Clinical diversity caused by novel IGHMBP2 variants

Yuan, Jun‐Hui; Hashiguchi, Akihiro; Yoshimura, Akinobu; Yaguchi, Hiroshi; Tsuzaki, Koji; Ikeda, Azusa; Wada‐Isoe, Kenji; Ando, Masahiro; Nakamura, Tomonori; Higuchi, Yujiro; Hiramatsu, Yoshihiro; Okamoto, Yuji; Takashima, Hiroshi

doi:10.1038/jhg.2017.15

Cited by 22 publications

(23 citation statements)

References 38 publications

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“…Second, these mutations alter the evolutionarily conserved amino acid residues of the mutated proteins and their pathogenicity was supported by in silico prediction, using Mutation Taster, PolyPhen‐2, CADD score, and SIFT programs. Third, six of the novel missense mutations change an amino acid residue where a different missense change determined to be pathogenic has been seen before, including GJB1 p.F51C, GJB1 p.Y135D, GJB1 p.R183F, NEFL p.N98Y, MFN2 p.R280P, and IGHMBP2 p.R595W. Five of these novel mutations lead to protein length changes, such as GJB1 p.T185Pfs*11, SH3TC2 L139del, LRSAM1 p.E680*, IGHMBP2 p.A786Pfs*45, and KIF5A p.Q764*.…”

Section: Resultsmentioning

confidence: 93%

Mutation spectrum of Charcot‐Marie‐Tooth disease among the Han Chinese in Taiwan

Hsu

Lin

Guo

et al. 2019

Ann Clin Transl Neurol

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Objective Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies. Mutations in more than 90 genes have been implicated in CMT; however, the mutational spectrum of CMT in Chinese population remains obscure. This study aims to provide a comprehensive overview of the frequency of mutations in Taiwanese patients with CMT and look for genotype‐phenotype correlations. Methods Mutational analyses were performed on 427 unrelated Taiwanese patients with CMT by polymorphic microsatellite markers analysis or real‐time fluorescent PCR for PMP22 duplication, Sanger sequencing for GJB1 mutations, and targeted sequencing covering 124 genes causing or relevant to inherited neuropathies. We also correlated the genotypes with the phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. Results Pathogenic mutations were identified in 312 patients (73.1%; 312/427), including 208 patients with a PMP22 duplication, 40 patients with a GJB1 mutation, and 64 patients with a mutation in one of other 18 CMT genes. A confirmed molecular diagnosis was achieved in 84.4% (266/315) of the patients with demyelinating CMT and 41.1% (46/112) of the patients with axonal CMT. Mutations in MPZ, MFN2, or NEFL are the most frequent disease causes in patients with infantile‐onset CMT (≤2 years), while PMP22 duplications and mutations in GJB1, MFN2, or MPZ are the frequent causes among patients with childhood‐ or adolescence‐onset CMT (3–9 years). Interpretation This study provides a genotype‐phenotype landscape of CMT in Taiwan and highlights the unique spectrum of CMT genes frequencies among patients of Chinese origin.

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Section: Resultsmentioning

confidence: 93%

Mutation spectrum of Charcot‐Marie‐Tooth disease among the Han Chinese in Taiwan

Hsu

Lin

Guo

et al. 2019

Ann Clin Transl Neurol

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“…WGS on the other hand captures both coding and non‐coding variants. Another additional advantage of WGS is that it has the potential to identify large structural variations such as deletions and duplications which was remains problematic with WES (Wagner et al., ; Yuan et al., )…”

Section: Resultsmentioning

confidence: 99%

Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice‐site and Charcot‐Marie‐Tooth phenotype with early onset symptoms

Cassini

Duncan

Rives

et al. 2019

Molec Gen & Gen Med

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Background Rare variants (RV) in immunoglobulin mu‐binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot‐Marie‐Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns. Methods and Results An 11‐year‐old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non‐coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT‐PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense‐mediated decay (NMD), resulting in halpoinsufficiency. Conclusion This case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.

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“…All GJB1 variants (NM_000166.5) were checked against the Human Gene Mutation Database (HGMD Professional; 2018.1). Novel GJB1 variants were further analyzed with a pipeline described previously , validated by Sanger sequencing and classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines .…”

Section: Methodsmentioning

confidence: 99%

Genetic and phenotypic profile of 112 patients with X‐linked Charcot–Marie–Tooth disease type 1

Yuan

Sakiyama

Hashiguchi

et al. 2018

Euro J of Neurology

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Clinical diversity caused by novel IGHMBP2 variants

Cited by 22 publications

References 38 publications

Mutation spectrum of Charcot‐Marie‐Tooth disease among the Han Chinese in Taiwan

Mutation spectrum of Charcot‐Marie‐Tooth disease among the Han Chinese in Taiwan

Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice‐site and Charcot‐Marie‐Tooth phenotype with early onset symptoms

Genetic and phenotypic profile of 112 patients with X‐linked Charcot–Marie–Tooth disease type 1

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