Copy number analysis reveals a novel multiexon deletion of the COLQ gene in congenital myasthenia

Abstract

Congenital myasthenic syndrome (CMS) is genetically and clinically heterogeneous.¹ Despite a considerable number of causal genes discovered, many patients are left without a specific diagnosis after genetic testing. The presumption is that novel genes yet to be discovered will account for the majority of such patients. However, it is also possible that we are neglecting a type of genetic variation: copy number changes (>50 bp) as causal for some of these patients. Next-generation sequencing (NGS) can simultaneously screen all known causal genes² and is increasingly being validated to have a potential to identify copy number changes.³ We present a CMS case who did not receive a genetic diagnosis from previous Sanger sequencing, but through a novel copy number analysis algorithm integrated into our targeted NGS panel, we discovered a novel copy number mutation in the COLQ gene and made a genetic diagnosis. This discovery expands the genotype-phenotype correlation of CMS, leads to improved genetic counsel, and allows for specific pharmacologic treatment.¹.

Figure. Novel compound heterozygous mutation in the COLQ gene causes congenital myasthenic syndrome

(A) Pedigree of the proband (II-1). Point mutation (IVS16+3A→G) in the COLQ gene was inherited from the father (I-1), and multiexon deletion from the mother (I-2). (B) Gene list of 21 known congenital myasthenic syndrome (CMS) genes included in the targeted CMS panel. (C) Genome view of PatternCNV analysis shows decreased copy number variation (CNV) log2 ratio for the COLQ gene in chromosome 3. (D) Exon-level CNV summary table shows the start and end position of deletion (984 base pairs) in the COLQ gene, which indicates 1 copy deletion of exons 14 and 15. SNR.db: signal noise ratio expressed in decibels; CNV.ratio: copy number ratio converted from CNV.log2ratio. CNV.ratio of 1 indicates no copy number change. (E) TaqMan Copy Number Assay results confirm exon deletions in the COLQ gene in the proband, which is also found in her mother (data not shown). Longer PCR cycle number (X-axis) denotes 1 less copy after normalization using RNasP.