Copy number analysis reveals a novel multiexon deletion of the
            <i>COLQ</i>
            gene in congenital myasthenia

Wang, Wei; Wu, Yanhong; Wang, Chen; Jiao, Jinsong; Klein, Christopher J.

doi:10.1212/nxg.0000000000000117

Cited by 10 publications

(14 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 1998, Ohno et al [ 15 ] reported a heterozygous truncation mutation consisting of a large-scale frameshift deletion [exon 2–3] in a CMS patient that abolished PRAD and followed the domain of the COLQ gene. Twenty years later, Wang et al [ 16 ] identified a novel copy number deletion encompassing exon 14 and exon 15 of the COLQ gene in compound heterozygosity with the IVS16 + 3A > G variant.…”

Section: Discussionmentioning

confidence: 99%

“…However, biallelic COLQ mutations are responsible for a minority of CMSs cases with mutations that have been described in each of the three COLQ domains. To date, most reported COLQ mutations are uniformly distributed on the three conserved domains of COLQ protein: proline-rich attachment domain (PRAD) [exons [1][2][3][4] in the N-terminal region, heparan sulfate proteoglycan-binding domain (HSPBD) in the collagen domain [exons [4][5][6][7][8][9][10][11][12][13][14], and the C-terminal region [exons [15][16][17]. The causative mutations would exert their effects by different mechanisms resulting in prolonged synaptic currents and different action potentials due to expanded residence of acetylcholine in the synaptic space.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular karyotype of the patient according to the International System for Human Cytogenetic Nomenclature (ISCN 2016) is: arr[GrCh37] 3p25.1(15491478x1,15492150_15511615x0,15511740x1). The deleted region in 3p25.1 contains part of the COLQ gene (i.e., exons [11][12][13][14][15][16][17]. Carrier testing in the parents was performed by chromosome microarray analysis (CMA) using the same platform (i.e., CytoScan HD Array) and resulted in heterozygous outcomes in both (Figure 3B).…”

Section: Genetic Findingsmentioning

confidence: 99%

See 2 more Smart Citations

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

Laforgia

Cosmo

Palumbo

et al. 2020

Genes

View full text Add to dashboard Cite

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”.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Findingsmentioning

confidence: 99%

See 1 more Smart Citation

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

Laforgia

Cosmo

Palumbo

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…Patients lacking a second heteroallelic mutation in DOK7 were reported in a previous study. 2 Moreover, multiexon genomic deletions of RAPSN 13 and COLQ 14 have also been identified as causative of CMS. It is therefore conceivable that CNVs in DOK7 may explain a proportion of cases assessed as negative or inconclusive by conventional sequencing analysis.…”

Section: Discussionmentioning

confidence: 99%

Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes

et al. 2017

View full text Add to dashboard Cite

Objective:To identify the genetic cause in a patient affected by ptosis and exercise-induced muscle weakness and diagnosed with congenital myasthenic syndromes (CMS) using whole-genome sequencing (WGS).Methods:Candidate gene screening and WGS analysis were performed in the case. Allele-specific PCR was subsequently performed to confirm the copy number variation (CNV) that was suspected from the WGS results.Results:In addition to the previously reported frameshift mutation c.1124_1127dup, an intragenic 6,261 bp deletion spanning from the 5′ untranslated region to intron 2 of the DOK7 gene was identified by WGS in the patient with CMS. The heterozygous deletion was suspected based on reduced coverage on WGS and confirmed by allele-specific PCR. The breakpoints had microhomology and an inverted repeat, which may have led to the development of the deletion during DNA replication.Conclusions:We report a CMS case with identification of the breakpoints of the intragenic DOK7 deletion using WGS analysis. This case illustrates that CNVs undetected by Sanger sequencing may be identified by WGS and highlights their relevance in the molecular diagnosis of a treatable neurologic condition such as CMS.

show abstract

“…122,134,135 In addition, deletions and duplications have emerged as common causes of several inherited myopathies, and diagnostic yield is thus increased by panels that include copy number variation analysis. 134,[136][137][138][139]…”

Section: General Approachmentioning

confidence: 99%

Guidelines for genetic testing of muscle and neuromuscular junction disorders

2021

View full text Add to dashboard Cite

Despite recent advances in the understanding of inherited muscle and neuromuscular junction diseases, as well as the advent of a wide range of genetic tests, patients continue to face delays in diagnosis of sometimes treatable disorders. These guidelines outline an approach to genetic testing in such disorders. Initially, a patient's phenotype is evaluated to identify myopathies requiring directed testing, including myotonic dystrophies, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, mitochondrial myopathies, dystrophinopathies, and oculopharyngodistal myopathy. Initial investigation in the remaining patients is generally a comprehensive gene panel by next-generation sequencing. Broad panels have a higher diagnostic yield and can be cost-effective. Due to extensive phenotypic overlap and treatment implications, genes responsible for congenital myasthenic syndromes should be included when evaluating myopathy patients. For patients whose initial genetic testing is negative or inconclusive, phenotypic re-evaluation is warranted, along with consideration of genes and variants not included initially, as well as their acquired mimickers.

show abstract

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

Cited by 10 publications

References 8 publications

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

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

Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes

Guidelines for genetic testing of muscle and neuromuscular junction disorders

Contact Info

Product

Resources

About