Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

Mubeen Khan, Stéphanie S Cornelis, Marta Del Pozo-Valero, Laura Whelan, Esmee H Runhart, Ketan Mishra, Femke Bults, Yahya AlSwaiti, Alaa AlTalbishi, Elfride De Baere, Sandro Banfi, Eyal Banin, Miriam Bauwens, Tamar Ben-Yosef, Camiel J F Boon, L Ingeborgh van den Born, Sabine Defoort, Aurore Devos, Adrian Dockery, Lubica DudakovaAna Fakin, G Jane Farrar, Juliana Maria Ferraz Sallum, Kaoru Fujinami, Christian Gilissen, Damjan Glavač, Michael B Gorin, Jacquie Greenberg, Takaaki Hayashi, Ymkje M Hettinga, Alexander Hoischen, Carel B Hoyng, Karsten Hufendiek, Herbert Jägle, Smaragda Kamakari, Marianthi Karali, Ulrich Kellner, Caroline C W Klaver, Bohdan Kousal, Tina M Lamey, Ian M MacDonald, Anna Matynia, Terri L McLaren, Marcela D Mena, Isabelle Meunier, Rianne Miller, Hadas Newman, Buhle Ntozini, Monika Oldak, Marc Pieterse, Osvaldo L Podhajcer, Bernard Puech, Raj Ramesar, Klaus Rüther, Manar Salameh, Mariana Vallim Salles, Dror Sharon, Francesca Simonelli, Georg Spital, Marloes Steehouwer, Jacek P Szaflik, Jennifer A Thompson, Caroline Thuillier, Anna M Tracewska, Martine van Zweeden, Andrea L Vincent, Xavier Zanlonghi, Petra Liskova, Heidi Stöhr, John N De Roach, Carmen Ayuso, Lisa Roberts, Bernhard H F Weber, Claire-Marie Dhaenens, Frans P M Cremers

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1235-1246
Number of pages12
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Volume22
Issue number7
Early online date20 Apr 2020
DOIs
Publication statusPublished - Jul 2020

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    Khan, M., Cornelis, S. S., Pozo-Valero, M. D., Whelan, L., Runhart, E. H., Mishra, K., Bults, F., AlSwaiti, Y., AlTalbishi, A., De Baere, E., Banfi, S., Banin, E., Bauwens, M., Ben-Yosef, T., Boon, C. J. F., van den Born, L. I., Defoort, S., Devos, A., Dockery, A., ... Cremers, F. P. M. (2020). Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics. Genetics in medicine : official journal of the American College of Medical Genetics, 22(7), 1235-1246. https://doi.org/10.1038/s41436-020-0787-4