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Jacque Duncan, Pooja Biswas, Igor Kozak, Mili Navani, Rafael Caruso, John Heckenlively, Austin Roorda, Radha Ayyagari; Exome analysis identified novel mutations in the FAM161A gene in a family with recessive retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3347. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To describe the clinical phenotype and identify the molecular basis of disease in an Indian family with autosomal recessive retinal degeneration (RD).
Five family members were characterized with visual acuity, perimetry, fundus photos, full-field electroretinography (ERG), and optical coherence tomography. Cone photoreceptors surrounding the fovea were imaged in one affected member, the proband, using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V4.0 probes and sequenced on llumina HiSeq. Read mapping and variant calling were performed with published protocols. Exome variants were analyzed using exomeSuite. Confirmation of variants and segregation analysis were performed using dideoxy sequencing.
Exome analysis detected 30,606 single nucleotide variants (SNVs) and indels in the proband. Analysis of these variants using exomeSuite identified 5 candidate SNVs. Further analysis revealed a novel homozygous nonsense change, c.1105 C>T, p.Arg335Ter, and a rare homozygous probably damaging (PolyPhen score=0.999) change, c.1791 G>T, p.E597D (rs201052209) in the FAM161A gene segregating with RD. These sequence variants were not detected in 100 ethnicity matched controls. Similar to prior reports of RD associated with FAM161A mutations, affected family members were myopic with visual acuity ranging from light perception to 20/40, with progressive visual acuity and field loss beginning at different ages. All affected members showed severely reduced ERG responses and grayish spots extending from the arcades, while prominent bone spicule pigmentary changes were observed only in the proband. Residual cones with increased cone spacing were observed near the fovea despite severely reduced visual acuity in the proband.
Exome analysis revealed two homozygous probably damaging variants in the FAM161A gene segregating with progressive RD. While the novel nonsense mutation alone could be sufficient to cause RD, the effect of the second missense change is not known. The severe progressive vision loss with a range of symptom onset observed among 3 siblings perhaps is a consequence of genetic or environmental modifiers. High-resolution retinal imaging of the proband revealed sparse central cones, suggesting FAM161A is important for normal photoreceptor structure and survival.
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