Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma

Tiger Zhou; Emmanuelle Souzeau; Owen M. Siggs; John Landers; Richard Mills; Ivan Goldberg; Paul R. Healey; Stuart Graham; Alex W. Hewitt; David A. Mackey; Anna Galanopoulos; Robert J. Casson; Jonathan B. Ruddle; Jonathan Ellis; Paul Leo; Matthew A. Brown; Stuart Macgregor; Shiwani Sharma; Kathryn P. Burdon; Jamie E. Craig

doi:10.1167/iovs.16-21049

Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma

Tiger Zhou^*, Emmanuelle Souzeau, Owen M. Siggs, John Landers, Richard Mills, Ivan Goldberg, Paul R. Healey, Stuart Graham, Alex W. Hewitt, David A. Mackey, Anna Galanopoulos, Robert J. Casson, Jonathan B. Ruddle, Jonathan Ellis, Paul Leo, Matthew A. Brown, Stuart Macgregor, Shiwani Sharma, Kathryn P. Burdon, Jamie E. Craig

^*Corresponding author for this work

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Abstract

Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG.

Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes.

Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31310^-16).

Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

Original language	English
Pages (from-to)	1537-1544
Number of pages	8
Journal	Investigative Ophthalmology and Visual Science
Volume	58
Issue number	3
DOIs	https://doi.org/10.1167/iovs.16-21049
Publication status	Published - Mar 2017

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

exome sequencing
OPTN
CYP1B1
LTBP2
MYOC

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10.1167/iovs.16-21049

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Zhou, T., Souzeau, E., Siggs, O. M., Landers, J., Mills, R., Goldberg, I., Healey, P. R., Graham, S., Hewitt, A. W., Mackey, D. A., Galanopoulos, A., Casson, R. J., Ruddle, J. B., Ellis, J., Leo, P., Brown, M. A., Macgregor, S., Sharma, S., Burdon, K. P., & Craig, J. E. (2017). Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma. Investigative Ophthalmology and Visual Science, 58(3), 1537-1544. https://doi.org/10.1167/iovs.16-21049

@article{dc9595c40c68442bbf64017a8f2ef485,

title = "Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma",

abstract = "Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31310-16). Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.",

keywords = "exome sequencing, OPTN, CYP1B1, LTBP2, MYOC",

author = "Tiger Zhou and Emmanuelle Souzeau and Siggs, {Owen M.} and John Landers and Richard Mills and Ivan Goldberg and Healey, {Paul R.} and Stuart Graham and Hewitt, {Alex W.} and Mackey, {David A.} and Anna Galanopoulos and Casson, {Robert J.} and Ruddle, {Jonathan B.} and Jonathan Ellis and Paul Leo and Brown, {Matthew A.} and Stuart Macgregor and Shiwani Sharma and Burdon, {Kathryn P.} and Craig, {Jamie E.}",

note = "Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2017",

month = mar,

doi = "10.1167/iovs.16-21049",

language = "English",

volume = "58",

pages = "1537--1544",

journal = "Investigative Ophthalmology and Visual Science",

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publisher = "Association for Research in Vision and Ophthalmology",

number = "3",

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Zhou, T, Souzeau, E, Siggs, OM, Landers, J, Mills, R, Goldberg, I, Healey, PR, Graham, S, Hewitt, AW, Mackey, DA, Galanopoulos, A, Casson, RJ, Ruddle, JB, Ellis, J, Leo, P, Brown, MA, Macgregor, S, Sharma, S, Burdon, KP & Craig, JE 2017, 'Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma', Investigative Ophthalmology and Visual Science, vol. 58, no. 3, pp. 1537-1544. https://doi.org/10.1167/iovs.16-21049

TY - JOUR

T1 - Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma

AU - Zhou, Tiger

AU - Souzeau, Emmanuelle

AU - Siggs, Owen M.

AU - Landers, John

AU - Mills, Richard

AU - Goldberg, Ivan

AU - Healey, Paul R.

AU - Graham, Stuart

AU - Hewitt, Alex W.

AU - Mackey, David A.

AU - Galanopoulos, Anna

AU - Casson, Robert J.

AU - Ruddle, Jonathan B.

AU - Ellis, Jonathan

AU - Leo, Paul

AU - Brown, Matthew A.

AU - Macgregor, Stuart

AU - Sharma, Shiwani

AU - Burdon, Kathryn P.

AU - Craig, Jamie E.

N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2017/3

Y1 - 2017/3

N2 - Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31310-16). Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

AB - Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31310-16). Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

KW - exome sequencing

KW - OPTN

KW - CYP1B1

KW - LTBP2

KW - MYOC

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U2 - 10.1167/iovs.16-21049

DO - 10.1167/iovs.16-21049

M3 - Article

C2 - 28282485

SN - 1552-5783

VL - 58

SP - 1537

EP - 1544

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

IS - 3

ER -

Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma

Abstract

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Keywords

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