Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

Abstract

Background Characterization of retinal degeneration (RD) using high-resolution retinal imaging and exome sequencing may identify phenotypic features that correspond with specific genetic defects. Materials and Methods Six members from a non-consanguineous Indian family (three affected siblings, their asymptomatic parents and an asymptomatic child) were characterized clinically, using visual acuity, perimetry, full-field electroretinography (ERG), optical coherence tomography and cone structure as outcome measures. Cone photoreceptors were imaged in the proband using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V3.0 probes and sequenced using lllumina HiSeq. Reads were mapped to reference hg19. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. Results Analysis of exome variants using exomeSuite identified five homozygous variants in four genes known to be associated with RD. Further analysis revealed a homozygous nonsense mutation, c.1105 C>T, p.Arg335Ter, in the FAM161A gene segregating with RD. Three additional variants were found to occur at high frequency. Affected members showed a range of disease severity beginning at different ages, but all developed severe visual field and outer retinal loss. Conclusions Exome analysis revealed a nonsense homozygous mutation in FAM161A segregating with RD with severe vision loss and a range of disease onset and progression. Loss of outer retinal structures demonstrated with high-resolution retinal imaging suggests FAM161A is important for normal photoreceptor structure and survival. Exome sequencing may identify causative genetic variants in autosomal recessive RD families when other genetic test strategies fail to identify a mutation.

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses

“…In one family, three members screened for mutations in this gene were observed to carry a homozygous nonsense mutation p.Arg335X. Genetic testing for these patients was ordered based on research findings (Duncan et al, 2016) (Table 2). …”

Diverse clinical phenotypes associated with a nonsense mutation in FAM161A

“…Our results are not dissimilar to findings from previous studies in North American and German populations in which FAM161A mutations accounted for~1% of recessive RP cases. 4,10 Notably, a higher disease frequency has been described in the Israeli and Palestinian populations. 3 In our study, three unrelated families harbouring the same FAM161A nonsense mutation (c.1309A4T, p. Arg437*) in the homozygous state were identified.…”

Repeatability of Cone Spacing Measures in Eyes With Inherited Retinal Degenerations

“…Genetic testing for mutations associated with Ashkenazi heritage for patient 40030 was performed through the Carver Nonprofit Genetic Testing Laboratory (Iowa City, IA, USA); no disease-causing mutations were identified in the DHDDS, LCA5, MAK, PCDH15, or CLRN1 genes. Genetic testing was performed through a research protocol (Radha Ayyagari, PhD, Project #081869, University of California San Diego, San Diego, CA, USA) using whole-exome sequencing 36,37 in families with autosomal recessive RP from a consanguineous pedigree (patient 40032). Mutation analysis of the CLRN1 gene in 30007 was carried out by sequencing the coding region.…”