A putative causal variant in SLC38A8 segregating with foveal hypoplasia in an autosomal recessive family with primary exotropia

Abstract

Purpose : To identify putative causal variants for foveal hypoplasia (FH), low vision (LV), nystagmus and exotropia (XT) in two siblings, fifth and seventh of a cohort of seven siblings with deceased parents.

Methods : This large two-generation informative family (Figure 1), with presumptive autosomal recessive (AR) inheritance pattern was recruited from the ophthalmic outpatients department (OPD) of Lady Hardinge Medical College, New Delhi. Whole exome sequencing (WES) was performed on four out of seven siblings [two affected and two unaffected] using Agilent V5 + UTR on an Illumina platform and the data analysed.

Results : WES based variant analysis demonstrated a homozygous stop gain mutation, (c.264 C>G: pY88*, exon 2, MAF SAS = 0.00006) in SLC38A8 (16q23.3) segregating with the phenotype of sub-normal best-corrected visual acuity (BCVA) with FH and nystagmus. The unaffected siblings were heterozygous for the mutation (Figure 2). While normal as far as BCVA and absence of nystagmus was concerned, one unaffected sibling (No. 15) had FH on optical coherence tomography [OCT] though to a lesser extent than the affected siblings.

Conclusions : Mutations in SLC38A8 have been previously reported in the European Caucasian and south Asian populations to be causal for the FH, optic-nerve-decussation defects and anterior segment dysgenesis (FHONDA) syndrome, with functional validation in medaka fish (Oryzias latipes) model. This mutation in SLC38A8 was novel for the phenotype of FH, nystagmus and subnormal BCVA, found in the study family. This novel index mutation was however not obtained in extended family members who demonstrated XT but did not demonstrate the phenotype of FH, nystagmus and LV.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Figure 1: Pedigree chart of the study family demonstrating two sisters (No. 14 and 16) with the phenotype of FH, nystagmus, exotropia and LV. No other family member in the index or the extended family demonstrated this phenotype. While the maternal cousin (No 19) of the proband (arrow, No 14) demonstrated XT, he did not demonstrate FH, LV and nystagmus.

 

Figure 2: Electropherogram of the proband and her sister (T2-1/2] demonstrates the homozygous stop variant. Phenotypically unaffected siblings (T2-4/5) were heterozygous for the mutation while members from the extended family who did not demonstrate the phenotype of FH, nystagmus and LV, did not show the mutation (T2-3/6).