SLC38A8 – Foveal Hypoplasia–Optic Nerve Decussation Defect–Anterior Segment Dysgenesis Syndrome

SLC38A8 encodes a neuronal sodium-coupled neutral amino acid transporter (SNAT8) whose biallelic pathogenic variants cause an autosomal recessive pan-ocular syndrome characterized by foveal hypoplasia, nystagmus, optic nerve decussation defects and anterior segment dysgenesis (PMID:33498813). Often misdiagnosed as ocular albinism, molecular confirmation of SLC38A8-related FHONDA syndrome (MONDO:0012216) is critical for accurate prognosis and genetic counselling.

Genetic studies identified nine patients from seven unrelated families with molecularly confirmed biallelic SLC38A8 variants via whole-genome sequencing or targeted panels; an additional 30 families have been reported worldwide (PMID:33498813). All pedigrees exhibit autosomal recessive inheritance with segregation of loss-of-function (LoF) and missense variants in affected individuals.

The variant spectrum now comprises 60 pathogenic alleles: 30 missense, 15 LoF (nonsense and splice-site), and 15 other types, predominantly clustering in transmembrane domains. Notable variants include c.848A>C (p.Asp283Ala) and c.632+1G>A, reinforcing the pathogenic role of both missense and canonical splice-site disruptions (PMID:33498813; PMID:38515398).

Functional assays in heterologous systems demonstrate that wild-type SNAT8 mediates Na+-dependent transport of L-glutamine, L-alanine, L-arginine and L-histidine, whereas pathogenic variants abrogate transport activity (PMID:25451601). Computational structural modeling of p.Asp283Ala and other missense mutations predicts destabilization of the channel pore and altered electrostatic potential (PMID:28546991).

Clinical imaging with OCT and OCT-angiography reveals arrested retinal development with absence of the foveal pit and loss of cone specialization, correlating with reduced visual acuity and infantile nystagmus (PMID:32744312). CRISPR/Cas9-engineered Slc38a8 mouse models recapitulate the human FHONDA phenotype—normal pigmentation, optic nerve misrouting, reduced electroretinogram responses and decreased visual acuity—confirming a loss-of-function mechanism (PMID:37862028).

No conflicting evidence has been reported. The combined genetic and functional data fulfill a strong ClinGen gene–disease association, supporting clinical diagnostic testing and future gene-based therapeutic strategies.

Key Take-home: SLC38A8 genetic testing should be integrated into the workup of unexplained foveal hypoplasia and nystagmus to enable accurate diagnosis, prognosis and family planning.

References

• International journal of molecular sciences • 2021 • Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia. PMID:33498813
• Journal of molecular biology • 2015 • Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS. PMID:25451601
• Molecular genetics & genomic medicine • 2017 • Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia. PMID:28546991
• Human molecular genetics • 2020 • SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization. PMID:32744312
• Investigative ophthalmology & visual science • 2023 • A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects. PMID:37862028
• European journal of ophthalmology • 2024 • Novel pathogenic variants of SLC38A8 gene and literature review. PMID:38515398

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