MYH10 heterozygous variants cause a dominant phenotype associating coloboma and ptosis reminiscent of the Baraitser-Winter syndrome spectrum

Abstract

Purpose : Syndromes associating both eyeball and periocular developmental anomalies, mostly combining coloboma and ptosis, are described in rare clinical entities such as Noonan syndrome or Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome.

Methods : We reported on a first family with a mother and her 2 daughters presenting with autosomal dominant eye malformations, including coloboma, ptosis and craniofacial features suggesting a BWCFF syndrome without neurodevelopmental anomalies as usually observed in this syndrome. As no pathogenic variants in the known BWCFF genes, ACTB and ACTG1, could be detected, whole exome sequencing (WES) was performed and allowed the identification of a novel heterozygous missense variant in the MYH10 gene, encoding the non-muscle myosin heavy chain II B. Heterozygous variants in MYH10 have been reported in neurodevelopmental disorders and congenital anomalies, but no patients were described with a coloboma and ptosis as main features. Recently, 2 additional families were identified by WES and WGS presenting similar eye malformations associated to MYH10 heterozygous variants: a mother and her son carrying a MYH10 donor splice variant and a boy with a de novo MYH10 single amino acid deletion. Patient fibroblasts analyses and myh10 knockdown morpholino in zebrafish models were used to study the role of MYH10.

Results : The 3 pathogenic variants reported occur in the tail domain of MYH10 required for myosin filament assembly. The MYH10 protein level is decreased and MYH10 is mislocalized leading to abnormal actin networks in the patient cells. Reduced expression of myh10 in zebrafish results in eye anomalies and affects muscle development.

Conclusions : Here, we show that MYH10 allelic variability can lead not only to neurodevelopmental disorders, but also to a new ocular phenotype closely related to the BWCFF actinopathy spectrum, with the rarely reported association of eyeball developmental anomalies and congenital ptosis. MYH10 dysfunction leads to abnormal actin length and polymerization in vitro and delayed development of the eye and muscular phenotype in the zebrafish model. This report describing similar phenotypes due to variant in MYH10 and ACTB or ACTG1 genes should raise awareness of analyzing effectors of the actin-myosin network to detect additional patients and to expand the clinical and genetic spectrum related to BWCFF.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.