Novel copy number variation of COLQ gene in a Moroccan patient with congenital myasthenic syndrome: a case report and review of the literature

Abstract

Background: Congenital myasthenic syndromes (CMSs) are rare genetic diseases due to abnormalities of the neuromuscular junction leading to permanent or transient muscle fatigability and weakness. To date, 32 genes were found to be involved in CMSs with autosomal dominant and/or recessive inheritance patterns. CMS with acetylcholinesterase deficiency, in particular, was determined to be due to biallelic mutations of COLQ gene with early-onset clinical signs. Here, we report clinical features and novel molecular findings of COLQ-related CMS in a Moroccan patient with a review of the literature for this rare form.

Case presentation: In this study, we report the case of a 28-month-old Moroccan female patient with hypotonia, associated to axial muscle weakness, global motor delay, bilateral ptosis, unilateral partial visual field deficiency with normal ocular motility, and fatigable muscle weakness. Clinical exome sequencing revealed a novel homozygous deletion of exon 13 in COLQ gene, NM_005677.4(COLQ):c.(814+1_815-1)_(954+1_955-1) del p.(Gly272Aspfs*11). This finding was subsequently confirmed by quantitative real-time PCR (qPCR) in the proband and her parents. In silico analysis of protein-protein interaction network by STRING tool revealed that 12 proteins are highly associated to COLQ with an elevated confidence score. Treatment with Salbutamol resulted in clear benefits and recovery.

Conclusions: This clinical observation illustrates the important place of next-generation sequencing in the precise molecular diagnosis of heterogeneous forms of CMS, the appropriate management and targeted treatment, and genetic counseling of families, with a better characterization of the mutational profile of this rare disease in the Moroccan population.

Keywords: COLQ gene; Case report; Congenital myasthenic syndrome; Novel CNV; Protein-protein interaction.

Fig. 1

Genealogical and molecular data of the Moroccan family with a novel CNV in the COLQ gene. A The family pedigree illustrates the affected patient (homozygous for the mutation) and both parents (Heterozygous carriers). The black arrow indicates the proband. B The representative amplification plots of the target gene (COLQ). C The representative amplification plots of the endogenous gene (housekeeping gene). Both Real-time PCR amplification plots show various amounts of the amplified region in the proband, both parents and two normal controls with determination of mean threshold cycle (Ct) values using QuantStudio^TM Real-Time PCR Software v1.7.1 (Applied Biosystems, Thermo Fisher Scientific). D Bar graph showed the copy number results calculated from delta-delta Ct

Fig. 2

Visualization of the aligned sequencing reads representing deletion of exon 13 in the COLQ gene using Integrative Genomics Viewer (IGV) v2.5.0

Fig. 3

Protein-protein interaction network of COLQ with predicted functional partners. A Screenshot of network map of predicted interactions from the STRING database v11.5. B Summary view shows predicted protein interactions with the confidence score. The Network nodes represent proteins and edges represent the type of protein-protein associations. Line color indicates the type of interaction evidence between two proteins. Black represents co-expression, turquoise database evidence, pink experimental evidence, light green text mining evidence, and violet protein homology.

Fig. 4.

Venn diagram showing possible genes with their different intersections involved in the differential diagnoses between myopathic forms and congenital myasthenic syndromes [, –20]

Fig. 5.

Schematic representation of COLQ domains and the CNV mutations reported in this gene. A Genomic location of COLQ gene (from UCSC browser GRCh37/hg19: http://genome.ucsc.edu) with the full transcript contains 17 coding exons (from the Ensembl database GRCh37 release 107 - Jul 2022). B COLQ exons with the three published pathogenic CNVs in the literature and the deletion described in this study (showed in red color). C Primary structure of COLQ with its three protein domains. D Consequences of mutations in human COLQ protein [11, 32]. Mutations in the N-terminal proline-rich attachment domain (PRAD) prohibit the association of each COLQ strand with an acetylcholinesterase tetramer. Mutations in the central collagen domain containing two heparan sulfate proteoglycan binding (HSPBP) domains cause loss of assembly of the COLQ strands in a triple helix, and mutations in the C-terminal region lead to the synthesis of single- or triple-strands of COLQ-AChE, which are unable to bind to the basal lamina [3, 9, 12, 33].