June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
ABCA4 c.859-25A>G, a frequent Palestinian founder mutation associated with retinal dystrophy, results in multiple splice defects
Author Affiliations & Notes
  • Manar Salameh
    Saint John Eye Hospital, Jerusalem, Palestine, State of
    Hadassah Medical Center Department of Ophthalmology, Jerusalem, Jerusalem, Israel
  • Zelia Corradi
    Human Genetics, Radboudumc, Nijmegen, Gelderland, Netherlands
    Radboud Universiteit Donders Institute for Brain Cognition and Behaviour, Nijmegen, Gelderland, Netherlands
  • Mubeen Khan
    Human Genetics, Radboudumc, Nijmegen, Gelderland, Netherlands
    Pathology and Medical Biology, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Ajoy Vincent
    Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Elise Heon
    Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
    Program of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Rebekkah Hitti-Malin
    Human Genetics, Radboudumc, Nijmegen, Gelderland, Netherlands
    Radboud Universiteit Donders Institute for Brain Cognition and Behaviour, Nijmegen, Gelderland, Netherlands
  • Yahya AlSwaiti
    Saint John Eye Hospital, Jerusalem, Palestine, State of
  • Eyal Banin
    Hadassah Medical Center Department of Ophthalmology, Jerusalem, Jerusalem, Israel
  • Claire-Marie Dhaenens
    Lille Neuroscience & Cognition, Centre Hospitalier Universitaire de Lille, Lille, Hauts-de-France, France
  • Dror Sharon
    Hadassah Medical Center Department of Ophthalmology, Jerusalem, Jerusalem, Israel
  • Alaa AlTalbishi
    Saint John Eye Hospital, Jerusalem, Palestine, State of
  • Frans P.M. Cremers
    Human Genetics, Radboudumc, Nijmegen, Gelderland, Netherlands
    Radboud Universiteit Donders Institute for Brain Cognition and Behaviour, Nijmegen, Gelderland, Netherlands
  • Footnotes
    Commercial Relationships   Manar Salameh, None; Zelia Corradi, None; Mubeen Khan, None; Ajoy Vincent, None; Elise Heon, None; Rebekkah Hitti-Malin, None; Yahya AlSwaiti, None; Eyal Banin, None; Claire-Marie Dhaenens, None; Dror Sharon, None; Alaa AlTalbishi, None; Frans Cremers, None
  • Footnotes
    Support  Marie Sklodowska-Curie Innovative Training Networks (ITN) grant No.813490
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 6. doi:
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      Manar Salameh, Zelia Corradi, Mubeen Khan, Ajoy Vincent, Elise Heon, Rebekkah Hitti-Malin, Yahya AlSwaiti, Eyal Banin, Claire-Marie Dhaenens, Dror Sharon, Alaa AlTalbishi, Frans P.M. Cremers; ABCA4 c.859-25A>G, a frequent Palestinian founder mutation associated with retinal dystrophy, results in multiple splice defects. Invest. Ophthalmol. Vis. Sci. 2021;62(8):6.

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

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Abstract

Purpose : The effect of noncoding variants is often unknown in the absence of functional tests. The purpose of this study was to characterize an ABCA4 intron 7 variant, c.859-25A>G, identified in Palestinian probands with a clinical diagnosis of Stargardt disease (STGD) or cone-rod dystrophy (CRD). We assessed the effect of this variant on the ABCA4 mRNA and retinal phenotype,and investigated its prevalence in inherited retinal dystrophy (IRD) cases from Palestine.

Methods : Molecular inversion probe (MIP)-based sequencing of ABCA4 was performed in 876 probands with STGD or CRD collected worldwide. In silico analysis of DNA variants was performed using SpliceAI. The effect of variant c.859-25A>G was investigated using in vitro splice assays in HEK293T cells using ABCA4 exon 7-11 midigenes. ABCA4 sequencing data was obtained or re-analyzed from another 890 Palestinian IRD cases using MIPs-based sequencing, whole exome sequencing, and targeted Sanger sequencing. The ophthalmologic characteristics were examined using retinal imaging techniques, including optical coherence tomography and also full field electroretinography.

Results : smMIPs-based ABCA4 sequencing revealed the c.859-25A>G variant in three Palestinian probands living in, or originating from, the city of Hebron. SpliceAI predicted a significant effect on the nearby splice acceptor site, and splice assays revealed an exon 8 deletion and two upstream elongations in mRNA. None of these products yields a functional ABCA4 protein. ABCA4 genotyping in 890 Palestinian cases revealed another 48 affected persons carrying this variant, all living in or originating from the Hebron area. Haplotype analysis in 22 of 38 homozygotes revealed a shared genomic segment. Homozygotes for variant c.859-25A>G show an average age at onset of 5.4 years confirming that this is a severe variant. The mean logmar best corrected visual acuity for these cases was 1.1. Of the 38 homozygotes 25, 7, and 6 cases had a clinical picture compatible with CRD, STGD1 and retinitis pigmentosa (RP) respectively.

Conclusions : ABCA4 variant c.859-25A>G results in multiple severe splice defects and CRD, RP or early-onset STGD1 in homozygotes. It was found in 50/892 IRD cases in Palestine and represents the most frequent IRD-causing variant to date in Palestine.

This is a 2021 ARVO Annual Meeting abstract.

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