SLC38A8 mutation spectrum in foveal hypoplasia

AbstractPurposeSignificant phenotypic overlap exists between ocular albinism and SLC38A8 related foveal hypoplasia (FH) which hinders differential diagnosis. To facilitate molecular testing, we catalogued the spectrum of known pathogenic variants in SLC38A8 responsible for FH.MethodsThe UK 100 000 genomes (100KG) datasets were analysed to detect pathogenic SLC38A8 variants compatible with recessive inheritance in cases with phenotypes reminiscent of FH. Published literature was accessed to capture deleterious variants reported in FH affected families. Additional variants identified locally were incorporated for bioinformatic analysis. Variant interpretation included in‐silico pathogenicity assessment, population data and protein modelling.ResultsIn total, 41 pathogenic variants in SLC38A8 have been identified in 51 FH families; 17 missense, 4 splice site, 2 in‐frame deletions, 6 frameshift, 6 nonsense, 4 large deletions, a multiple exon inversion and a whole gene deletion. Nonsense variants are evenly distributed throughout the gene and protein, while missense variants are more likely to reside in transmembrane domains. 38 SLC38A8 variants were reported in the literature and we have identified 3 novel and 2 known variants in 4 families derived from the 100KG datasets and our local cohort. In one patient, a novel g.84049578_84060679inv (GRCh37) was detected in a homozygous state. Another harboured novel variant c.922_923insTG, p.(Thr308Metfs*14) and c.922A>G, p.(Thr308Ala). Other homozygous variants include c.848A>C, p.(Asp283Ala) and novel variant c.77C>T, p.(Ser26leu). Protein modelling of SLC38A8 predicted a destabilising effect by both p.(Ser26leu) and p.(Thr308Ala). Haplotype analysis of Pakistani, Bangladeshi and Indian patients harbouring c.264C>G, p.(Tyr88*) suggest a South Asian founder effect.ConclusionsWe reviewed and extended the spectrum of SLC38A8 variants causative for FH. The presence of multiple nonsense variants and in‐silico modelling of missense variants suggests a complete loss of function as the likely disease mechanism.