Chromatin assembly factor subunit CHAF1A as a monogenic cause for oculo-auriculo-vertebral spectrum

Véronique Pingault; Cécilia Neiva-Vaz; Judite de Oliveira; Núria Martínez-Gil; Amaia Lasa-Aranzasti; Berta Campos; Inge M M Lakeman; Esther A R Nibbeling; Radka Stoeva; Parul Jayakar; Tabib Dabir; Houda Zghal Elloumi; Alanna Strong; Sylvain Hanein; Arnaud Picard; Francoise Ochsenbein; Pierre Blanc; Jeanne Amiel

doi:10.1038/s41431-024-01698-5

Chromatin assembly factor subunit CHAF1A as a monogenic cause for oculo-auriculo-vertebral spectrum

Eur J Hum Genet. 2024 Sep 27. doi: 10.1038/s41431-024-01698-5. Online ahead of print.

Authors

Véronique Pingault^{1

2

3}, Cécilia Neiva-Vaz⁴, Judite de Oliveira⁵, Núria Martínez-Gil^{6

7}, Amaia Lasa-Aranzasti^{6

7}, Berta Campos^{6

7}, Inge M M Lakeman⁸, Esther A R Nibbeling⁸, Radka Stoeva⁹, Parul Jayakar¹⁰, Tabib Dabir¹¹, Houda Zghal Elloumi¹², Alanna Strong^{13

14}, Sylvain Hanein¹⁵, Arnaud Picard⁴, Francoise Ochsenbein¹⁶, Pierre Blanc¹⁷, Jeanne Amiel^{18

5}

Affiliations

¹ Laboratoire « Embryologie et Génétique des Malformations », Institut Imagine, INSERM UMR1163, Université Paris Cité, Paris, France. veronique.pingault@inserm.fr.
² Service de Médecine Génomique des maladies rares, AP-HP.Centre, Hôpital Necker-Enfants Malades, F-75015, Paris, France. veronique.pingault@inserm.fr.
³ Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France. veronique.pingault@inserm.fr.
⁴ Chirurgie Maxillofaciale, Hôpital Necker-Enfants Malades, AP-HP Centre, Paris, France.
⁵ Service de Médecine Génomique des maladies rares, AP-HP.Centre, Hôpital Necker-Enfants Malades, F-75015, Paris, France.
⁶ Department of Clinical and Molecular Genetics, Vall d'Hebron University Hospital, Barcelona, Spain.
⁷ Medical Genetics Group, Vall d'Hebron Research Institute, Barcelona, Spain.
⁸ Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Department of Medical Genetics, Le Mans Hospital, Le Mans, France.
¹⁰ Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA.
¹¹ Medical Genetics Dept, Belfast City Hospital, Belfast, BT9 7AB, UK.
¹² GeneDx, Gaithersburg, MD, USA.
¹³ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁴ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Bioinformatic Platform, Institute of Genetic Diseases, INSERM UMR1163, Institut Imagine, Université Paris-Cité and Structure Fédérative de Recherche Necker, 75015, Paris, France.
¹⁶ Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Institute Joliot, Gif-sur-Yvette, France.
¹⁷ Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.
¹⁸ Laboratoire « Embryologie et Génétique des Malformations », Institut Imagine, INSERM UMR1163, Université Paris Cité, Paris, France.

PMID: 39333427
DOI: 10.1038/s41431-024-01698-5

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).