Exploring the molecular basis of microphthalmia and anophthalmia: Insights from an Egyptian cohort

Abstract Purpose The aim of this study was to gain insight into the molecular spectrum of anophthalmia and microphthalmia (A/M) in the Egyptian population. Methods We studied a cohort of 34 patients from 31 unrelated families affected by the A/M spectrum. All patients underwent a thorough clinical examination, ophthalmological assessment, and genetic testing including conventional karyotyping and exome sequencing (ES). Results Chromosomal anomalies were identified in six patients. ES was performed on the remaining cases, revealing potentially causative variants in 13 families. The implicated genes were SOX2, OTX2, CHD7, HMX1, PRR12, ATOH7, ZBTB11, B3GALNT2, GCNT2, DPH1, GJA8, FRAS1 and UBE3B. Among the variants, six were classified as pathogenic, five as likely pathogenic, and two as variants of uncertain significance. Notably, a DPH1 pathogenic variant was identified in a patient with bilateral severe microphthalmia, representing a novel phenotype. Additionally, we report the fifth family diagnosed with oculo-auricular syndrome. Conclusions Our findings confirm that genetic factors are a predominant cause of both syndromic and non-syndromic A/M and underscore the value of ES in uncovering the molecular basis of this spectrum. By reporting novel variants and unusual phenotypes within our cohort, we contribute to expanding both the mutational landscape and the phenotypic spectrum of A/M associated syndromes.