June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Identification of pathogenic mutations in patients with inherited retinal dystrophies using whole genome sequencing
Author Affiliations & Notes
  • Kari E Branham
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Pooja Biswas
    Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Luis Alexandre Rassi Gabriel
    Department of Ocular Genetics, Brazilian Center of Eye Surgery, Goiania, GO, Brazil
  • Angel Soto-Hermida
    Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Hiroko Matsui
    Institute for Genomic Medicine, University of California San Diego, San Diego, 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, San Diego, California, United States
    Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, California, United States
  • John R Heckenlively
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Paul A Sieving
    National Eye Institute, National Institutes of Helath, Bethesda, Maryland, United States
  • Radha Ayyagari
    Shiley Eye Institute, University of California San Diego, La Jolla, California, United States
  • Footnotes
    Commercial Relationships   Kari Branham, None; Pooja Biswas, None; Luis Alexandre Rassi Gabriel, None; Angel Soto-Hermida, None; Hiroko Matsui, None; Amalio Telenti, Human Longevity, Inc (E); Kelly Frazer, None; John Heckenlively, None; Paul Sieving, None; Radha Ayyagari, Spouse-Pfizer (E)
  • Footnotes
    Support  Foundation Fighting Blindness, Research to Prevent Blindness, P30EY022589, NIHEY13198, NIH-EY21237
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2754. doi:
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    • Get Citation

      Kari E Branham, Pooja Biswas, Luis Alexandre Rassi Gabriel, Angel Soto-Hermida, Hiroko Matsui, Amalio Telenti, Kelly A Frazer, John R Heckenlively, Paul A Sieving, Radha Ayyagari; Identification of pathogenic mutations in patients with inherited retinal dystrophies using whole genome sequencing. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2754.

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

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Abstract

Purpose : To identify the genetic basis for disease in patients affected with inherited retinal dystrophies (IRD).

Methods : Blood samples were collected from members of families in which pathogenic mutations had not been identified. Whole genome sequencing (WGS) of affected and unaffected family members was performed using Illumina HiSeq X10. Sequence reads were aligned to hg19 using BWA-MEM and variant calling was performed using GATK. Variants were annotated with SnpEff v4.11, PolyPhen v2.2.2, and CADD v1.3. Copy number variations (CNVs) were called using Genome STRiP (svtoolkit 2.00.1611) and SpeedSeq software. Variants were filtered to detect rare, potentially pathogenic variants segregating with disease. Segregation of candidate variants was tested in all available members by Sanger sequencing. Clinical phenotype data of patients with IRD, including ophthalmic examination, electroretinography, visual field testing, fundus photography, and pedigree analysis was reviewed.

Results : The results presented here are part of a larger ongoing study to screen families affected with IRD. In total, we screened 22 families and pathogenic or likely pathogenic variants were found in 19 families. The results of 4 families affected with IRD are reported here. One to four members from each family were included in the WGS. On average, 4 to 6 million SNVs were identified in each family. After filtering, 2 to 9 possible disease-causing variants were identified. Among these, deletions in RPGR and CERKL, a nonsense change in CERKL, a single nucleotide duplication in PDE6G, and a missense change in CRX were found to segregate with disease in 4 unrelated families. Of note, the patient with the RPGR mutation was affected with retinitis pigmentosa (RP) and a Coat’s like neovascularization, which is uncommon in patients with XLRP. The family with the duplication in PDE6G is only the second family to have been reported with likely pathogenic variants in this gene and the only one reported to date with a congenital stationary night blindness phenotype. The phenotype from the other two families matched with previous genotype-phenotype correlations: one had autosomal dominant RP (CRX mutation) and the other autosomal recessive Cone-Rod Dystrophy (CERKL mutations).

Conclusions : Performing WGS is an effective method for identifying the underlying genetic basis for disease in patients affected with IRD.

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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