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DOI 10.1038/s41436-020-0787-4

Медицинская библиотека · Genetics in medicine : official journal of the American College of Medical Genetics · 2020

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

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

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Аннотация

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.

Для цитирования: Khan Mubeen, Cornelis Stéphanie S, Pozo-Valero Marta Del, Whelan Laura, Runhart Esmee H, Mishra Ketan, Bults Femke, AlSwaiti Yahya, AlTalbishi Alaa, De Baere Elfride, Banfi Sandro, Banin Eyal, Bauwens Miriam, Ben-Yosef Tamar, Boon Camiel J F, van den Born L Ingeborgh, Defoort Sabine, Devos Aurore, Dockery Adrian, Dudakova Lubica, Fakin Ana, Farrar G Jane, Sallum Juliana Maria Ferraz, Fujinami Kaoru, Gilissen Christian, Glavač Damjan, Gorin Michael B, Greenberg Jacquie, Hayashi Takaaki, Hettinga Ymkje M, Hoischen Alexander, Hoyng Carel B, Hufendiek Karsten, Jägle Herbert, Kamakari Smaragda, Karali Marianthi, Kellner Ulrich, Klaver Caroline C W, Kousal Bohdan, Lamey Tina M, MacDonald Ian M, Matynia Anna, McLaren Terri L, Mena Marcela D, Meunier Isabelle, Miller Rianne, Newman Hadas, Ntozini Buhle, Oldak Monika, Pieterse Marc, Podhajcer Osvaldo L, Puech Bernard, Ramesar Raj, Rüther Klaus, Salameh Manar, Salles Mariana Vallim, Sharon Dror, Simonelli Francesca, Spital Georg, Steehouwer Marloes, Szaflik Jacek P, Thompson Jennifer A, Thuillier Caroline, Tracewska Anna M, van Zweeden Martine, Vincent Andrea L, Zanlonghi Xavier, Liskova Petra, Stöhr Heidi, Roach John N De, Ayuso Carmen, Roberts Lisa, Weber Bernhard H F, Dhaenens Claire-Marie, Cremers Frans P M. 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. 2020. DOI: 10.1038/s41436-020-0787-4.

Предметные рубрики MeSH

ATP-Binding Cassette TransportersGenomicsHumansIntronsMacular DegenerationMutationPedigreeStargardt DiseaseTranscriptome
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