OBJECTIVE: This study aimed to analyze the clinical and genetic characteristics of 6 Chinese patients with foveal hypoplasia (FH) caused by the variants of solute carrier family 38 member 8 (SLC38A8), and to describe the genotype and phenotype of SLC38A8 variants from previous literature.
METHODS: All subjects underwent comprehensive ophthalmic examinations. Optical coherence tomography (OCT) was performed to evaluate the structural grade of FH. Pathogenic variants of SLC38A8 gene were identified using panel-based next-generation sequencing and direct Sanger sequencing techniques. Further, all previously reported cases of SLC38A8 variants were re-analyzed together with the novel ones identified in this study.
RESULTS: Nystagmus and FH were present in 6 patients with variants of SLC38A8 gene, accompanied by a normal anterior segment. Grade 4 FH was identified in 4 patients. A total of 12 variants of SLC38A8 gene were identified, including 9 novel variants. Systematical analysis revealed that half of the variants (30/60) were missense, the majority of which (23/30) were distributed in the transmembrane (TM) domains. Grade 4 FH was detected in the majority of patients (66%, 23/35). There was no statistical difference in the clinical features between the subgroups of patients with 0, 1 and 2 missense variants.
CONCLUSIONS: Severe arrest of foveal development was identified in patients with variants of SLC38A8. This study provides a brief summary of the clinical and genetic characteristics of the pathogenic SLC38A8 variants, which is helpful in the differentiation diagnosis of FH.

UNASSIGNED: The aim of the study is to present a rare case of Foveal Hypoplasia, Optic Nerve Decussation defects, and Anterior segment dysgenesis (FHONDA) confirmed by genetic testing with two separate pathogenic mutations in the SLC38A8 gene.
UNASSIGNED: This was a case report.
UNASSIGNED: A 3-month-old female presented to a neuro-ophthalmology clinic with nystagmus. Her past medical and family history was unremarkable. Her examination demonstrated horizontal pendular nystagmus and small optic nerves with foveal hypoplasia bilaterally. Neuroimaging was unremarkable. She underwent an examination under anesthesia and electroretinogram (ERG). Her anterior segment examination was normal, and dilated fundus examination demonstrated foveal hypoplasia with diffuse pigment granularity. The ERG was normal. Genetic testing revealed two mutations in the SLC38A8 gene, p.Glu233Lys:c.697 G>A (pathogenic) and p.Asp283Ala:c.848A>C (likely pathogenic) with positive parental segregation analysis. Therefore, she was diagnosed with FHONDA.
UNASSIGNED: To our knowledge, this is the first report of a patient with FHONDA who is compound heterozygous for these two SLC38A8 mutations, which represents an expansion of the known mutational spectrum associated with this syndrome. Moreover, it may provide guidance into genetic counseling for patients and parents with these mutations.

To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH).
Multicenter, observational study.
A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384).
Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans.
Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA).
The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH.
We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

To characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene.
We performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation.
In the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting.
This report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.

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.

A recently described subtype of foveal hypoplasia with congenital nystagmus and optic-nerve-decussation defects was found to be associated with mutations in the SLC38A8 gene. The aim of this study is to advance the clinical and molecular knowledge of SLC38A8 gene mutations.
Five Israeli families with congenital foveal hypoplasia were studied, two of Karait Jewish origins and three of Indian Jewish origins. Subjects underwent a comprehensive ophthalmic examination including retinal photography and ocular coherence tomography. Molecular analysis including whole exome sequencing and screening of the SLC38A8 gene for specific disease-causing variants was performed.
Eight affected individuals were identified, all had congenital nystagmus and all but one had hypoplastic foveal pits. Anterior segment dysgenesis was observed in only one patient, one had evidence of developmental delay and another displayed early age-related macular degeneration (AMD). Molecular analysis revealed a recently described homozygous mutation, c.95T > G; p.Ile32Ser, in two families of Jewish Indian descent, and the same mutation in two families of Karaite Jewish descent. In a patient with only one pathogenic mutation (c.95T > G; p.Ile32Ser), a possible partial clinical expression of the disorder was seen. One patient of Jewish Indian descent was found to be compound heterozygous for c.95T > G; p.Ile32Ser and a novel mutation c.490_491delCT; p.L164Vfs*41.
In five unrelated families with congenital nystagmus and foveal hypoplasia, mutations in the SLC38A8 gene were identified. Possible partial expression in a heterozygous patient was observed and novel potential disease-related phenotypes were identified including early-onset AMD and developmental delay. A novel mutation was also identified and a similar mutation in both Indian and Karaite Jewish ethnicities could be suggestive for common ancestry.

BACKGROUND: Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium-coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT-angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations.
METHODS: Fundus autofluorescence, SD-OCT, and OCT-angiography were used to make the clinical diagnosis. Whole-exome sequencing led to the identification of a novel disease-causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function.
RESULTS: We identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT-angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore.
CONCLUSIONS: Our results demonstrate a novel use for OCT-angiography in confirming FH, and also uncover genotype-phenotype correlations of FH-linked SLC38A8 mutations.