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Research Reports

Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

Jacque L. DuncanDepartment of Ophthalmology, University of California, San Francisco, CA, USA,

Pooja BiswasShiley Eye Center, University of California, San Diego, La Jolla, CA, USA,

Igor KozakShiley Eye Center, University of California, San Diego, La Jolla, CA, USA,

Mili NavaniShiley Eye Center, University of California, San Diego, La Jolla, CA, USA,

Reema SyedDepartment of Ophthalmology, University of California, San Francisco, CA, USA,

Shiri SoudryDepartment of Ophthalmology, University of California, San Francisco, CA, USA,

Moreno MenghiniDepartment of Ophthalmology, University of California, San Francisco, CA, USA,

Rafael C. CarusoNational Eye Institute, NIH, Bethesda, MD, USA, ;Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA,

Brett G. JeffreyNational Eye Institute, NIH, Bethesda, MD, USA,

John R. HeckenlivelyDepartment of Ophthalmology, University of Michigan, Ann Arbor, MI, USA,

G. Bhanuprakash ReddyNational Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India,

Pauline LeeShiley Eye Center, University of California, San Diego, La Jolla, CA, USA, ;Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA, and

Austin RoordaSchool of Optometry and Vision Science Graduate Group, University of California, Berkeley, CA, USA

Radha AyyagariShiley Eye Center, University of California, San Diego, La Jolla, CA, USA, Correspondence[email protected]

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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.

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Acknowledgments

Dr. Ayyagari, the principal investigator and corresponding author, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of interest

Austin Roorda holds patents on AOSLO technology (US Patents #7,118,216 and 6,890,076) and he is a consultant on AOSLO technology to Canon, Inc. There are no other conflicts of interest to report.

Funding

This work was supported by RO1EYO21237 (RA), NIH-P30EY22589 (Department of Ophthalmology, UCSD), NIH-NEI EY002162 (JD), Foundation Fighting Blindness (RA, JD), Research to Prevent Blindness (RA, JD), That Man May See, Inc. (JD), The Bernard A. Newcomb Macular Degeneration Research Fund (JD), Hope for Vision (JD), The Scripps Research Institute (grants DK53505-12 and U54 RR025204 to PL), and The Beutler Foundation (PL).

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Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

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Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration

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