Dataset Information

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

ABSTRACT: Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.

SUBMITTER: Sivera R

PROVIDER: S-EPMC5532232 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

Sivera Rafael R Frasquet Marina M Lupo Vincenzo V García-Sobrino Tania T Blanco-Arias Patricia P Pardo Julio J Fernández-Torrón Roberto R de Munain Adolfo López AL Márquez-Infante Celedonio C Villarreal Liliana L Carbonell Pilar P Rojas-García Ricard R Segovia Sonia S Illa Isabel I Frongia Anna Lia AL Nascimento Andrés A Ortez Carlos C García-Romero María Del Mar MDM Pascual Samuel Ignacio SI Pelayo-Negro Ana Lara AL Berciano José J Guerrero Antonio A Casasnovas Carlos C Camacho Ana A Esteban Jesús J Chumillas María José MJ Barreiro Marisa M Díaz Carmen C Palau Francesc F Vílchez Juan Jesús JJ Espinós Carmen C Sevilla Teresa T

Scientific reports 20170727 1

Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common geno ...[more]

PMID: 28751717

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Project description:Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-? signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (?(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

Dataset Information

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

Publications

Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

Similar Datasets

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