High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

Abstract

OBJECTIVE: Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. METHODS: This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. RESULTS: In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Wholeexome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. CONCLUSION: The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.

Síndrome de Charcot-Marie-Tooth e surto psicótico: um estudo de caso abordando características, diagnóstico e evolução clínica rara

“…A Síndrome de Charcot-Marie-Tooth (SCMT) é uma rara morbidade abrangida dentro do arcabouço das neuropatias periféricas hereditárias 1,2 . Desse modo, corresponde a uma configuração específica de neuropatia sensorial motora hereditária, e resulta em uma clínica multifatorial heterogênea no que diz respeito a sua sintomatologia e etiologia 2,3 .…”

“…Logo, configura-se, portanto, com características fenotípicas, mutagênicas e de herança suficientemente singulares. Além disso, apresenta uma prevalência que a discrimina de outras neuropatias em virtude de sua frequente apresentação: de aproximadamente 9,7 a 82 casos a cada 100 mil indivíduos 1,3 . Dessa forma, é a neuropatia hereditária mais frequente e um dos distúrbios neurogenéticos mais comuns 4,5 .…”

“…Este padrão heterogêneo da SCMT foi descrito pelo uso frequente de sequenciamento de próxima geração (NGS). Em virtude disto, mais de 100 genes foram descritos como tendo mutações causadoras de CMT 1,12 . Além disso, quatro genes são responsáveis por quase 80% das CMTs herdadas geneticamente: PMP22, GJB1, MFN2 e MPZ 13 .…”

“…O Sequenciamento de Próxima Geração era um método mais dispendioso, o qual tem se tornado cada vez mais econômico recentemente, de modo que seja adequado e amplo para múltiplas doenças de herança genética, incluindo a SCMT 1 . Poucos estudos epidemiológicos relataram a prevalência da CMT no mundo.…”