Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Christèle Dubourg (1, 2) , Wilfrid Carré (1, 2) , Houda Hamdi-Rozé (1, 2) , Charlotte Mouden (1) , Joëlle Roume (3) , Benmansour Abdelmajid , Daniel Amram (4) , Clarisse Baumann (5) , Nicolas Chassaing (6) , Christine Coubes (7) , Laurence Faivre-Olivier (8) , Emmanuelle Ginglinger (9) , Marie Gonzales (10) , Annie Levy-Mozziconacci (11) , Sally-Ann Lynch , Sophie Naudion (12) , Laurent Pasquier (13) , Amélie Poidvin (14) , Fabienne Prieur (15) , Pierre Sarda (16) , Annick Toutain (17) , Valérie Dupé (1) , Linda Akloul (18) , Sylvie Odent (1, 18, 13) , Marie De Tayrac (1) , Véronique David (1, 2)

1 IGDR - Institut de Génétique et Développement de Rennes
2 Service de biologie moléculaire
3 Service de Génétique
4 Service de Pneumologie [CHI Créteil]
5 Département de Génétique Médicale
6 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
7 Service de Génétique Clinique
8 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
9 CH E.Muller Mulhouse - Centre Hospitalier Emile Muller [Mulhouse]
10 Service de génétique et embryologie médicales [CHU Trousseau]
11 Service de Gynécologie et Obstétrique [Marseille]
12 CHU Bordeaux [Bordeaux]
13 CHU Pontchaillou [Rennes]
14 Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré]
15 CHU de Saint-Etienne - Centre Hospitalier Universitaire de Saint-Etienne
16 CHU Montpellier
17 Service de génétique [Tours]
18 Service de génétique clinique [Rennes]

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.

Keywords: targeted NGS; brain malformation; multigenic inheritance; Holoprosencephaly; FGF signaling pathway

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

Christèle Dubourg, Wilfrid Carré, Houda Hamdi-Rozé, Charlotte Mouden, Joëlle Roume, et al.. Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway. Human Mutation, 2016, 37 (12), pp.1329-1339. ⟨10.1002/humu.23038⟩. ⟨hal-01439363⟩