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  Targeted sequencing and in vitro splice assays shed light on ABCA4-associated retinopathies missing heritability

Corradi, Z., Khan, M., Hitti-Malin, R., Mishra, K., Whelan, L., Cornelis, S. S., et al. (2023). Targeted sequencing and in vitro splice assays shed light on ABCA4-associated retinopathies missing heritability. Human Genetics and Genomics Advances, 4(4): 100237. doi:10.1016/j.xhgg.2023.100237.

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2023
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© 2023 The Authors This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

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 Creators:
Corradi, Zelia1, Author
Khan, Mubeen2, 3, Author           
Hitti-Malin, Rebekkah1, Author
Mishra, Ketan1, Author
Whelan, Laura2, Author
Cornelis, Stéphanie S.1, Author
ABCA4-Study Group, Author              
Hoyng, Carel B.1, Author
Kämpjärvi, Kati4, Author
Klaver, Caroline C. W.1, 5, 6, Author
Liskova, Petra7, Author
Stohr, Heidi8, Author
Weber, Bernhard H. F.8, 9, Author
Banfi, Sandro10, Author
Farrar, G. Jane2, Author
Sharon, Dror11, Author
Zernant, Jana12, Author
Allikmets, Rando12, Author
Dhaenens, Claire-Marie1, 13, Author
Cremers, Frans P. M.1, Author
Affiliations:
1Radboud University Medical Center, Nijmegen, The Netherlands, ou_persistent22              
2Trinity College Dublin, Dublin, Ireland, ou_persistent22              
3Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, ou_792549              
4Blueprint Genetics, Espoo, Finland, ou_persistent22              
5Erasmus Medical Center, Rotterdam, The Netherlands, ou_persistent22              
6Institute of Molecular & Clinical Ophthalmology, Basel, Switzerland, ou_persistent22              
7Charles University and General University Hospital in Prague, Prague, Czech Republic, ou_persistent22              
8University of Regensburg, Regenburgs, Germany, ou_persistent22              
9University Hospital Regensburg, Regensburg, Germany, ou_persistent22              
10University of Campania “Luigi Vanvitelli” , Pozzuoli, Italy, ou_persistent22              
11The Hebrew University of Jerusalem, Jerusalem, Israel, ou_persistent22              
12Columbia University, New York, NY, USA, ou_persistent22              
13Centre Hospitalier Universitaire de Lille, Lille, France, ou_persistent22              

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 Abstract: The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed. After single molecule molecular inversion probes (smMIPs)-based sequencing of the complete 128-kb ABCA4 locus, the effect of putative splice variants was assessed in vitro by midigene splice assays in HEK293T cells. The breakpoints of copy number variants (CNVs) were determined by junction PCR and Sanger sequencing. ABCA4 sequence analysis solved 207/520 (39.8%) naïve or unsolved cases and 70/202 (34.7%) monoallelic cases, while additional causal variants were identified in 54/136 (39.7%) of probands carrying two variants. Seven novel DIVs and six novel non-canonical splice site variants were detected in a total of 35 alleles and characterized, including the c.6283-321C>G variant leading to a complex splicing defect. Additionally, four novel CNVs were identified and characterized in five alleles. These results confirm that smMIPs-based sequencing of the complete ABCA4 gene provides a cost-effective method to genetically solve retinopathy cases and that several rare structural and splice altering defects remain undiscovered in STGD1 cases.

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Language(s): eng - English
 Dates: 2023-09-112023
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.xhgg.2023.100237
 Degree: -

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Title: Human Genetics and Genomics Advances
  Other : HGG Advances
Source Genre: Journal
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Publ. Info: [Verlagsort nicht ermittelbar] : American Society of Human Genetics
Pages: - Volume / Issue: 4 (4) Sequence Number: 100237 Start / End Page: - Identifier: Other: 2666-2477
CoNE: https://pure.mpg.de/cone/journals/resource/2666-2477