Portal de Periódicos da CAPES

Artigo Produção Nacional Revisado por pares

BIBTEX RIS

G.P.33

2014; Elsevier BV; Volume: 24; Issue: 9-10 Linguagem: Inglês

10.1016/j.nmd.2014.06.047

1873-2364

Osório Lopes Abath Neto, Clóvis de Arruda Martins, Umbertina Conti Reed, Valérie Biancalana, C. Bönnemann, Jocelyn Laporte, Edmar Zanoteli,

Neurogenetic and Muscular Disorders Research

In this work we present results of the molecular analyses of 22 families diagnosed with myotubular or centronuclear myopathies (MTM/CNM) on clinical and histological grounds in an outpatient neuromuscular diseases service. Patients were initially screened with focused Sanger sequencing of known genes implicated in MTM/CNM: MTM1, DNM2 and BIN1. Out of 8 families with a typical picture of MTM, 7 were diagnosed with known and novel mutations in MTM1. The remaining 14 families had typical or atypical CNM: two families had DNM2 as the implicated gene, and one family with a single moderately affected female had a macrodeletion in MTM1 demonstrated via MLPA. No mutation was found in BIN1. A focused panel of 81 genes was performed in two families and allowed a compound TTN truncation, confirmed by Sanger, to be identified as the probable implicated gene in one family. Eleven families without a diagnosis had then whole exome sequencing (WES) performed, followed by a stringent variant filtering pipeline taking into account pathogenicity prediction and population frequency data to filter out polymorphisms. Suitable variants were confirmed with Sanger sequencing. RYR1 was the putative implicated gene in four families, in which mutations were private compound heterozygous, comprising three splice site disruptions and one nonsense. Three additional families with compound missense RYR1 variants with a prediction of high pathogenicity in various tools will need functional validation. The enrichment for RYR1 mutations in this cohort suggests that RYR1 might be a very frequently implicated gene in CNM, especially in cases with atypical histology. Moreover, there does not seem to be a hot spot for mutations in this gene in CNM. Four families still do not have a molecular diagnosis, thus novel genes are probably involved. Ongoing WES sequencing of additional members of these families may help identify novel genes among various candidates. In this work we present results of the molecular analyses of 22 families diagnosed with myotubular or centronuclear myopathies (MTM/CNM) on clinical and histological grounds in an outpatient neuromuscular diseases service. Patients were initially screened with focused Sanger sequencing of known genes implicated in MTM/CNM: MTM1, DNM2 and BIN1. Out of 8 families with a typical picture of MTM, 7 were diagnosed with known and novel mutations in MTM1. The remaining 14 families had typical or atypical CNM: two families had DNM2 as the implicated gene, and one family with a single moderately affected female had a macrodeletion in MTM1 demonstrated via MLPA. No mutation was found in BIN1. A focused panel of 81 genes was performed in two families and allowed a compound TTN truncation, confirmed by Sanger, to be identified as the probable implicated gene in one family. Eleven families without a diagnosis had then whole exome sequencing (WES) performed, followed by a stringent variant filtering pipeline taking into account pathogenicity prediction and population frequency data to filter out polymorphisms. Suitable variants were confirmed with Sanger sequencing. RYR1 was the putative implicated gene in four families, in which mutations were private compound heterozygous, comprising three splice site disruptions and one nonsense. Three additional families with compound missense RYR1 variants with a prediction of high pathogenicity in various tools will need functional validation. The enrichment for RYR1 mutations in this cohort suggests that RYR1 might be a very frequently implicated gene in CNM, especially in cases with atypical histology. Moreover, there does not seem to be a hot spot for mutations in this gene in CNM. Four families still do not have a molecular diagnosis, thus novel genes are probably involved. Ongoing WES sequencing of additional members of these families may help identify novel genes among various candidates.