| Title: |
Integrated clinical and omics approach to rare diseases:Novel genes and oligogenic inheritance in holoprosencephaly |
| Authors: |
Kim,Artem; Savary,Clara; Dubourg,Christèle; Carré,Wilfrid; Mouden,Charlotte; Hamdi-Rozé,Houda; Guyodo,Hélène; Douce,Jerome Le; Génin,Emmanuelle; Campion,Dominique; Dartigues,Jean François; Deleuze,Jean François; Lambert,Jean Charles; Redon,Richard; Ludwig,Thomas; Grenier-Boley,Benjamin; Letort,Sébastien; Lindenbaum,Pierre; Meyer,Vincent; Quenez,Olivier; Dina,Christian; Bellenguez,Céline; Charbonnier-Le Clézio,Camille; Giemza,Joanna; Chatel,Stéphanie; Férec,Claude; Le Marec,Hervé; Letenneur,Luc; Nicolas,Gaël; Rouault,Karen; Bacq,Delphine; Boland,Anne; Lechner,Doris; Wijmenga,Cisca; Swertz,Morris A.; Eline Slagboom,P.; Van Ommen,Gert Jan B.; Van Duijn,Cornelia M.; Boomsma,Dorret I.; De Bakker, Paul I.W.; Bovenberg,Jasper A.; De Craen,Anton J.M.; Beekman,Marian; Hofman,Albert; Willemsen,Gonneke; Wolffenbuttel,Bruce; Platteel,Mathieu; Du,Yuanping; Chen,Ruoyan; Cao,Hongzhi; Cao,Rui; Sun,Yushen; Sujie Cao,Jeremy; Van Dijk,Freerk; Neerincx,Pieter B.T.; Deelen, Patrick; Dijkstra,Martijn; Byelas,George; Kanterakis,Alexandros; Bot,Jan; Ye,Kai; Lameijer,Eric Wubbo; Vermaat,Martijn; Laros,Jeroen F.J.; Den Dunnen,Johan T.; De Knijff,Peter; Karssen,Lennart C.; Van Leeuwen,Elisa M.; Amin,Najaf; Koval,Vyacheslav; Rivadeneira,Fernando; Estrada,Karol; Hehir-Kwa,Jayne Y.; De Ligt, Joep; Abdellaoui,Abdel; Hottenga,Jouke Jan; Mathijs Kattenberg,V.; Van Enckevort,David; Mei,Hailiang; Santcroos,Mark; Van Schaik,Barbera D.C.; Handsaker,Robert E.; McCarroll,Steven A.; Eichler,Evan E.; Ko,Arthur; Sudmant,Peter; Francioli, Laurent C.; Kloosterman, Wigard P.; Nijman, Isaac J.; Guryev, Victor; Pasquier,Laurent; Flori,Elisabeth; Gonzales,Marie; Bénéteau,Claire; Boute,Odile; Attié-Bitach,Tania; Roume,Joelle; Goujon,Louise; Akloul,Linda; Odent,Sylvie; Watrin,Erwan; Dupé,Valérie; De Tayrac,Marie; David,Véronique; CMM Groep Kaaij; Genetica Klinische Genetica; Cancer; CMM Groep De Ridder; Child Health; CMM Groep Kloosterman; CMM USEQ Facility; Hubrecht Institute with UMC |
| Publication Year: |
2019 |
| Subject Terms: |
exome; holoprosencephaly; oligogenic inheritance; primary cilia; sonic hedgehog; Taverne; Clinical Neurology |
| Description: |
Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10 -9). We also show that depending on the affected genes, patients present with particular clinical features. This study ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
0006-8950 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/392174 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/392174 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.CABBCEC9 |
| Database: |
BASE |