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 Dudakova; Ana 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 ‐M Dhaenens; Frans P.M. Cremers

doi:https://doi.org/10.1038/s41436-020-0787-4

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 ‐M Dhaenens, Frans P.M. Cremers

Tel Aviv University, Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	1235-1246
Number of pages	12
Journal	Genetics in Medicine
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/s41436-020-0787-4
State	Published - 1 Jul 2020

Keywords

ABCA4
Stargardt disease
deep-intronic variants
smMIPs
structural variants

All Science Journal Classification (ASJC) codes

Genetics(clinical)

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https://doi.org/10.1038/s41436-020-0787-4

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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, 22(7), 1235-1246. https://doi.org/10.1038/s41436-020-0787-4

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

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.",

keywords = "ABCA4, Stargardt disease, deep-intronic variants, smMIPs, structural variants",

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

note = "Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",

year = "2020",

month = jul,

day = "1",

doi = "https://doi.org/10.1038/s41436-020-0787-4",

language = "الإنجليزيّة",

volume = "22",

pages = "1235--1246",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "7",

}

Khan, M, Cornelis, SS, Pozo-Valero, MD, Whelan, L, Runhart, EH, Mishra, K, Bults, F, AlSwaiti, Y, AlTalbishi, A, De Baere, E, Banfi, S, Banin, E, Bauwens, M, Ben-Yosef, T, Boon, CJF, van den Born, LI, Defoort, S, Devos, A, Dockery, A, Dudakova, L, Fakin, A, Farrar, GJ, Sallum, JMF, Fujinami, K, Gilissen, C, Glavač, D, Gorin, MB, Greenberg, J, Hayashi, T, Hettinga, YM, Hoischen, A, Hoyng, CB, Hufendiek, K, Jägle, H, Kamakari, S, Karali, M, Kellner, U, Klaver, CCW, Kousal, B, Lamey, TM, MacDonald, IM, Matynia, A, McLaren, TL, Mena, MD, Meunier, I, Miller, R, Newman, H, Ntozini, B, Oldak, M, Pieterse, M, Podhajcer, OL, Puech, B, Ramesar, R, Rüther, K, Salameh, M, Salles, MV, Sharon, D, Simonelli, F, Spital, G, Steehouwer, M, Szaflik, JP, Thompson, JA, Thuillier, C, Tracewska, AM, van Zweeden, M, Vincent, AL, Zanlonghi, X, Liskova, P, Stöhr, H, Roach, JND, Ayuso, C, Roberts, L, Weber, BHF, Dhaenens, CMM & Cremers, FPM 2020, 'Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics', Genetics in Medicine, vol. 22, no. 7, pp. 1235-1246. https://doi.org/10.1038/s41436-020-0787-4

TY - JOUR

T1 - Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

AU - Khan, Mubeen

AU - Cornelis, Stéphanie S.

AU - Pozo-Valero, Marta Del

AU - Whelan, Laura

AU - Runhart, Esmee H.

AU - Mishra, Ketan

AU - Bults, Femke

AU - AlSwaiti, Yahya

AU - AlTalbishi, Alaa

AU - De Baere, Elfride

AU - Banfi, Sandro

AU - Banin, Eyal

AU - Bauwens, Miriam

AU - Ben-Yosef, Tamar

AU - Boon, Camiel J.F.

AU - van den Born, L. Ingeborgh

AU - Defoort, Sabine

AU - Devos, Aurore

AU - Dockery, Adrian

AU - Dudakova, Lubica

AU - Fakin, Ana

AU - Farrar, G. Jane

AU - Sallum, Juliana Maria Ferraz

AU - Fujinami, Kaoru

AU - Gilissen, Christian

AU - Glavač, Damjan

AU - Gorin, Michael B.

AU - Greenberg, Jacquie

AU - Hayashi, Takaaki

AU - Hettinga, Ymkje M.

AU - Hoischen, Alexander

AU - Hoyng, Carel B.

AU - Hufendiek, Karsten

AU - Jägle, Herbert

AU - Kamakari, Smaragda

AU - Karali, Marianthi

AU - Kellner, Ulrich

AU - Klaver, Caroline C.W.

AU - Kousal, Bohdan

AU - Lamey, Tina M.

AU - MacDonald, Ian M.

AU - Matynia, Anna

AU - McLaren, Terri L.

AU - Mena, Marcela D.

AU - Meunier, Isabelle

AU - Miller, Rianne

AU - Newman, Hadas

AU - Ntozini, Buhle

AU - Oldak, Monika

AU - Pieterse, Marc

AU - Podhajcer, Osvaldo L.

AU - Puech, Bernard

AU - Ramesar, Raj

AU - Rüther, Klaus

AU - Salameh, Manar

AU - Salles, Mariana Vallim

AU - Sharon, Dror

AU - Simonelli, Francesca

AU - Spital, Georg

AU - Steehouwer, Marloes

AU - Szaflik, Jacek P.

AU - Thompson, Jennifer A.

AU - Thuillier, Caroline

AU - Tracewska, Anna M.

AU - van Zweeden, Martine

AU - Vincent, Andrea L.

AU - Zanlonghi, Xavier

AU - Liskova, Petra

AU - Stöhr, Heidi

AU - Roach, John N.De

AU - Ayuso, Carmen

AU - Roberts, Lisa

AU - Weber, Bernhard H.F.

AU - Dhaenens, Claire‐Marie ‐M

AU - Cremers, Frans P.M.

PY - 2020/7/1

Y1 - 2020/7/1

N2 - 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.

AB - 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.

KW - ABCA4

KW - Stargardt disease

KW - deep-intronic variants

KW - smMIPs

KW - structural variants

UR - http://www.scopus.com/inward/record.url?scp=85083673696&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41436-020-0787-4

DO - https://doi.org/10.1038/s41436-020-0787-4

M3 - مقالة

C2 - 32307445

SN - 1098-3600

VL - 22

SP - 1235

EP - 1246

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 7

ER -

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

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