Abstract
Although recessive mutations in LAMA2 are already known to cause laminin α2-related muscular dystrophy, a rare neuromuscular disorder, large deletions or duplications within this gene are not well-characterized. In this study, we applied next-generation sequencing-based copy number variation profiling in 114 individuals clinically diagnosed with laminin α2-related muscular dystrophy, including 96 who harboured LAMA2 mutations and 34 who harboured intragenic rearrangements. In total, we detected 18 distinct LAMA2 copy number variations that have been reported only among Chinese, 10 of which are novel. The frequency of CNVs in the cohort was 19.3%. Deletion of exon 4 was detected in 10 alleles of eight patients, accounting for 27% of all copy number variations. These patients are Han Chinese and were found to have the same haplotype and sequence at the breakpoint junction, suggesting that exon 4 deletion is a founder mutation in Chinese Han and a mutation hotspot. Moreover, the data highlight our approach, a modified next-generation sequencing assay, as a robust and sensitive tool to detect LAMA2 variants; the assay identifies 85.7% of breakpoint junctions directly alongside sequence information. The method can be applied to clinical samples to determine causal variants underlying various Mendelian disorders.
Highlights
Recessive mutations in LAMA2 are already known to cause laminin α2-related muscular dystrophy, a rare neuromuscular disorder, large deletions or duplications within this gene are not wellcharacterized
34 cases from 29 families were genetically characterized in detail for pathogenic copy-number variations (CNVs) in LAMA2, following detection of non-recurrent genomic rearrangements among a large cohort of patients with LAMA2 MD
Screening for LAMA2 point mutations, followed by analysis of LAMA2 CNVs, especially exon 4 deletion, may be appropriate as an initial strategy for patients with features consistent with congenital muscular dystrophy, such as muscular dystrophy combined with white matter changes in brain MRI
Summary
Recessive mutations in LAMA2 are already known to cause laminin α2-related muscular dystrophy, a rare neuromuscular disorder, large deletions or duplications within this gene are not wellcharacterized. We applied next-generation sequencing-based copy number variation profiling in 114 individuals clinically diagnosed with laminin α2-related muscular dystrophy, including 96 who harboured LAMA2 mutations and 34 who harboured intragenic rearrangements. Laminin α2-related muscular dystrophy (LAMA2 MD) is a rare autosomal-recessive genetic disorder affecting between 0.7 and 2.5 in 100,000 individuals in predominantly European cohorts[1] It is caused by pathogenic variants in LAMA2 [MIM: 607855], which is located on chromosome 6q22-23 and consists of 65 exons[2]. Multiplex ligation-dependent probe amplification (MLPA) enables the detection of many large deletions and duplications These methods do not provide a comprehensive overview of CNVs in terms of breakpoint junctions, preventing full understanding of the pathogenic and mutational mechanisms. Accurate identification of CNVs at the nucleotide sequence level by NGS remains challenging[14], even though several algorithms have been developed to detect CNVs in exomes[15,16,17,18] and DNA samples[19,20] based on depth-of-coverage
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