June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
A common haplotype in the PRPH2 gene modifies Stargardt/ABCA4 disease.
Author Affiliations & Notes
  • Jana Zernant
    Ophthalmology, Columbia University, New York, New York, United States
  • Winston Lee
    Ophthalmology, Columbia University, New York, New York, United States
    Genetics, Columbia University, New York, New York, United States
  • Jun Wang
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • KERRY GOETZ
    National Eye Institute, Bethesda, Maryland, United States
  • Ehsan Ullah
    National Eye Institute, Bethesda, Maryland, United States
  • Takayuki Nagasaki
    Ophthalmology, Columbia University, New York, New York, United States
  • PEI-YIN SU
    Ophthalmology, Columbia University, New York, New York, United States
  • Gerald A Fishman
    The Chicago Lighthouse, Chicago, Illinois, United States
  • Stephen H Tsang
    Ophthalmology, Columbia University, New York, New York, United States
    Pathology & Cell Biology, Columbia University, New York, New York, United States
  • Santa J Tumminia
    National Eye Institute, Bethesda, Maryland, United States
  • Brian Brooks
    National Eye Institute, Bethesda, Maryland, United States
  • Robert B Hufnagel
    National Eye Institute, Bethesda, Maryland, United States
  • Rui Chen
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Rando Allikmets
    Ophthalmology, Columbia University, New York, New York, United States
    Pathology & Cell Biology, Columbia University, New York, New York, United States
  • Footnotes
    Commercial Relationships   Jana Zernant None; Winston Lee None; Jun Wang None; KERRY GOETZ None; Ehsan Ullah None; Takayuki Nagasaki None; PEI-YIN SU None; Gerald Fishman None; Stephen Tsang None; Santa Tumminia None; Brian Brooks None; Robert Hufnagel None; Rui Chen None; Rando Allikmets None
  • Footnotes
    Support  NIH/NEI grants R01EY028203, R01EY028954, R01EY029315, P30EY019007, FFB USA PPA-1218-0751-COLU, and the Unrestricted funds from the Research to Prevent Blindness (RPB)
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1596 – A0385. doi:
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      Jana Zernant, Winston Lee, Jun Wang, KERRY GOETZ, Ehsan Ullah, Takayuki Nagasaki, PEI-YIN SU, Gerald A Fishman, Stephen H Tsang, Santa J Tumminia, Brian Brooks, Robert B Hufnagel, Rui Chen, Rando Allikmets; A common haplotype in the PRPH2 gene modifies Stargardt/ABCA4 disease.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1596 – A0385.

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

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Abstract

Purpose : ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, with over 1,500 causal variants reported in the ABCA4 locus. The vast clinical variability, ranging from early onset fast progressing cone-rod dystrophy to late-onset macular disease, is mostly explained by extensive heterogeneity in the ABCA4 locus, including several cis-modifier alleles. While comprehensively studied, the penetrance of several causal variants and variant combinations is still not completely understood. We hypothesized that variants in unlinked loci influence the ABCA4 disease penetrance and tested if variation in the PRPH2 gene – known to most often clinically phenocopy ABCA4 disease – may play a modifying role.

Methods : We performed exome sequencing in 622 confirmed and well characterized Stargardt/ABCA4 disease patients and compared variation in the PRPH2 gene to cohorts of ethnically matched controls and between genetically determined subgroups of ABCA4 disease.

Results : The frequent haplotype in the 3’ end of PRPH2, including common variants c.910G>C (p.Glu304Gln), c.929A>G (p.Lys310Arg) and c.1013G>A (p.Gly338Asp), and tagged by the p.Asp338 variant with MAF=0.21 in the general population, was significantly increased in the patient cohort, MAF 0.25, p=0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant, the allele frequency for the PRPH2 p.Asp338 variant was 0.16 vs 0.26 in the remaining cohort, p=0.0065. Known functional data allows suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1030 cases, p=4.00E-05 for all patients and p=0.00014 for the hypomorph subgroup.

Conclusions : We suggest that the common haplotype in PRPH2 gene plays substantial trans-modifying role in ABCA4 disease overall, and specifically in the disease subgroup defined by the hypomorphic p.Asn1868Ile allele.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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