Whole Exome Sequencing as a Diagnostic Tool for Unidentified Muscular Dystrophy in a Vietnamese Family

Abstract

Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.

Limb girdle muscular dystrophy 23 caused by compound heterozygous mutations of LAMA2 gene

“…She also had other typical symptoms like elevated creatine kinase level, transient pneumonia, delayed motor milestones, difficulty in chewing and abnormal electromyography. Additionally, the proband presented with toe walking which was also observed in a Turkish origin male at 10 years old ( 20 ) and in a Chinese origin female at 4 years old and a male at 6 years old ( 21 ).…”

Merosin-deficient congenital muscular dystrophy type 1a: detection of LAMA2 variants in Vietnamese patients

“…None of the seven identified variants were missense, while another Vietnamese patient with MDC1A harbored a missense mutation c.1964T>C (p.L655P) and c.3556-13T>A ( Tran et al, 2020 ). Two missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), have been reported in Vietnamese patients with late-onset LAMA2 -MD who achieved independent walking ( Nguyen et al, 2020 ). This result is consistent with the findings of Oliveira et al (2018) and Tan et al (2021) , where missense variants were more frequent in late-onset LAMA2 -MD than MDC1A.…”

“…Four pathogenic/likely pathogenic LAMA2 variants have been reported in Vietnamese patients with muscular dystrophy, including c.778C>T (p.H260Y) and c.2987G>A (p.C996Y) ( Nguyen et al, 2020 ), c.1964T>C (p.L655P) and c.3556-13T>A ( Tran et al, 2020 ). However, a large number of LAMA2 variants can be further detected in Vietnamese patients with MDC1A.…”