Phenotypic variability of SLC7A14 mutations in patients with inherited retinal dystrophy

Inherited retinal dystrophy (IRD) is a group of retinal disorders that are both clinically and genetically diverse, typically with loss of photoreceptor function. Herein, we aimed to identify the underlying genetic defect in IRD patients with mutations in the SLC7A14 gene.

A targeted exome capture panel was applied for mutational screening of SLC7A14. Targeted exome sequencing (TES) was performed on 200 non-syndromic and unrelated autosomal recessive or sporadic IRD families. Candidate variants were validated by direct sequencing and further examined using bioinformatics analyses for determination of their potential effect.

We identified compound heterozygous missense mutations (c.988G>A, p.G330R; c.1970G>A, p.R657Q) in an autosomal recessive retinitis pigmentosa (RP) case and a homozygous mutation (c.988G>A, p.G330R) in a simplex case with Leber congenital amaurosis (LCA) in the SLC7A14 gene. Both G330R and R657Q were deleterious based on in silico predictive tools. Our proposed topological model of the SLC7A14 polypeptide suggested that both G330R and R657Q affected evolutionarily highly conserved amino acid residues in SLC7A14 that occurred in transmembrane helixes. Structural modeling revealed a broken arginine and aspartic acid connection between residues 657 and 406.

We applied TES to the molecular diagnosis of patients with IRD and for the first time identified SLC7A14 mutations in two unrelated families with RP and LCA separately. Our findings uniquely add the knowledge of the phenotypic variability of SLC7A14 mutations.