Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene

Samar Yahya; Claire E.L. Smith; James A. Poulter; Martin McKibbin; Gavin Arno; Jamie Ellingford; Kati Kämpjärvi; Muhammad I. Khan; Frans P.M. Cremers; Alison J. Hardcastle; Bruce Castle; David H.W. Steel; Andrew R. Webster; Graeme C. Black; Mohammed E. El-Asrag; Manir Ali; Carmel Toomes; Chris F. Inglehearn; Stuart Ingram; Rachel Taylor; Forbes Manson; Panagiotis Sergouniotis; Nikolas Pontikos; Michael Cheetham; Alessia Fiorentino; Susan Downes; Jing Yu; Stephanie Halford; Suzanne Broadgate; Veronica van Heyningen; John C. Ambrose; Prabhu Arumugam; Roel Bevers; Marta Bleda; Freya Boardman-Pretty; Christopher R. Boustred; Helen Brittain; Mark J. Caulfield; Georgia C. Chan; Greg Elgar; Tom Fowler; Adam Giess; Angela Hamblin; Shirley Henderson; Tim J.P. Hubbard; Rob Jackson; Louise J. Jones; Dalia Kasperaviciute; Melis Kayikci; Athanasios Kousathanas; Lea Lahnstein; Sarah E.A. Leigh; Ivonne U.S. Leong; Javier F. Lopez; Fiona Maleady-Crowe; Meriel McEntagart; Federico Minneci; Loukas Moutsianas; Michael Mueller; Nirupa Murugaesu; Anna C. Need; Peter O'Donovan; Chris A. Odhams; Christine Patch; Mariana Buongermino Pereira; Daniel Perez-Gil; John Pullinger; Tahrima Rahim; Augusto Rendon; Tim Rogers; Kevin Savage; Kushmita Sawant; Richard H. Scott; Afshan Siddiq; Alexander Sieghart; Samuel C. Smith; Alona Sosinsky; Alexander Stuckey; Mélanie Tanguy; Ana Lisa Taylor Tavares; Ellen R.A. Thomas; Simon R. Thompson; Arianna Tucci; Matthew J. Welland; Eleanor Williams; Katarzyna Witkowska; Suzanne M. Wood

doi:10.1016/j.ophtha.2022.07.023

Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene

Samar Yahya, Claire E.L. Smith, James A. Poulter, Martin McKibbin, Gavin Arno, Jamie Ellingford, Kati Kämpjärvi, Muhammad I. Khan, Frans P.M. Cremers, Alison J. Hardcastle, Bruce Castle, David H.W. Steel, Andrew R. Webster, Graeme C. Black, Mohammed E. El-Asrag, Manir Ali, Carmel Toomes, Chris F. Inglehearn^*, Stuart Ingram, Rachel TaylorForbes Manson, Panagiotis Sergouniotis, Nikolas Pontikos, Michael Cheetham, Alessia Fiorentino, Susan Downes, Jing Yu, Stephanie Halford, Suzanne Broadgate, Veronica van Heyningen, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Freya Boardman-Pretty, Christopher R. Boustred, Helen Brittain, Mark J. Caulfield, Georgia C. Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O'Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Ana Lisa Taylor Tavares, Ellen R.A. Thomas, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood

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Abstract / Description of output

Purpose: To characterize the phenotype observed in a case series with macular disease and determine the cause. Design: Multicenter case series. Participants: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration. Methods: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing. Main Outcome Measures: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients. Results: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. Conclusions: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.

Original language	English
Pages (from-to)	68-76
Number of pages	9
Journal	Ophthalmology
Volume	130
Issue number	1
DOIs	https://doi.org/10.1016/j.ophtha.2022.07.023
Publication status	Published - 5 Aug 2023

Keywords / Materials (for Non-textual outputs)

AMD
CRX
Macular disease
Retinal disease
SULT2A1
TPRX1

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Yahya, S., Smith, C. E. L., Poulter, J. A., McKibbin, M., Arno, G., Ellingford, J., Kämpjärvi, K., Khan, M. I., Cremers, F. P. M., Hardcastle, A. J., Castle, B., Steel, D. H. W., Webster, A. R., Black, G. C., El-Asrag, M. E., Ali, M., Toomes, C., Inglehearn, C. F., Ingram, S., ... Wood, S. M. (2023). Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene. Ophthalmology, 130(1), 68-76. https://doi.org/10.1016/j.ophtha.2022.07.023

@article{79219fde63f1492caaf1e863ee3ddc0b,

title = "Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene",

abstract = "Purpose: To characterize the phenotype observed in a case series with macular disease and determine the cause. Design: Multicenter case series. Participants: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration. Methods: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing. Main Outcome Measures: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients. Results: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. Conclusions: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.",

keywords = "AMD, CRX, Macular disease, Retinal disease, SULT2A1, TPRX1",

author = "Samar Yahya and Smith, {Claire E.L.} and Poulter, {James A.} and Martin McKibbin and Gavin Arno and Jamie Ellingford and Kati K{\"a}mpj{\"a}rvi and Khan, {Muhammad I.} and Cremers, {Frans P.M.} and Hardcastle, {Alison J.} and Bruce Castle and Steel, {David H.W.} and Webster, {Andrew R.} and Black, {Graeme C.} and El-Asrag, {Mohammed E.} and Manir Ali and Carmel Toomes and Inglehearn, {Chris F.} and Stuart Ingram and Rachel Taylor and Forbes Manson and Panagiotis Sergouniotis and Nikolas Pontikos and Michael Cheetham and Alessia Fiorentino and Susan Downes and Jing Yu and Stephanie Halford and Suzanne Broadgate and {van Heyningen}, Veronica and Ambrose, {John C.} and Prabhu Arumugam and Roel Bevers and Marta Bleda and Freya Boardman-Pretty and Boustred, {Christopher R.} and Helen Brittain and Caulfield, {Mark J.} and Chan, {Georgia C.} and Greg Elgar and Tom Fowler and Adam Giess and Angela Hamblin and Shirley Henderson and Hubbard, {Tim J.P.} and Rob Jackson and Jones, {Louise J.} and Dalia Kasperaviciute and Melis Kayikci and Athanasios Kousathanas and Lea Lahnstein and Leigh, {Sarah E.A.} and Leong, {Ivonne U.S.} and Lopez, {Javier F.} and Fiona Maleady-Crowe and Meriel McEntagart and Federico Minneci and Loukas Moutsianas and Michael Mueller and Nirupa Murugaesu and Need, {Anna C.} and Peter O'Donovan and Odhams, {Chris A.} and Christine Patch and Pereira, {Mariana Buongermino} and Daniel Perez-Gil and John Pullinger and Tahrima Rahim and Augusto Rendon and Tim Rogers and Kevin Savage and Kushmita Sawant and Scott, {Richard H.} and Afshan Siddiq and Alexander Sieghart and Smith, {Samuel C.} and Alona Sosinsky and Alexander Stuckey and M{\'e}lanie Tanguy and {Taylor Tavares}, {Ana Lisa} and Thomas, {Ellen R.A.} and Thompson, {Simon R.} and Arianna Tucci and Welland, {Matthew J.} and Eleanor Williams and Katarzyna Witkowska and Wood, {Suzanne M.}",

note = "Funding Information: The authors thank the families involved in this research. This research was made possible through access to the data and findings generated by the 100 000 Genomes Project. The 100 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100 000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100 000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Funding Information: Financial support: This work was funded by Retinitis Pigmentosa Fighting Blindness and Fight for Sight UK (RP Genome Project GR586) and by a scholarship from the Saudi Arabian Cultural Bureau and King Abdulaziz University (to S.Y.). Funding organizations had no role in the design and conduct of this research. Publisher Copyright: {\textcopyright} 2022 American Academy of Ophthalmology",

year = "2023",

month = aug,

day = "5",

doi = "10.1016/j.ophtha.2022.07.023",

language = "English",

volume = "130",

pages = "68--76",

journal = "Ophthalmology",

issn = "0161-6420",

publisher = "Elsevier",

number = "1",

}

Yahya, S, Smith, CEL, Poulter, JA, McKibbin, M, Arno, G, Ellingford, J, Kämpjärvi, K, Khan, MI, Cremers, FPM, Hardcastle, AJ, Castle, B, Steel, DHW, Webster, AR, Black, GC, El-Asrag, ME, Ali, M, Toomes, C, Inglehearn, CF, Ingram, S, Taylor, R, Manson, F, Sergouniotis, P, Pontikos, N, Cheetham, M, Fiorentino, A, Downes, S, Yu, J, Halford, S, Broadgate, S, van Heyningen, V, Ambrose, JC, Arumugam, P, Bevers, R, Bleda, M, Boardman-Pretty, F, Boustred, CR, Brittain, H, Caulfield, MJ, Chan, GC, Elgar, G, Fowler, T, Giess, A, Hamblin, A, Henderson, S, Hubbard, TJP, Jackson, R, Jones, LJ, Kasperaviciute, D, Kayikci, M, Kousathanas, A, Lahnstein, L, Leigh, SEA, Leong, IUS, Lopez, JF, Maleady-Crowe, F, McEntagart, M, Minneci, F, Moutsianas, L, Mueller, M, Murugaesu, N, Need, AC, O'Donovan, P, Odhams, CA, Patch, C, Pereira, MB, Perez-Gil, D, Pullinger, J, Rahim, T, Rendon, A, Rogers, T, Savage, K, Sawant, K, Scott, RH, Siddiq, A, Sieghart, A, Smith, SC, Sosinsky, A, Stuckey, A, Tanguy, M, Taylor Tavares, AL, Thomas, ERA, Thompson, SR, Tucci, A, Welland, MJ, Williams, E, Witkowska, K & Wood, SM 2023, 'Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene', Ophthalmology, vol. 130, no. 1, pp. 68-76. https://doi.org/10.1016/j.ophtha.2022.07.023

TY - JOUR

T1 - Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene

AU - Yahya, Samar

AU - Smith, Claire E.L.

AU - Poulter, James A.

AU - McKibbin, Martin

AU - Arno, Gavin

AU - Ellingford, Jamie

AU - Kämpjärvi, Kati

AU - Khan, Muhammad I.

AU - Cremers, Frans P.M.

AU - Hardcastle, Alison J.

AU - Castle, Bruce

AU - Steel, David H.W.

AU - Webster, Andrew R.

AU - Black, Graeme C.

AU - El-Asrag, Mohammed E.

AU - Ali, Manir

AU - Toomes, Carmel

AU - Inglehearn, Chris F.

AU - Ingram, Stuart

AU - Taylor, Rachel

AU - Manson, Forbes

AU - Sergouniotis, Panagiotis

AU - Pontikos, Nikolas

AU - Cheetham, Michael

AU - Fiorentino, Alessia

AU - Downes, Susan

AU - Yu, Jing

AU - Halford, Stephanie

AU - Broadgate, Suzanne

AU - van Heyningen, Veronica

AU - Ambrose, John C.

AU - Arumugam, Prabhu

AU - Bevers, Roel

AU - Bleda, Marta

AU - Boardman-Pretty, Freya

AU - Boustred, Christopher R.

AU - Brittain, Helen

AU - Caulfield, Mark J.

AU - Chan, Georgia C.

AU - Elgar, Greg

AU - Fowler, Tom

AU - Giess, Adam

AU - Hamblin, Angela

AU - Henderson, Shirley

AU - Hubbard, Tim J.P.

AU - Jackson, Rob

AU - Jones, Louise J.

AU - Kasperaviciute, Dalia

AU - Kayikci, Melis

AU - Kousathanas, Athanasios

AU - Lahnstein, Lea

AU - Leigh, Sarah E.A.

AU - Leong, Ivonne U.S.

AU - Lopez, Javier F.

AU - Maleady-Crowe, Fiona

AU - McEntagart, Meriel

AU - Minneci, Federico

AU - Moutsianas, Loukas

AU - Mueller, Michael

AU - Murugaesu, Nirupa

AU - Need, Anna C.

AU - O'Donovan, Peter

AU - Odhams, Chris A.

AU - Patch, Christine

AU - Pereira, Mariana Buongermino

AU - Perez-Gil, Daniel

AU - Pullinger, John

AU - Rahim, Tahrima

AU - Rendon, Augusto

AU - Rogers, Tim

AU - Savage, Kevin

AU - Sawant, Kushmita

AU - Scott, Richard H.

AU - Siddiq, Afshan

AU - Sieghart, Alexander

AU - Smith, Samuel C.

AU - Sosinsky, Alona

AU - Stuckey, Alexander

AU - Tanguy, Mélanie

AU - Taylor Tavares, Ana Lisa

AU - Thomas, Ellen R.A.

AU - Thompson, Simon R.

AU - Tucci, Arianna

AU - Welland, Matthew J.

AU - Williams, Eleanor

AU - Witkowska, Katarzyna

AU - Wood, Suzanne M.

N1 - Funding Information: The authors thank the families involved in this research. This research was made possible through access to the data and findings generated by the 100 000 Genomes Project. The 100 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100 000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100 000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Funding Information: Financial support: This work was funded by Retinitis Pigmentosa Fighting Blindness and Fight for Sight UK (RP Genome Project GR586) and by a scholarship from the Saudi Arabian Cultural Bureau and King Abdulaziz University (to S.Y.). Funding organizations had no role in the design and conduct of this research. Publisher Copyright: © 2022 American Academy of Ophthalmology

PY - 2023/8/5

Y1 - 2023/8/5

N2 - Purpose: To characterize the phenotype observed in a case series with macular disease and determine the cause. Design: Multicenter case series. Participants: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration. Methods: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing. Main Outcome Measures: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients. Results: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. Conclusions: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.

AB - Purpose: To characterize the phenotype observed in a case series with macular disease and determine the cause. Design: Multicenter case series. Participants: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration. Methods: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing. Main Outcome Measures: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients. Results: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. Conclusions: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.

KW - AMD

KW - CRX

KW - Macular disease

KW - Retinal disease

KW - SULT2A1

KW - TPRX1

U2 - 10.1016/j.ophtha.2022.07.023

DO - 10.1016/j.ophtha.2022.07.023

M3 - Article

C2 - 35934205

AN - SCOPUS:85137676713

SN - 0161-6420

VL - 130

SP - 68

EP - 76

JO - Ophthalmology

JF - Ophthalmology

IS - 1

ER -

Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene

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