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J Hum Genet. 2015 Jun;60(6):305-12. doi: 10.1038/jhg.2015.20. Epub 2015 Mar 5.

New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing.

Author information

1
1] Unidade de Genética Molecular, Centro de Genética Médica Dr Jacinto de Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal [2] Departamento de Microscopia, Laboratório de Biologia Celular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal [3] Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
2
Consulta de Doenças Neuromusculares, Hospitais da Universidade de Coimbra, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
3
Unidade de Neuropediatria, Centro de Desenvolvimento da Criança Luís Borges, Hospital Pediátrico de Coimbra, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
4
Unidade de Neuropatologia, Centro Hospitalar do Porto, Porto, Portugal.
5
1] Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal [2] Serviço de Genética Médica, Centro de Genética Médica Dr Jacinto Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal.
6
1] Unidade de Genética Molecular, Centro de Genética Médica Dr Jacinto de Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal [2] Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
7
Unidade de Sequenciação Avançada, Biocant, Parque Tecnológico de Cantanhede, Núcleo 04, Cantanhede, Portugal.
8
1] Unidade de Genética Molecular, Centro de Genética Médica Dr Jacinto de Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal [2] Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal [3] UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
9
1] Departamento de Microscopia, Laboratório de Biologia Celular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal [2] Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal [3] Centro de Genética da Reprodução Professor Alberto Barros, Porto, Portugal.

Abstract

Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis.

PMID:
25740612
DOI:
10.1038/jhg.2015.20
[Indexed for MEDLINE]

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