Khan, Mubeen and Cornelis, Stephanie S. and Del Pozo-Valero, Marta and Whelan, Laura and Runhart, Esmee H. and Mishra, Ketan and Bults, Femke and AlSwaiti, Yahya and AlTalbishi, Alaa and De Baere, Elfride and Banfi, Sandro and Banin, Eyal and Bauwens, Miriam and Ben-Yosef, Tamar and Boon, Camiel J. F. and van den Born, L. Ingeborgh and Defoort, Sabine and Devos, Aurore and Dockery, Adrian and Dudakova, Lubica and Fakin, Ana and Farrar, G. Jane and Sallum, Juliana Maria Ferraz and Fujinami, Kaoru and Gilissen, Christian and Glavac, Damjan and Gorin, Michael B. and Greenberg, Jacquie and Hayashi, Takaaki and Hettinga, Ymkje M. and Hoischen, Alexander and Hoyng, Carel B. and Hufendiek, Karsten and Jaegle, Herbert and Kamakari, Smaragda and Karali, Marianthi and Kellner, Ulrich and Klaver, Caroline C. W. and Kousal, Bohdan and Lamey, Tina M. and MacDonald, Ian M. and Matynia, Anna and McLaren, Terri L. and Mena, Marcela D. and Meunier, Isabelle and Miller, Rianne and Newman, Hadas and Ntozini, Buhle and Oldak, Monika and Pieterse, Marc and Podhajcer, Osvaldo L. and Puech, Bernard and Ramesar, Raj and Ruether, Klaus and Salameh, Manar and Salles, Mariana Vallim and Sharon, Dror and Simonelli, Francesca and Spital, Georg and Steehouwer, Marloes and Szaflik, Jacek P. and Thompson, Jennifer A. and Thuillier, Caroline and Tracewska, Anna M. and van Zweeden, Martine and Vincent, Andrea L. and Zanlonghi, Xavier and Liskova, Petra and Stoehr, Heidi and Roach, John N. De and Ayuso, Carmen and Roberts, Lisa and Weber, Bernhard H. F. and Dhaenens, Claire-Marie and Cremers, Frans P. M. (2020) Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics. GENETICS IN MEDICINE, 22 (7). pp. 1235-1246. ISSN 1098-3600, 1530-0366
Full text not available from this repository. (Request a copy)Abstract
Purpose Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MATERNAL UNIPARENTAL ISODISOMY; DEEP-INTRONIC VARIANTS; RETINAL DYSTROPHY; GENE; MUTATION; CHROMOSOME-1; PATIENT; REVEALS; REPAIR; RPE65; ABCA4; Stargardt disease; smMIPs; deep-intronic variants; structural variants |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2021 11:26 |
| Last Modified: | 26 Mar 2021 11:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44731 |
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