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Evaluation of somatic and/or germline mosaicism in congenital malformation of the eye

European Journal of Human Genetics volume 31, pages 526–530 (2023)Cite this article

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A Correction to this article was published on 02 December 2022

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Abstract

Microphthalmia, Anophthalmia and Coloboma (MAC) form a spectrum of congenital eye malformations responsible for severe visual impairment. Despite the exploration of hundreds of genes by High-Throughput Sequencing (HTS), most of the patients remain without genetic diagnosis. One explanation could be the not yet demonstrated involvement of somatic mosaicism (undetected by conventional analysis pipelines) in those patients. Furthermore, the proportion of parental germline mosaicism in presumed de novo variations is still unknown in ocular malformations. Thus, using dedicated bioinformatics pipeline designed to detect mosaic variants, we reanalysed the sequencing data obtained from a 119 ocular development genes panel performed on blood samples of 78 probands with sporadic MAC without genetic diagnosis. Using the same HTS strategy, we sequenced 80 asymptomatic parents of 41 probands carrying a disease-causing variant in an ocular development gene considered de novo after Sanger sequencing of both parents. Reanalysis of the previously sequencing data did not find any mosaic variant in probands without genetic diagnosis. However, HTS of parents revealed undetected SOX2 and PAX6 mosaic variants in two parents. Finally, this work, performed on two large cohorts of patients with MAC spectrum, provides for the first time an overview of the interest of looking for mosaicism in ocular development disorders. Somatic mosaicism does not appear to be frequent in MAC spectrum and might explain only few diagnoses. Thus, other approaches such as whole genome sequencing should be considered in those patients. Parental mosaicism is however not that rare (around 5%) and challenging for genetic counselling.

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Fig. 1: Pedigrees and molecular results of the three families with suspected or confirmed parental mosaicism.

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files. Newly described variants have been added to ClinVar database (SCV002583597 - SCV002583623).

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Acknowledgements

We appreciated the generous support received from patients and their families and are grateful for the contributions of physicians who evaluated or followed up patients with ocular malformation.

Funding

Patients were recruited through the Rare Diseases Cohorts (RaDiCo) programme which is funded by the French National Research Agency under the specific programme “Investments for the Future”, Cohort grant agreement ANR-10-COHO-0003.

Author information

Authors and Affiliations

  1. Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, Toulouse, France

    Bertrand Chesneau, Véronique Ivashchenko, Christophe Habib, Véronique Gaston, Patrick Calvas, Nicolas Chassaing & Julie Plaisancié

  2. Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU de Toulouse, Toulouse, France

    Bertrand Chesneau, Patrick Calvas, Nicolas Chassaing & Julie Plaisancié

  3. Département d’anatomopathologie, IUCT Oncopole, Toulouse, France

    Fréderic Escudié

  4. Service de Génétique Médicale, CHU de Rennes, Rennes, France

    Godelieve Morel

  5. Service de Génétique Médicale, Hôpital Robert Debré, APHP, Paris, France

    Yline Capri

  6. Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France

    Catherine Vincent-Delorme

  7. INSERM U1214, ToNIC, Université Toulouse III, Toulouse, France

    Julie Plaisancié

Authors
  1. Bertrand Chesneau
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  2. Véronique Ivashchenko
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  3. Christophe Habib
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  4. Véronique Gaston
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  6. Godelieve Morel
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  7. Yline Capri
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  8. Catherine Vincent-Delorme
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  9. Patrick Calvas
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  10. Nicolas Chassaing
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  11. Julie Plaisancié
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Contributions

All authors have actively participated in data collection or interpretation and have revised and approved the manuscript. BC and JP designed experiments and write the first version of manuscript. GM, YC, CVD, PC collected data from patients. VG performed sequencing. VI, CH, and FE performed bioinformatic analysis. BC, NC, and JP performed analysis and interpretation.

Corresponding author

Correspondence to Julie Plaisancié.

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Competing interests

The authors declare no competing interests.

Ethics approval

Patients gave informed consent to genetic analyses and research. This study is a retrospective study based on the exploitation of usual care data. A submission at an ethic committee is not required according to the French ethic and regulatory law (public health code).

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The original online version of this article was revised: All authors’ surnames and given names had been swapped.

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Chesneau, B., Ivashchenko, V., Habib, C. et al. Evaluation of somatic and/or germline mosaicism in congenital malformation of the eye. Eur J Hum Genet 31, 526–530 (2023). https://doi.org/10.1038/s41431-022-01234-3

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  • DOI: https://doi.org/10.1038/s41431-022-01234-3

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