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, Laurent Pasquier, Elisabeth Flori, Marie Gonzales, Claire Bénéteau, Odile Boute, Tania Attié-Bitach, Joelle Roume, Louise Goujon, Linda Akloul, Erwan Watrin, Valérie Dupé, Sylvie Odent, Marie de Tayrac, Véronique David
2018 · doi:10.1101/320127
preprint OA: closed CC-BY-NC-ND-4.0
📄 Open PDF View at publisher
⚙ AI-generated summary by claude@2026-07, 2026-07-15 ⓘ

This study analyzed exome data from holoprosencephaly patients, identifying novel genes and revealing oligogenic inheritance patterns resulting from variants in SHH-related genes.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

Abstract

Purpose Holoprosencephaly (HPE) is a pathology of forebrain development characterized by high phenotypic and locus heterogeneity. Seventeen genes are known so far in HPE but the understanding of its genetic architecture remains to be refined. Here, we investigated the oligogenic nature of HPE resulting from accumulation of variants in different relevant genes. Methods Exome data from 29 patients diagnosed with HPE and 51 relatives from 26 unrelated families were analyzed. Standard variant classification approach 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. Results We identified 232 rare deleterious variants in HPE patients representing 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 novel HPE genes including recurrently mutated genes ( FAT1, NDST1, COL2A1 and SCUBE2 ) and genes implicated in cilia function. Conclusions This study reports novel HPE-relevant genes and reveals the existence of oligogenic cases resulting from several mutations in SHH-related genes. It also underlines that integrating clinical phenotyping in genetic studies will improve the identification of causal variants in rare disorders.

My notes (saved in your browser only)

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. The paper's references may be in our DB but unresolved to ``paper_id`` (resolution happens at ingest when the cited DOI matches a row we already have). Run the cross-source citation reconcile pass to retry.

References (37)

Source provenance

crossref
last seen: 2026-05-25T01:00:12.078711+00:00
europepmc
last seen: 2026-05-19T01:45:01.086888+00:00
unpaywall
last seen: 2026-05-21T05:10:58.409756+00:00
License: CC-BY-NC-ND-4.0