Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics
- Autores
- Khan, Mubeen; Cornelis, Stéphanie S.; Del Pozo Valero, Marta; 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; Ferraz Sallum, Juliana Maria; Fujinami, Kaoru; Gilissen, Christian; Glavac, 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 Luis; 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; De Roach, John N.; Ayuso, Carmen; Roberts, Lisa; Weber, Bernhard H. F.; Dhaenens, Claire Marie; Cremers, Frans P. M.
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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.
Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Whelan, Laura. Trinity College; Estados Unidos
Fil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP)
Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP)
Fil: De Baere, Elfride. University of Ghent; Bélgica
Fil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; Italia
Fil: Banin, Eyal. The Hebrew University of Jerusalem; Israel
Fil: Bauwens, Miriam. University of Ghent; Bélgica
Fil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; Israel
Fil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países Bajos
Fil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países Bajos
Fil: Defoort, Sabine. Universite Lille; Francia
Fil: Devos, Aurore. Universite Lille; Francia
Fil: Dockery, Adrian. Trinity College; Estados Unidos
Fil: Dudakova, Lubica. Charles University and General University Hospital; República Checa
Fil: Fakin, Ana. Charles University and General University Hospital; República Checa
Fil: Farrar, G. Jane. Trinity College; Estados Unidos
Fil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; Brasil
Fil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino Unido
Fil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Glavac, Damjan. University of Ljubljana; Eslovenia
Fil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados Unidos
Fil: Greenberg, Jacquie. University of Cape Town; Sudáfrica
Fil: Hayashi, Takaaki. The Jikei University School of Medicine; Japón
Fil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países Bajos
Fil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; Alemania
Fil: Jägle, Herbert. University Regensburg; Alemania
Fil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; Grecia
Fil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; Italia
Fil: Kellner, Ulrich. No especifíca;
Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Kousal, Bohdan. Charles University and General University Hospital; República Checa
Fil: Lamey, Tina M.. University of Western Australia; Australia
Fil: MacDonald, Ian M.. University of Alberta; Canadá
Fil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados Unidos
Fil: McLaren, Terri L.. University of Western Australia; Australia
Fil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Meunier, Isabelle. Université Montpellier II; Francia
Fil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Newman, Hadas. Universitat Tel Aviv; Israel
Fil: Ntozini, Buhle. University of Cape Town; Sudáfrica
Fil: Oldak, Monika. No especifíca;
Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Puech, Bernard. Universite Lille; Francia
Fil: Ramesar, Raj. University of Cape Town; Sudáfrica
Fil: Rüther, Klaus. No especifíca;
Fil: Salameh, Manar. No especifíca;
Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; Brasil
Fil: Sharon, Dror. The Hebrew University of Jerusalem; Israel
Fil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; Italia
Fil: Spital, Georg. No especifíca;
Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Szaflik, Jacek P.. No especifíca;
Fil: Thompson, Jennifer A.. No especifíca;
Fil: Thuillier, Caroline. Universite Lille; Francia
Fil: Tracewska, Anna M.. No especifíca;
Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Vincent, Andrea L.. University of Auckland; Nueva Zelanda
Fil: Zanlonghi, Xavier. No especifíca;
Fil: Liskova, Petra. Charles University and General University Hospital; República Checa
Fil: Stöhr, Heidi. Universitat Regensburg; Alemania
Fil: De Roach, John N.. University of Western Australia; Australia
Fil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; España
Fil: Roberts, Lisa. University of Cape Town; Sudáfrica
Fil: Weber, Bernhard H. F.. Universitat Regensburg; Alemania
Fil: Dhaenens, Claire Marie. Universite Lille; Francia
Fil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajos - Materia
-
ABCA4
DEEP-INTRONIC VARIANTS
SMMIPS
STARGARDT DISEASE
STRUCTURAL VARIANTS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/140677
Ver los metadatos del registro completo
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oai:ri.conicet.gov.ar:11336/140677 |
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| repository_id_str |
3498 |
| network_name_str |
CONICET Digital (CONICET) |
| spelling |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomicsKhan, MubeenCornelis, Stéphanie S.Del Pozo Valero, MartaWhelan, LauraRunhart, Esmee H.Mishra, KetanBults, FemkeAlSwaiti, YahyaAlTalbishi, AlaaDe Baere, ElfrideBanfi, SandroBanin, EyalBauwens, MiriamBen Yosef, TamarBoon, Camiel J. F.van den Born, L. IngeborghDefoort, SabineDevos, AuroreDockery, AdrianDudakova, LubicaFakin, AnaFarrar, G. JaneFerraz Sallum, Juliana MariaFujinami, KaoruGilissen, ChristianGlavac, DamjanGorin, Michael B.Greenberg, JacquieHayashi, TakaakiHettinga, Ymkje M.Hoischen, AlexanderHoyng, Carel B.Hufendiek, KarstenJägle, HerbertKamakari, SmaragdaKarali, MarianthiKellner, UlrichKlaver, Caroline C. W.Kousal, BohdanLamey, Tina M.MacDonald, Ian M.Matynia, AnnaMcLaren, Terri L.Mena, Marcela D.Meunier, IsabelleMiller, RianneNewman, HadasNtozini, BuhleOldak, MonikaPieterse, MarcPodhajcer, Osvaldo LuisPuech, BernardRamesar, RajRüther, KlausSalameh, ManarSalles, Mariana VallimSharon, DrorSimonelli, FrancescaSpital, GeorgSteehouwer, MarloesSzaflik, Jacek P.Thompson, Jennifer A.Thuillier, CarolineTracewska, Anna M.van Zweeden, MartineVincent, Andrea L.Zanlonghi, XavierLiskova, PetraStöhr, HeidiDe Roach, John N.Ayuso, CarmenRoberts, LisaWeber, Bernhard H. F.Dhaenens, Claire MarieCremers, Frans P. M.ABCA4DEEP-INTRONIC VARIANTSSMMIPSSTARGARDT DISEASESTRUCTURAL VARIANTShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Purpose: 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.Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países BajosFil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países BajosFil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países BajosFil: Whelan, Laura. Trinity College; Estados UnidosFil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países BajosFil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países BajosFil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países BajosFil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP)Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP)Fil: De Baere, Elfride. University of Ghent; BélgicaFil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; ItaliaFil: Banin, Eyal. The Hebrew University of Jerusalem; IsraelFil: Bauwens, Miriam. University of Ghent; BélgicaFil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; IsraelFil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países BajosFil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países BajosFil: Defoort, Sabine. Universite Lille; FranciaFil: Devos, Aurore. Universite Lille; FranciaFil: Dockery, Adrian. Trinity College; Estados UnidosFil: Dudakova, Lubica. Charles University and General University Hospital; República ChecaFil: Fakin, Ana. Charles University and General University Hospital; República ChecaFil: Farrar, G. Jane. Trinity College; Estados UnidosFil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; BrasilFil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino UnidoFil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países BajosFil: Glavac, Damjan. University of Ljubljana; EsloveniaFil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Greenberg, Jacquie. University of Cape Town; SudáfricaFil: Hayashi, Takaaki. The Jikei University School of Medicine; JapónFil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países BajosFil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países BajosFil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países BajosFil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; AlemaniaFil: Jägle, Herbert. University Regensburg; AlemaniaFil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; GreciaFil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; ItaliaFil: Kellner, Ulrich. No especifíca;Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países BajosFil: Kousal, Bohdan. Charles University and General University Hospital; República ChecaFil: Lamey, Tina M.. University of Western Australia; AustraliaFil: MacDonald, Ian M.. University of Alberta; CanadáFil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados UnidosFil: McLaren, Terri L.. University of Western Australia; AustraliaFil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Meunier, Isabelle. Université Montpellier II; FranciaFil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países BajosFil: Newman, Hadas. Universitat Tel Aviv; IsraelFil: Ntozini, Buhle. University of Cape Town; SudáfricaFil: Oldak, Monika. No especifíca;Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países BajosFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Puech, Bernard. Universite Lille; FranciaFil: Ramesar, Raj. University of Cape Town; SudáfricaFil: Rüther, Klaus. No especifíca;Fil: Salameh, Manar. No especifíca;Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; BrasilFil: Sharon, Dror. The Hebrew University of Jerusalem; IsraelFil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; ItaliaFil: Spital, Georg. No especifíca;Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países BajosFil: Szaflik, Jacek P.. No especifíca;Fil: Thompson, Jennifer A.. No especifíca;Fil: Thuillier, Caroline. Universite Lille; FranciaFil: Tracewska, Anna M.. No especifíca;Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países BajosFil: Vincent, Andrea L.. University of Auckland; Nueva ZelandaFil: Zanlonghi, Xavier. No especifíca;Fil: Liskova, Petra. Charles University and General University Hospital; República ChecaFil: Stöhr, Heidi. Universitat Regensburg; AlemaniaFil: De Roach, John N.. University of Western Australia; AustraliaFil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; EspañaFil: Roberts, Lisa. University of Cape Town; SudáfricaFil: Weber, Bernhard H. F.. Universitat Regensburg; AlemaniaFil: Dhaenens, Claire Marie. Universite Lille; FranciaFil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países BajosLippincott Williams2020-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/140677Khan, Mubeen; Cornelis, Stéphanie S.; Del Pozo Valero, Marta; Whelan, Laura; Runhart, Esmee H.; et al.; Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics; Lippincott Williams; Genetics In Medicine; 22; 7; 7-2020; 1235-12461098-36001530-0366CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/doi/10.1038/s41436-020-0787-4info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:15:57Zoai:ri.conicet.gov.ar:11336/140677instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:15:58.143CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| title |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| spellingShingle |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics Khan, Mubeen ABCA4 DEEP-INTRONIC VARIANTS SMMIPS STARGARDT DISEASE STRUCTURAL VARIANTS |
| title_short |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| title_full |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| title_fullStr |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| title_full_unstemmed |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| title_sort |
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics |
| dc.creator.none.fl_str_mv |
Khan, Mubeen Cornelis, Stéphanie S. Del Pozo Valero, Marta 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 Ferraz Sallum, Juliana Maria Fujinami, Kaoru Gilissen, Christian Glavac, 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 Luis 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 De Roach, John N. Ayuso, Carmen Roberts, Lisa Weber, Bernhard H. F. Dhaenens, Claire Marie Cremers, Frans P. M. |
| author |
Khan, Mubeen |
| author_facet |
Khan, Mubeen Cornelis, Stéphanie S. Del Pozo Valero, Marta 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 Ferraz Sallum, Juliana Maria Fujinami, Kaoru Gilissen, Christian Glavac, 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 Luis 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 De Roach, John N. Ayuso, Carmen Roberts, Lisa Weber, Bernhard H. F. Dhaenens, Claire Marie Cremers, Frans P. M. |
| author_role |
author |
| author2 |
Cornelis, Stéphanie S. Del Pozo Valero, Marta 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 Ferraz Sallum, Juliana Maria Fujinami, Kaoru Gilissen, Christian Glavac, 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 Luis 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 De Roach, John N. Ayuso, Carmen Roberts, Lisa Weber, Bernhard H. F. Dhaenens, Claire Marie Cremers, Frans P. M. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
ABCA4 DEEP-INTRONIC VARIANTS SMMIPS STARGARDT DISEASE STRUCTURAL VARIANTS |
| topic |
ABCA4 DEEP-INTRONIC VARIANTS SMMIPS STARGARDT DISEASE STRUCTURAL VARIANTS |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.2 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
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. Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Whelan, Laura. Trinity College; Estados Unidos Fil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países Bajos Fil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: De Baere, Elfride. University of Ghent; Bélgica Fil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; Italia Fil: Banin, Eyal. The Hebrew University of Jerusalem; Israel Fil: Bauwens, Miriam. University of Ghent; Bélgica Fil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; Israel Fil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países Bajos Fil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países Bajos Fil: Defoort, Sabine. Universite Lille; Francia Fil: Devos, Aurore. Universite Lille; Francia Fil: Dockery, Adrian. Trinity College; Estados Unidos Fil: Dudakova, Lubica. Charles University and General University Hospital; República Checa Fil: Fakin, Ana. Charles University and General University Hospital; República Checa Fil: Farrar, G. Jane. Trinity College; Estados Unidos Fil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; Brasil Fil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino Unido Fil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Glavac, Damjan. University of Ljubljana; Eslovenia Fil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Greenberg, Jacquie. University of Cape Town; Sudáfrica Fil: Hayashi, Takaaki. The Jikei University School of Medicine; Japón Fil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países Bajos Fil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; Alemania Fil: Jägle, Herbert. University Regensburg; Alemania Fil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; Grecia Fil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; Italia Fil: Kellner, Ulrich. No especifíca; Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Kousal, Bohdan. Charles University and General University Hospital; República Checa Fil: Lamey, Tina M.. University of Western Australia; Australia Fil: MacDonald, Ian M.. University of Alberta; Canadá Fil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: McLaren, Terri L.. University of Western Australia; Australia Fil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Meunier, Isabelle. Université Montpellier II; Francia Fil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Newman, Hadas. Universitat Tel Aviv; Israel Fil: Ntozini, Buhle. University of Cape Town; Sudáfrica Fil: Oldak, Monika. No especifíca; Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Puech, Bernard. Universite Lille; Francia Fil: Ramesar, Raj. University of Cape Town; Sudáfrica Fil: Rüther, Klaus. No especifíca; Fil: Salameh, Manar. No especifíca; Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; Brasil Fil: Sharon, Dror. The Hebrew University of Jerusalem; Israel Fil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; Italia Fil: Spital, Georg. No especifíca; Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Szaflik, Jacek P.. No especifíca; Fil: Thompson, Jennifer A.. No especifíca; Fil: Thuillier, Caroline. Universite Lille; Francia Fil: Tracewska, Anna M.. No especifíca; Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Vincent, Andrea L.. University of Auckland; Nueva Zelanda Fil: Zanlonghi, Xavier. No especifíca; Fil: Liskova, Petra. Charles University and General University Hospital; República Checa Fil: Stöhr, Heidi. Universitat Regensburg; Alemania Fil: De Roach, John N.. University of Western Australia; Australia Fil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; España Fil: Roberts, Lisa. University of Cape Town; Sudáfrica Fil: Weber, Bernhard H. F.. Universitat Regensburg; Alemania Fil: Dhaenens, Claire Marie. Universite Lille; Francia Fil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajos |
| description |
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. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020-07 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/140677 Khan, Mubeen; Cornelis, Stéphanie S.; Del Pozo Valero, Marta; Whelan, Laura; Runhart, Esmee H.; et al.; Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics; Lippincott Williams; Genetics In Medicine; 22; 7; 7-2020; 1235-1246 1098-3600 1530-0366 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/140677 |
| identifier_str_mv |
Khan, Mubeen; Cornelis, Stéphanie S.; Del Pozo Valero, Marta; Whelan, Laura; Runhart, Esmee H.; et al.; Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics; Lippincott Williams; Genetics In Medicine; 22; 7; 7-2020; 1235-1246 1098-3600 1530-0366 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/ info:eu-repo/semantics/altIdentifier/doi/10.1038/s41436-020-0787-4 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
| eu_rights_str_mv |
openAccess |
| rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
| dc.format.none.fl_str_mv |
application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Lippincott Williams |
| publisher.none.fl_str_mv |
Lippincott Williams |
| dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
| reponame_str |
CONICET Digital (CONICET) |
| collection |
CONICET Digital (CONICET) |
| instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
| _version_ |
1846083307647795200 |
| score |
13.22299 |