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


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
Issue number7
Early online date20 Apr 2020
Publication statusPublished - Jul 2020


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