The First Case of Congenital Myasthenic Syndrome Caused by a Large Homozygous Deletion in the C-Terminal Region of COLQ (Collagen Like Tail Subunit of Asymmetric Acetylcholinesterase) Protein

Abstract

Congenital myasthenic syndromes (CMSs) are caused by mutations in genes that encode proteins involved in the organization, maintenance, function, or modification of the neuromuscular junction. Among these, the collagenic tail of endplate acetylcholinesterase protein (COLQ; MIM 603033) has a crucial role in anchoring the enzyme into the synaptic basal lamina. Here, we report on the first case of a patient with a homozygous deletion affecting the last exons of the COLQ gene in a CMS patient born to consanguineous parents of Pakistani origin. Electromyography (EMG), electroencephalography (EEG), clinical exome sequencing (CES), and single nucleotide polymorphism (SNP) array analyses were performed. The subject was born at term after an uneventful pregnancy and developed significant hypotonia and dystonia, clinical pseudoseizures, and recurring respiratory insufficiency with a need for mechanical ventilation. CES analysis of the patient revealed a homozygous deletion of the COLQ gene located on the 3p25.1 chromosome region. The SNP-array confirmed the presence of deletion that extended from exon 11 to the last exon 17 with a size of 19.5 Kb. Our results add new insights about the underlying pathogenetic mechanisms expanding the spectrum of causative COLQ mutations. It is relevant, considering the therapeutic implications, to apply suitable molecular approaches so that no type of mutation is missed: "each lost mutation means a baby treated improperly".

Keywords: COLQ; SNP-array; clinical exome sequencing; congenital myasthenic syndrome.

Figure 1

Pedigree chart of the family. Squares and circles indicate men and women, respectively. A diagonal line through a symbol indicates a deceased individual. A small rhombus indicates a miscarriage. Affected individuals are indicated by filled symbols. Carrier individuals are indicated by filled-empty symbols. II-4 genetic analysis revealed a homozygous microdeletion involving the 3p25.1 chromosome region that contains part of the collagenic tail of endplate acetylcholinesterase (COLQ) gene. The microdeletion resulted in heterozygous status in I-1 and I-2.

Figure 2

Electroencephalography (EEG). (A,B) High voltage slow waves from right occipital areas with bilateral involvement. Video EEG recording showed associated chaotic movements. (C,D) Occipital bilateral slow waves with suppression of electrical activity. Video EEG recording showed apnea and lack of motion.

Figure 3

Schematic representation of the COLQ gene and results of single nucleotide polymorphism (SNP)-array analysis in the patient and his parents (A) COLQ exons with 28 published pathogenic variants (upper part) and the microdeletion described in this study (lower part). Three COLQ domains: (1) conserved domains of COLQ include an N-terminal proline-rich attachment domain (PRAD) that associates each COLQ strand with an acetylcholinesterase tetramer, (2) a central collagen domain that contains two heparan sulfate proteoglycan binding (HSPBP) domains, and (3) a C-terminal region needed for assembly of the COLQ strands in a triple helix. (B) Results of SNP-array analysis in the patient and his parents. The copy number state of each probe is drawn along chromosome 3 from 15.44 to 15.56 Mb (University of California Santa Cruz (UCSC) Genome Browser, buildGRCh37/hg19). The upper panel represents the copy number state of the proband, the middle panel that of the father, and the lower panel that of the mother. Values on the Y-axis indicate the inferred copy number according the probes’ intensities. Red bars indicate the deletion identified in the patient (homozygous state, copy number = 0) and his parents (heterozygous state, copy number = 1).