title: Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway.
abstract: 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.
authors.affiliation: Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.|UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Dubourg
authors.affiliation: Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.|UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Wilfrid
authors.initials: W
authors.lastname: Carré
authors.affiliation: Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.|UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Hamdi-Rozé
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Mouden
authors.affiliation: Service de Génétique Médicale, CHI, Poissy, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.affiliation: Cabinet de Pédiatrie, Oran, Algérie.
authors.forename: Benmansour
authors.initials: B
authors.lastname: Abdelmajid
authors.affiliation: Unité de Génétique Clinique, CHI, Créteil, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Amram
authors.affiliation: Unité de Génétique Clinique, CHU Robert Debré, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Service de Génétique Médicale, CHU, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.affiliation: Département de Génétique Médicale, CHU, Montpellier, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Coubes
authors.affiliation: Centre de Génétique, CHU, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre-Olivier
authors.affiliation: Service de Génétique, CH, Mulhouse, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Ginglinger
authors.affiliation: Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.affiliation: Service de Gynécologie, CHU, Marseille, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Levy-Mozziconacci
authors.affiliation: Medical Genetics, Our Lady's Children Hospital, Dublin, Ireland.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Lynch
authors.affiliation: Service de Génétique Médicale, CHU, Bordeaux, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Naudion
authors.affiliation: Service de Génétique Clinique, CHU, Rennes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.affiliation: Service d'Endocrinologie, CHU Robert Debré, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Poidvin
authors.affiliation: Service de Génétique Clinique, CHU, Saint-Etienne, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Prieur
authors.affiliation: Département de Génétique Médicale, CHU, Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.affiliation: Service de Génétique, CHU, Tours, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dupé
authors.affiliation: Service de Génétique Clinique, CHU, Rennes, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Akloul
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.|Service de Génétique Clinique, CHU, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.|UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: de Tayrac
authors.affiliation: Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.|UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: David
mesh_terms: D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D053823:Hedgehog Proteins / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: FGF signaling pathway; brain malformation; holoprosencephaly; multigenic inheritance; targeted NGS