Dubourg Christèle, Carré Wilfrid, Hamdi-Rozé Houda, Mouden Charlotte, Roume Joëlle, Abdelmajid Benmansour, Amram Daniel, Baumann Clarisse, Chassaing Nicolas, Coubes Christine, Faivre-Olivier Laurence, Ginglinger Emmanuelle, Gonzales Marie, Levy-Mozziconacci Annie, Lynch Sally-Ann, Naudion Sophie, Pasquier Laurent, Poidvin Amélie, Prieur Fabienne, Sarda Pierre, Toutain Annick, Dupé Valérie, Akloul Linda, Odent Sylvie, de Tayrac Marie, David Véronique
Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.
UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
Hum Mutat. 2016 Dec;37(12):1329-1339. doi: 10.1002/humu.23038. Epub 2016 Aug 23.
Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.
前脑无裂畸形（HPE）是人类最常见的先天性脑畸形，其特征为前脑分裂受损和中线面部异常。它在临床和遗传学方面均表现出高度的异质性。我们开发了一种新型靶向二代测序（NGS）检测方法，并对257例HPE患者进行了筛查。在约24%的病例中鉴定出具有高度有害效应置信度的突变，并将其用于诊断，而在10%的病例中鉴定出意义未明的变异。本研究提供了参与HPE的基因的新分类。就频率而言，SHH、ZIC2和SIX3与GLI2仍然是主要基因，其次是FGF8和FGFR1。我们的研究鉴定出的三个次要HPE基因是DLL1、DISP1和SUFU。在此，我们证明成纤维细胞生长因子信号通路现在必须被视为参与HPE的主要途径。有趣的是，发现了几例双突变病例，这支持了HPE的多基因遗传。总之，这支持了在HPE诊断中实施NGS以改善遗传咨询的必要性。
