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.

Expression assay of the COLQ in a family with congenital myasthenic syndrome and symptomatic carriers

“…Ocular muscle involvement is common among patients with CMS5, and it usually presents as bilateral ptosis; however, asymmetric ptosis has also been reported in some cases 8 . Hypotonia, dysarthria, scoliosis and lordosis, ophthalmoparesis, and delayed pupillary light reflex have also been reported as clinical findings of CMS5 patients; however, it is worth mentioning that features mentioned above are not consistent in all patients, and phenotypic variation in severity and symptoms could be seen 15,32,33 . The main clinical symptoms in our patient were delayed motor milestone, bilateral ptosis, ophthalmoparesis, generalized weakness due to a defect at the neuromuscular junction exacerbated by exertion, and difficulty in smiling, speaking, and chewing for an extended time.…”

“… 8 Hypotonia, dysarthria, scoliosis and lordosis, ophthalmoparesis, and delayed pupillary light reflex have also been reported as clinical findings of CMS5 patients; however, it is worth mentioning that features mentioned above are not consistent in all patients, and phenotypic variation in severity and symptoms could be seen. 15 , 32 , 33 The main clinical symptoms in our patient were delayed motor milestone, bilateral ptosis, ophthalmoparesis, generalized weakness due to a defect at the neuromuscular junction exacerbated by exertion, and difficulty in smiling, speaking, and chewing for an extended time. Delayed motor milestone, ptosis, facial weakness and proximal weakness are the shared symptoms between our patient and two other patients that had been reported with the (p.Arg227Ter) variant in the COLQ (Table 2 ).…”

A Pediatric Case of COLQ-Related Congenital Myasthenic Syndrome with Marked Fatigue

“…Although most CMS cases can be treated with drugs, unfortunately a delayed diagnosis can affect prognosis [9]. The rate of misdiagnosis in CMS is high due to non-specific and fluctuating presenting symptoms [6,10,11]. The initial manifestation in this patient was only marked fatigue.…”

Identification and validation of key genes associated with atrial fibrillation in the elderly

“…Studies have shown that mutations in COLQ can lead to congenital myasthenic syndrome (CMS), which causes cardiac autonomic dysfunction ( 32 , 33 ). Interestingly, Çubukçuoğlu et al ( 34 ) found that the expression of COLQ was higher in degenerative mitral regurgitation patients with AF than in those with SR ( P = 0.003), which is consistent with the results of our study.…”