Characterization of Ocular Developmental Disorders in the Israeli Population: Genotype-Phenotype Correlations and...

Microphthalmia, anophthalmia and ocular coloboma (MAC) are rare developmental eye disorders. Although over 100 causative genes have been identified, the molecular spectrum and genotype-phenotype correlations remain incompletely understood, particularly in genetically diverse populations. We set out to molecularly characterize MAC in the Israeli population. Forty-seven MAC-affected individuals from 43 unrelated families were enrolled. DNA of all probands was subjected to whole exome sequencing. The most common phenotype was microphthalmia (64% of patients). Definite or possible molecular diagnoses were achieved in 13/43 probands (30%) and involved 10 different genes (MFRP, SMO, GJA8, SOX2, RARB, TSPAN12, SHH, PTPN11, BEST1, and TP63). An in vitro splicing assay was used to explore the pathogenicity of a variant in the SMO gene. Following stringent filtering of exome data, 226 rare possibly pathogenic variants were identified in 218 genes not previously associated with MAC. The rate of molecular diagnosis achieved in this Israeli MAC cohort is similar to the reported range in other studies. The results further demonstrate the genetic heterogeneity of MAC, while supporting the involvement of complex inheritance and/or environmental factors in many of the cases. Further studies are required to reveal these underlying etiological factors, and to support the novel genotype-phenotype associations suggested here.