Unveiling ocular developmental disorders through short-read whole-genome sequencing
Abstract
Congenital eye malformations represent a clinically and genetically heterogeneous group of disorders. Despite advances in genetic testing, fewer than half of affected patients receive a definitive molecular diagnosis. However, obtaining a molecular diagnosis is crucial for these patients and their families. Whole genome sequencing (WGS) is now standard practice in the genetic investigation of patients, but its contribution has not been extensively evaluated in patients with ocular malformations. In this work, we performed short-read WGS in a cohort of 100 families presenting with eye developmental disorders, including microphthalmia-anophthalmia spectrum (M/A), coloboma, anterior segment dysgenesis, congenital cataracts and/or foveal hypoplasia. Prior to WGS, 47 individuals had undergone targeted next-generation sequencing (NGS) of genes panels related to ocular development, 11 had chromosomal microarray analysis (CGH-array) and 20 had a combination of both. None had received a definitive genetic diagnosis. WGS identified a (likely) pathogenic variant in eighteen patients. In addition, candidate variants of uncertain significance were detected in nine patients. Notably, fourteen of these variants would have been missed by conventional genes panels or CGH-array, underscoring the broader diagnostic scope of WGS. Our findings demonstrate that short-read WGS significantly improves diagnostic yield in patients with congenital eye malformations, including those previously undiagnosed despite NGS panel testing. These results support the integration of WGS in the genetic evaluation of ocular developmental disorders.
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BibTeX
@article{chesneau2026unveiling,
title = {{Unveiling ocular developmental disorders through short-read whole-genome sequencing}},
author = {Bertrand Chesneau and Timotéo Cousteix and Abdelhakim Bouazzaoui and Hélène Dollfus and Marjolaine Willems and Audrey Putoux and Philippe Khau van Kien and Vincent Michaud and Aurore Garde and Isabelle Meunier and David Geneviève and Elise Brischoux-Boucher and Fanny Laffargue and Justine Wourms and Marine Lebrun and Valentin Ruault and Julie Plaisancié and Nicolas Chassaing},
journal = {European Journal of Human Genetics},
year = {2026},
month = jul,
doi = {10.1038/s41431-026-02160-4},
url = {https://hal.science/hal-05755803v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Unveiling ocular developmental disorders through short-read whole-genome sequencing
AU - Bertrand Chesneau
AU - Timotéo Cousteix
AU - Abdelhakim Bouazzaoui
AU - Hélène Dollfus
AU - Marjolaine Willems
AU - Audrey Putoux
AU - Philippe Khau van Kien
AU - Vincent Michaud
AU - Aurore Garde
AU - Isabelle Meunier
AU - David Geneviève
AU - Elise Brischoux-Boucher
AU - Fanny Laffargue
AU - Justine Wourms
AU - Marine Lebrun
AU - Valentin Ruault
AU - Julie Plaisancié
AU - Nicolas Chassaing
PY - 2026
DA - 2026/07/14
JO - European Journal of Human Genetics
DO - 10.1038/s41431-026-02160-4
UR - https://hal.science/hal-05755803v1
AB - Congenital eye malformations represent a clinically and genetically heterogeneous group of disorders. Despite advances in genetic testing, fewer than half of affected patients receive a definitive molecular diagnosis. However, obtaining a molecular diagnosis is crucial for these patients and their families. Whole genome sequencing (WGS) is now standard practice in the genetic investigation of patients, but its contribution has not been extensively evaluated in patients with ocular malformations. In this work, we performed short-read WGS in a cohort of 100 families presenting with eye developmental disorders, including microphthalmia-anophthalmia spectrum (M/A), coloboma, anterior segment dysgenesis, congenital cataracts and/or foveal hypoplasia. Prior to WGS, 47 individuals had undergone targeted next-generation sequencing (NGS) of genes panels related to ocular development, 11 had chromosomal microarray analysis (CGH-array) and 20 had a combination of both. None had received a definitive genetic diagnosis. WGS identified a (likely) pathogenic variant in eighteen patients. In addition, candidate variants of uncertain significance were detected in nine patients. Notably, fourteen of these variants would have been missed by conventional genes panels or CGH-array, underscoring the broader diagnostic scope of WGS. Our findings demonstrate that short-read WGS significantly improves diagnostic yield in patients with congenital eye malformations, including those previously undiagnosed despite NGS panel testing. These results support the integration of WGS in the genetic evaluation of ocular developmental disorders.
SN - 1018-4813
SN - 1476-5438
ER -