title: Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing.
abstract: Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling.
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Mouden
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.|Laboratoire de Génétique Moléculaire et Génomique, C.H.U. de Rennes, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Dubourg
authors.affiliation: Laboratoire de Génétique Moléculaire et Génomique, C.H.U. de Rennes, Rennes, France.
authors.forename: W
authors.initials: W
authors.lastname: Carré
authors.affiliation: UMR1085 Institut de Recherche sur la Santé, l'Environnement et le Travail, Université de Rennes 1, Rennes, France.
authors.forename: S
authors.initials: S
authors.lastname: Rose
authors.affiliation: Service de Génétique Clinique, C.H.U. de Rennes, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Quelin
authors.affiliation: Service de Génétique Clinique, C.H.U. de Rennes, Rennes, France.
authors.forename: L
authors.initials: L
authors.lastname: Akloul
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.|Laboratoire de Génétique Moléculaire et Génomique, C.H.U. de Rennes, Rennes, France.
authors.forename: H
authors.initials: H
authors.lastname: Hamdi-Rozé
authors.affiliation: Service de Génétique Médicale, Maternité Port Royal, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Viot
authors.affiliation: Foetopathologie et Anatomie Pathologique Pédiatrique, Hôpital Cochin, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Salhi
authors.affiliation: Service de Radiologie et Imagerie Médicale, C.H.U. de Rennes, Rennes, France.
authors.forename: P
authors.initials: P
authors.lastname: Darnault
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.|Service de Génétique Clinique, C.H.U. de Rennes, Rennes, France.
authors.forename: S
authors.initials: S
authors.lastname: Odent
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: V
authors.initials: V
authors.lastname: Dupé
authors.affiliation: UMR6290 Institut de Génétique et Développement de Rennes, Université de Rennes 1, Rennes, France.|Laboratoire de Génétique Moléculaire et Génomique, C.H.U. de Rennes, Rennes, France.
authors.forename: V
authors.initials: V
authors.lastname: David
mesh_terms: D002648:Child; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D005315:Fetal Diseases / Q000235:genetics / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics; D016142:Holoprosencephaly / Q000235:genetics* / Q000473:pathology; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C502279:DISP3 protein, human; D053823:Hedgehog Proteins; D008565:Membrane Proteins; C509239:SHH protein, human
keywords: DISP1; SHH; holoprosencephaly; multigenic inheritance; whole exome sequencing