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”.

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

“…The COLQ gene encodes a collagen-like strand associated into a triple helix to form a tail that anchors catalytic subunits of acetylcholinesterase (ACHE; MIM*100740) to the synaptic basal lamina. Mutations in the COLQ gene are uniformly distributed on the three conserved domains of COLQ protein: proline-rich attachment domain (PRAD) in the N-terminal region from exon 1 to exon 4, heparan sulfate proteoglycan-binding domain (HSPBD) in the collagen-like domain from exon 4 to exon 14, including the CNV identified in our patient, and the C-terminal region encodes by genomic exons 15 to 17 [11,12]. These Fig.…”

“…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.…”

“…In 2016, Wang et al reported a Chinese girl with a large deletion encompassing exons 14-15 of COLQ gene c.(954+1_955-1)_(1195+1_1196-1) del inherited from the mother, and compound heterozygosity with the splicing c.1298+3A>G mutation located at donor (5') site within intron 16-17 inherited from the father [10]. In 2020, Laforgia et al identified a homozygous extended deletion encompassing exons 11-17, arr [GrCh37] 3p25.1(15491478x1,15492150_ 15511615x0,15511740x1) of the COLQ gene in a Pakistani male child with severe clinical presentation of CMS [11]. Lastly, in 2021, Luo and their colleagues reported deletion of exons 14-15 at homozygous state in a 12-year-old boy with mild symptoms [29] (Table 1).…”

“…We present, to the best of our knowledge, the second clinical and molecular genetic diagnosis of CMS type-5 in Morocco and the fourth copy number variation (CNV) worldwide through the case of a Moroccan female patient born to healthy parents (first cousins). She harbored a novel homozygous deletion of exon 13 in the COLQ gene identified by the clinical exome sequencing (CES) approach, integrated with a copy number analysis algorithm [8][9][10][11]. Four other unrelated CMS patients, previously described in the literature with large exon deletions in the COLQ gene are also discussed here.…”

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…COLQ -CMS has been reported in 30 original articles since 1998 [ 62 , 73 , 78 , 140 , 141 , 221 , 222 , 225 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 ]. Interestingly, a grandmother and a father of two siblings with COLQ -CMS carried a heterozygous truncation variant of COLQ , and showed congenital ptosis [ 246 ].…”