June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Whole genome sequencing revealed mutations in two independent genes as the underlying cause of retinal degeneration (RD) in an Ashkenazi Jewish Pedigree
Author Affiliations & Notes
  • Kevin Gustafson
    Ophthalmology, University of California, San Francisco, San Francisco, California, United States
  • Jacque L. Duncan
    Ophthalmology, University of California, San Francisco, San Francisco, California, United States
  • Pooja Biswas
    Shiley Eye Institute, University of California, San Diego, La Jolla, California, United States
  • Hiroko Matsui
    Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, United States
  • Angel Soto-Hermida
    Shiley Eye Institute, University of California, San Diego, La Jolla, California, United States
  • John Suk
    Shiley Eye Institute, University of California, San Diego, La Jolla, California, United States
  • Amalio Telenti
    Human Longevity, Inc., San Diego, California, United States
  • Kelly A Frazer
    Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, United States
    Department of Pediatrics, Rady Children’s Hospital, Division of Genome Information Sciences, San Diego, California, United States
  • Radha Ayyagari
    Shiley Eye Institute, University of California, San Diego, La Jolla, California, United States
  • Footnotes
    Commercial Relationships   Kevin Gustafson, None; Jacque Duncan, None; Pooja Biswas, None; Hiroko Matsui, None; Angel Soto-Hermida, None; John Suk, None; Amalio Telenti, Human Longevity, Inc. (E); Kelly Frazer, None; Radha Ayyagari, Spouse - Pfizer (E)
  • Footnotes
    Support  NIH grants EY13198, EY21237, EY002162 and P30EY022589; FDA grant R01-41001; Foundation Fighting Blindness; Research to Prevent Blindness; Claire Giannini Foundation; L.L. Hillblom Foundation; That Man May See, Inc.
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2759. doi:
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    • Get Citation

      Kevin Gustafson, Jacque L. Duncan, Pooja Biswas, Hiroko Matsui, Angel Soto-Hermida, John Suk, Amalio Telenti, Kelly A Frazer, Radha Ayyagari; Whole genome sequencing revealed mutations in two independent genes as the underlying cause of retinal degeneration (RD) in an Ashkenazi Jewish Pedigree. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2759.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To clinically characterize the phenotype and identify the underlying cause of RD in 2 affected siblings and an affected cousin in a non-consanguineous 4-generation pedigree.

Methods : Detailed ophthalmic evaluation was performed in 3 affected family members. Whole exomes of 3 affected and 2 unaffected family members were sequenced (WES) using Agilent probes and Illumina HISeq. Similarly, whole genomes of family members were sequenced (WGS) at 30X depth using Illumina HiSeq X10. Sequence reads were aligned using BWA-MEM and variant calling was performed using GATK. Copy number variations (CNVs) were called using Genome STRiP and SpeedSeq software. Variants were filtered to detect rare potentially deleterious variants segregating with disease. Segregation was tested by dideoxy sequencing.

Results : Two affected sisters presented with nyctalopia, epiretinal membrane, minimal retinal pigmentary change, midperipheral visual field loss and rod-greater-than-cone dysfunction beginning in the 3rd decade in the older sister and 5th decade in the younger sister; their cousin showed bilateral cystoid macular edema and reduced visual acuity at age 39, but later developed midperipheral scotomas and nyctalopia at age 56. WES did not identify potentially pathogenic variants shared by all 3 affected members. However, a previously reported mutation p. Arg 76* in KIZ was observed in the homozygous state in both affected sisters, but not in the cousin. WGS identified about 4 million variants in each individual, but filtering these did not find potentially disease causing variants shared by all 3 affected members. Further analysis revealed the presence of a 1.5 kb homozygous deletion encoding a region in a retina specific transcript of the C21orf2 in the affected cousin. The sisters with the KIZ mutation carried no copies of the C21orf2 mutation, and the cousin with the C21orf2 mutation carried no copies of the KIZ mutation.

Conclusions : This study revealed two independent homozygous mutations in KIZ and C21orf2 genes associated with autosomal recessive rod-cone dystrophy in a 4 generation pedigree. The results demonstrate the importance of comprehensive genetic analysis in all affected family members, given that more than one gene may be responsible for RD in the same family.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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