Abstract
Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.
Highlights
Phenotypical characteristics of foveal hypoplasia (FH) and abnormalities of optic nerve decussation have previously been described in association with albinism and albinism syndromes due to disruption of the melanin biosynthesis pathway [1]
We identified a total of 17 SLC38A8 mutations in 11 affected subjects from nine families (Table 1)
We describe the detailed genetic and phenotypical characteristics in patients with SLC38A8 mutations
Summary
Phenotypical characteristics of foveal hypoplasia (FH) and abnormalities of optic nerve decussation have previously been described in association with albinism and albinism syndromes due to disruption of the melanin biosynthesis pathway [1]. Al-Araimi et al described a new recessively inherited disorder called FH, optic nerve decussation defects and anterior segment dysgenesis (FHONDA), which had significant overlap of phenotypical characteristics with albinism. Poulter et al identified that mutations of SLC38A8, a putative glutamine transporter gene found on chromosomes 16q23.3–24.1, were causative of FHONDA [3] This is thought to be part of a melanin-independent pathway affecting foveal development. Two patients with FHONDA were reported to have iris transillumination defects (TID) Both with compound heterozygous mutation of SLC38A8; with an amino acid substitution at Thr308 [6]. The detailed phenotypical characteristics including nystagmus features and degree of arrested retinal development in SLC38A8 mutations have not been systematically analyzed in relation to genotypes
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