Abstract
Syndromes associating both eyeball and periocular developmental anomalies, combining iris chorioretinal (ocular) coloboma and ptosis, are described in very rare clinical entities such as Baraitser-Winter cerebrofrontofacial syndrome (BWCFF). We report on six individuals from 3 unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features suggesting BWCFF. However, no neurodevelopmental disorders (NDD) as usually observed in this syndrome were detected. Exome sequencing (ES) or genome sequencing (GS) was performed and allowed the identification of 3 novel heterozygous variants in the MYH10 gene, encoding the non-muscle myosin heavy chain II B. These 3 likely causative variants occur in the MYH10 tail domain required for myosin filament assembly. The MYH10 protein is mislocalized leading to abnormal actin networks in the patients’ fibroblasts compared to controls. MYH10 dysfunction leads to delayed development of the eye, as well as a muscular phenotype in the zebrafish model. Heterozygous variants in MYH10 have been recently reported to be associated with an autosomal dominant NDD with other congenital anomalies, but no patients were reported with the association of ocular coloboma and ptosis as main features. Herein, we report other MYH10 variants which cause mainly an ophthalmic phenotype without NDD expanding the phenotype associated with MYH10 and representing a differential diagnosis with BWCFF. The reason for the genotype-phenotype variability with either prominent NDD or prominent ocular features will require further investigations.
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Data availability
Data generated or analysed during this study are included in the published article and the corresponding supplemental data. The raw sequencing data generated in the course of this study are not publicly available due to the protocol and the corresponding consent used that did not include such information. The variants identified have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) using the following accessions numbers SCV000898494, SCV000898495, SCV005043360 and SCV005043361.
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Acknowledgements
We wish to warmly thank the families for their participation. We would like to thank Alain Verloes (Hôpital Robert-Debré, Paris, France), Nicola Ragge (Oxford Brookes University, Oxford, UK) and Patrick Calvas (CHU Toulouse, France) as well as the ERN-Eye network for attempting to identify patients with the same phenotype. The authors would like to thank the BiGEst-ICube Platform for assistance. This research formed part of a doctoral dissertation by Ariane Kröll-Hermi, entitled “Identification and Validation of novel genes implicated in Neurosensory and Neurological Diseases” [44, 45].
Funding
We would like to thank Jean-Louis Mandel, the financial support of the Centre Régional de Génétique Médicale de Strasbourg and the Caisse d’Assurance Retraite et de la Santé au Travail Alsace-Moselle. AK-H was supported by a doctoral fellowship from the Initiatives d’Excellence (IdEx) through the University of Strasbourg and by the Franco-German University (UFA/DFH). SB and SF were supported by INSERM and grants from the Initiatives d’Excellence (IdEx, Université de Strasbourg) and the AFM-Téléthon. Sequencing was performed by the GenomEast platform, a member of the “France Génomique” consortium (ANR-10-INBS-0009).
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HD and SF provided direction for the project, conceived and designed the experiments; BR performed cloning and mutagenesis experiments; SB, CS, CD, SS, SaS, and CJ performed cell biology experiments and data analyses; SS, ES, XZ, AK, ER, and HD, gathered data from patients and performed clinical investigations; AK-H, CE, OK, and US designed and performed the zebrafish experiments and data analyses; VG, J-BL, and JM gathered sequencing data and performed analyses for families 1 and 3; AB-A and EZ. analysed the genetic data for Family 2; HD, SF, SS, and SB analysed the data and wrote the paper. All authors critically revised the manuscript.
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This research followed the tenets of the Declaration of Helsinki. Approval was obtained from the institutional review boards “Comité de Protection des Personnes” (EST IV, N◦DC-20142222), Northern Ostrobothnia Hospital District, Oulu, Finland (EETTMK: 45/2015, amendment 2020), and Strasbourg University Hospital ethics committee as part of the ultra-rare disease cohort. Informed consent was obtained before study inclusion. Written informed consent for publication of images was also obtained.
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Scheidecker, S., Bär, S., Kröll-Hermi, A. et al. Novel MYH10 heterozygous variants associated to a syndrome combining mainly ptosis and ocular coloboma expand the MYH10 related phenotypes. Eur J Hum Genet 33, 1432–1441 (2025). https://doi.org/10.1038/s41431-025-01803-2
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DOI: https://doi.org/10.1038/s41431-025-01803-2
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