Abstract
Oculo-auriculo-vertebral spectrum (OAVS) is characterized by abnormal development of the 1st and 2nd branchial arches. Despite arguments against a monogenic condition, a few genes have been involved in a minority of cases. We now report heterozygous, presumably loss-of function variants in the CHAF1A gene in 8 individuals, including 3 members of the same family. Four cases fulfill stringent diagnostic criteria for OAVS, including asymmetric ear dysplasia, preauricular tags, mandibular asymmetry +/− vertebral malformations. Two patients also presented with kidney malformations. CHAF1A encodes a subunit of CAF-1 (chromatin assembly factor-1), a heterotrimeric protein complex responsible for the deposition of newly synthesized histones H3-H4 onto the newly synthetized DNA strand during replication. The identification of loss-of-unction variants in CHAF1A is consistent with the hypothesis of early developmental genes dysregulation driving OAVS and other associations recently lumped under the acronym Recurrent Constellations of Embryonic Malformations (RCEM).
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Data availability
The variants have been submitted to ClinVar, accession number SCV005061834 to 1839. Other data generated or analyzed during this study are included in the published article. Details are available from the corresponding author upon reasonable request.
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Acknowledgements
We sincerely thank the families for their participation. This research benefited access to the data generated by the “Plan France Médecine Génomique”, the DECIPHER community and the DDD project in the UK funded through partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute.
Funding
This work was supported by the Philanthropy Department of the Mutuelles AXA through the Imagine-Head and Heart Chair.
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VP, JDE, NMG, ALA, BC, IMML, EARN, RS, PJ, TD, HZE, AS, SH, AP, PB, JA conducted molecular and clinical evaluation of the patients. FO revised the manuscript according to CAF-1 function. VP set up the study and collected the data. JA and VP wrote the manuscript that was reviewed and edited by all authors.
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There is no competing interest. HZE is an employee of GeneDx, LLC, USA.
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These studies have been approved by institutional committees in each country when performed on a research basis. Ethical approvement was not required for case reports based on analysis performed in diagnostic conditions. Consent for publication of photos was obtained.
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Pingault, V., Neiva-Vaz, C., de Oliveira, J. et al. Chromatin assembly factor subunit CHAF1A as a monogenic cause for oculo-auriculo-vertebral spectrum. Eur J Hum Genet 33, 131–136 (2025). https://doi.org/10.1038/s41431-024-01698-5
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DOI: https://doi.org/10.1038/s41431-024-01698-5
