequencing (NGS) is important in the evaluation of LGMD. Methods In this report, we applied a custom target capture‐based NGS panel covering 31 LGMD‐associated genes (MYOT, LMNA, CAV3, DES, DNAJB6, FLNC, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FRKP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT1, DAG1, PLEC, GAA, GMPPB, HNRNPDL, TNPO3, LIMS2, POMK, TRAPPC11, ISPD) in 74 patients suspected of LGMD. Results In 25 (33.8%) out of 74 patients analyzed, one or more pathogenic/likely pathogenic variants in 13 different genes were detected. Six of the patients had the variants that were not found in databases and literature; thus, they were interpreted as novel pathogenic variants. Discussion The diagnosis rate achieved (33.8%) is consistent with previous literature reports and underlines the efficiency and importance of NGS technology in the molecular genetic evaluation of LGMD.

A familial case of limb-girdle muscular dystrophy with CAV3 mutation

“…LGMD is a very heterogeneous disorder caused by a variety of genes, and advance in genetic diagnosis have increased the diagnostic rates of LGMD [3]. However, genomic variants are often hard to interpret in many cases, and segregation or functional validations are essential for making the final molecular diagnosis.…”

“…Therefore, comprehensive molecular diagnosis in addition to the classic pathological approaches is needed to identify this disease group. High-throughput technologies such as next generation sequencing (NGS) can be helpful in the genetic diagnosis of inherited myopathies because a wide variety of genes needs to be targeted [3].…”

Compound heterozygous DYSF variants causing limb‐girdle muscular dystrophy type 2B in a Chinese family

“…The limb‐girdle muscular dystrophies (LGMDs), comprsing the fourth most common muscular dystrophies only after myotonic dystrophy type I, Duchenne muscular dystrophy and facioscapulohumeral dystrophy, can affect people of any age and often worsen over time, mostly characterized by progressive wasting and weakness of the proximal limb muscles, predominantly involving pelvic and shoulder girdle muscles, with an estimated prevalence of 0.8–5.7 per 100,000 individuals 2,4–7 . The phenotypic spectrum of LGMDs varies significantly as a result of genetic heterogeneity, ranging from a very mild form in adults without serious impact on life expectancy and activity levels to a severe form in infants with rapid onset and progression 8–10 .…”

“…individuals. 2,[4][5][6][7] The phenotypic spectrum of LGMDs varies significantly as a result of genetic heterogeneity, ranging from a very mild form in adults without serious impact on life expectancy and activity levels to a severe form in infants with rapid onset and progression. [8][9][10] Additionally, patients with LGMDs may present respiratory and cardiac muscles degeneration, distal limb weakness, uncommon mental deficiency, microcephaly, contractures, scoliosis and motor impairment that involves abnormal gait, frequent falling, running disability and difficulty in climbing stairs.…”

“…The definitive diagnosis and classification of LGMDs generally rely on the age of onset, family history, the distribution of weakness and atrophy in muscles, high levels of serum creatine kinase (CK), electromyography (EMG), muscle biopsy, magnetic resonance imaging (MRI) and genetic testing. 2,6 With the development of high-throughput genetic testing techniques, whole exome sequencing (WES) is an effective, fast and cost-effective strategy for detecting the causative variants of various Mendelian disorders. 4,18 As for the rare and complicated diseases with highly clinical and genetic heterogeneity such as LGMDs, it is difficult to differentiate subtypes simply according to typical symptoms and signs.…”