Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes

Cold Spring Harbor Molecular Case Studies
Jana ZernantRando Allikmets

Abstract

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ∼75% of patients and only one mutation in ∼15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 have been identified in the latter group. We extended our analyses of deep intronic ABCA4 variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic ABCA4 allele, 23/160 (14.38%), MAF = 0.072, compared to MAF = 0.013 in all STGD1 cases and MAF = 0.006 in the matching general population (P < 1 × 10-7). The variant, which is not predicted to have any effect on splicing, is the first reported intronic "extremely hypomorphic allele" in the ABCA4 locus; that is, it is pathogenic only when in trans with a loss-of-function ABCA4 allele. It results in a distinct clinical phenotype characterized by late onset of symptoms and foveal sparing. In ∼70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which w...Continue Reading

References

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Citations

Nov 28, 2018·Investigative Ophthalmology & Visual Science·Rando AllikmetsWinston Lee
Aug 10, 2019·Investigative Ophthalmology & Visual Science·Nathalie M BaxUNKNOWN for the Foveal Sparing Atrophy Study Team (FAST)
Sep 3, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Marta UnoltDonna McDonald-McGinn
Apr 21, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Mubeen KhanFrans P M Cremers
Jan 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mor HananyDror Sharon
Aug 4, 2020·Expert Opinion on Investigational Drugs·Kanmin Xue, Robert E MacLaren
Aug 21, 2020·JAMA Ophthalmology·Esmee H RunhartUNKNOWN Disease Consortium Study Group
May 18, 2020·International Journal of Molecular Sciences·Aneta ŚcieżyńskaJacek Malejczyk
Dec 28, 2018·Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Für Klinische Und Experimentelle Ophthalmologie·Jian LiangXiaodong Sun
Oct 17, 2019·Investigative Ophthalmology & Visual Science·Esmee H RunhartCarel B Hoyng
Nov 27, 2019·Genes·Anna M TracewskaKrystyna H Chrzanowska
Dec 2, 2020·Acta Ophthalmologica·Josephine Prener HoltanRagnheiður Bragadóttir
Feb 7, 2021·International Journal of Molecular Sciences·Jordi MaggiWolfgang Berger
Apr 13, 2020·Progress in Retinal and Eye Research·Frans P M CremersRando Allikmets
Mar 7, 2021·International Journal of Molecular Sciences·Izarbe Aísa-MarínGemma Marfany
May 1, 2021·International Journal of Molecular Sciences·Tomasz Z TomkiewiczAlejandro Garanto
Aug 28, 2021·Genes·Saoud Al-KhuzaeiStephanie Halford

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Methods Mentioned

BETA
454 sequencing
genotyping
ChIP-seq

Software Mentioned

MaxEntScan
SpliceSiteFinder
Human Splicing Finder
Alamut
ENCODE
GeneSplicer
NNSPLICE

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