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

Artem Kim, Clara Savary, Marie de Tayrac, Véronique David, FREX Consortium, Dorret Boomsma, Gonneke Willemsen, A. Abdellaoui, Jouke Jan Hottenga, Mathijs Kattenberg

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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.

Original languageEnglish
Pages (from-to)35-49
Number of pages15
JournalBrain : a journal of neurology
Issue number1
Early online date30 Nov 2018
Publication statusPublished - Jan 2019


To test whether the identified oligogenic combinations were specific to the HPE cohort, we used SNV and INDELS data from 248 healthy trios (744 individuals) provided by Genome of the Netherlands (GoNL) sequencing project as a control cohort (Genome of the Netherlands Consortium, 2014). Additional control cohort consisting of 574 unrelated French individuals was provided by the French Exome Project (FREX). This work was supported by Fondation Maladie Rares (grant PMO1201204), Agence Nationale de la Recherche (grant ANR-12-BSV1-0007-01) and the Agence de la Biomedecine (AMP2016). This work was supported by La Fondation Maladie Rares and the Agence de la Biomedecine. The authors acknowledge the Centre de Ressources Biologiques (CRB)-Santé ( of Rennes for managing patient samples. This Work was supported by France Génomique National infrastructure, funded as part of “Investissement d’avenir” program managed by Agence Nationale pour la Recherche (contrat ANR-10-INBS-09) https://www.france-genomique. org/spip/spip.php?article158. This study makes use of data generated by the Genome of the Netherlands Project. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184 021 007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). Samples where contributed by LifeLines ( lifelines-research/general), The Leiden Longevity Study (;, The Netherlands Twin Registry (NTR:, The Rotterdam studies, ( and the Genetic Research in Isolated Populations program (http://www. The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI).

FundersFunder number
French Exome Project
Fondation Maladies RaresPMO1201204
Agence Nationale de la RechercheANR-12-BSV1-0007-01, ANR-10-INBS-09
Nederlandse Organisatie voor Wetenschappelijk Onderzoek184 021 007
Agence de la BiomédecineAMP2016


    • Case-Control Studies
    • Comparative Genomic Hybridization
    • Exome/genetics
    • Female
    • Holoprosencephaly/genetics
    • Humans
    • Male
    • Multifactorial Inheritance/genetics
    • Mutation
    • Pedigree
    • Phenotype
    • Rare Diseases/genetics


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