Integrated clinical and omics approach to rare diseases: Novel genes and oligogenic inheritance in holoprosencephaly

Artem Kim, Clara Savary, Christèle Dubourg, Wilfrid Carré, Charlotte Mouden, Houda Hamdi-Rozé, Hélène Guyodo, Jerome Le Douce, Emmanuelle Génin, Dominique Campion, Jean François Dartigues, Jean François Deleuze, Jean Charles Lambert, Richard Redon, Thomas Ludwig, Benjamin Grenier-Boley, Sébastien Letort, Pierre Lindenbaum, Vincent Meyer, Olivier QuenezChristian Dina, Céline Bellenguez, Camille Charbonnier-Le Clézio, Joanna Giemza, Stéphanie Chatel, Claude Férec, Hervé Le Marec, Luc Letenneur, Gaël Nicolas, Karen Rouault, Delphine Bacq, Anne Boland, Doris Lechner, Cisca Wijmenga, Morris A. Swertz, P. Eline Slagboom, Gert Jan B. Van Ommen, Cornelia M. Van Duijn, Dorret I. Boomsma, Paul I.W. De Bakker, Jasper A. Bovenberg, P. Eline Slagboom, Anton J.M. De Craen, Marian Beekman, Albert Hofman, Gonneke Willemsen, Bruce Wolffenbuttel, Mathieu Platteel, Yuanping Du, Ruoyan Chen, Hongzhi Cao, Rui Cao, Yushen Sun, Jeremy Sujie Cao, Freerk Van Dijk, Pieter B.T. Neerincx, Patrick Deelen, Martijn Dijkstra, George Byelas, Alexandros Kanterakis, Jan Bot, Kai Ye, Eric Wubbo Lameijer, Martijn Vermaat, Jeroen F.J. Laros, Johan T. Den Dunnen, Peter De Knijff, Lennart C. Karssen, Elisa M. Van Leeuwen, Najaf Amin, Vyacheslav Koval, Fernando Rivadeneira, Karol Estrada, Jayne Y. Hehir-Kwa, Joep De Ligt, Abdel Abdellaoui, Jouke Jan Hottenga, V. Mathijs Kattenberg, David Van Enckevort, Hailiang Mei, Mark Santcroos, Barbera D.C. Van Schaik, Robert E. Handsaker, Steven A. McCarroll, Evan E. Eichler, Arthur Ko, Peter Sudmant, Laurent C. Francioli, Wigard P. Kloosterman, Isaac J. Nijman, Victor Guryev, Laurent Pasquier, Elisabeth Flori, Marie Gonzales, Claire Bénéteau, Odile Boute, Tania Attié-Bitach, Joelle Roume, Louise Goujon, Linda Akloul, Sylvie Odent, Erwan Watrin, Valérie Dupé, Marie De Tayrac, Véronique David

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

36 Citaten (Scopus)


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 reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.

Originele taal-2Engels
Pagina's (van-tot)35-49
Aantal pagina's15
Nummer van het tijdschrift1
StatusGepubliceerd - 1 jan. 2019


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