Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia

Abstract

Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies.

Infantile nystagmus without overt eye abnormality: Early features and neuro‐ophthalmological diagnosis

“…FRMD7, GPR143, and SLC38A8 are the genes most frequently reported in literature. [28][29][30] With regard to the role of VEPs abnormalities, they were seen in some of our patients with optic nerve or brain disorders affecting the visual pathways and consisted of delayed latency and/or reduced amplitude. Considering that VEPs represent the visual cortex activation after a visual stimulus, but they do not localize the pathological site, the diagnosis of optic nerve hypoplasia was supported by a combination of VEPs and MRI focused on the optic nerves.…”

“…In recent years, new knowledge about OCT technology 27 combined with next‐generation sequencing whole exome analysis made it possible to understand that some children previously diagnosed with IIN may be affected by genetic retinal disorders. FRMD7 , GPR143 , and SLC38A8 are the genes most frequently reported in literature 28–30 …”

Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma

“… 11 Genomic DNA was processed using Illumina TruSeq DNA PCR-Free Sample Preparation kits (Illumina) and sequenced using the Illumina HiSeq X Ten high-throughput sequencing platform, generating minimum coverage of 15X for >97% of the callable autosomal genome. 12 Readings were aligned to build GRCh37/GRCh38 of the human genome using an Isaac aligner (Illumina Inc). Single-nucleotide variants and indels were identified using Platypus software (V.0.8.1) and annotated using Cellbase ( https://github.com/opencb/cellbase ).…”

“…aCGH, which is able to detect pathogenic CNVs, was performed through GOSH, together with segregation of known familial variants as previously described. 12 …”

“…aCGH, which is able to detect pathogenic CNVs, was performed through GOSH, together with segregation of known familial variants as previously described. 12 Literature searches along with public databases HGMD (http://www.hgmd.cf.ac.uk), 13 Clinvar (https://www.ncbi.nlm. nih.gov/clinvar/) 14 and gnomAD 15 were examined for prior reports of variants found in this cohort.…”