Complex Microphthalmia due to a Homozygous Novel Variant in SIX Homeobox 6 Gene

Microphthalmia is an ocular anomaly with wide genetic heterogeneity. Many monogenic causes have been identified recently by next-generation sequencing. Here, we describe the genotype and phenotype of two siblings with complex microphthalmia. The siblings had bilateral cataracts, and a persistent hyperplastic primary vitreous was additionally noted in the younger sibling. Exome sequencing performed in the elder sibling detected a novel missense variant (c.549C>G [p.Asp183Glu]) in SIX homeobox 6 (SIX6) gene in homozygous state. On targeted Sanger sequencing, this variant was also present in homozygous state in the similarly affected younger sibling. In silico structural modeling showed that the c.549C>G variant which lies in the homeobox domain might alter the SIX6 protein structure. Both the affected siblings also had dental anomalies. This feature has not been reported in the three published reports describing biallelic SIX6-related ocular phenotype. SIX6 disease-causing variants are a very rare cause of microphthalmia/anophthalmia.