Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma leads to early identification of at-risk individuals

Emmanuelle Souzeau, Kien Hou Tram, Martin Witney, Jonathan B. Ruddle, Stuart L. Graham, Paul R. Healey, Ivan Goldberg, David Mackey, Alex W. Hewitt, Kathryn P. Burdon, Jamie E. Craig

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Abstract

Purpose To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). Design Retrospective clinical and molecular study. Participants Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. Methods Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. Main Outcome Measures Glaucoma clinical parameters and age at presentation. Results At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (−10.0±10.3 vs. −1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. Conclusions Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.

Original languageEnglish
Pages (from-to)303-309
Number of pages7
JournalOphthalmology
Volume124
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

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Genetic Testing
Glaucoma
Ocular Hypertension
Critical Pathways
trabecular meshwork-induced glucocorticoid response protein
Primary Open Angle Glaucoma
Visual Fields
Intraocular Pressure
New Zealand
General Practitioners
Registries
Outcome Assessment (Health Care)
Mutation

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Souzeau, E., Tram, K. H., Witney, M., Ruddle, J. B., Graham, S. L., Healey, P. R., ... Craig, J. E. (2017). Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma leads to early identification of at-risk individuals. Ophthalmology, 124(3), 303-309. https://doi.org/10.1016/j.ophtha.2016.11.011
Souzeau, Emmanuelle ; Tram, Kien Hou ; Witney, Martin ; Ruddle, Jonathan B. ; Graham, Stuart L. ; Healey, Paul R. ; Goldberg, Ivan ; Mackey, David ; Hewitt, Alex W. ; Burdon, Kathryn P. ; Craig, Jamie E. / Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma leads to early identification of at-risk individuals. In: Ophthalmology. 2017 ; Vol. 124, No. 3. pp. 303-309.
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author = "Emmanuelle Souzeau and Tram, {Kien Hou} and Martin Witney and Ruddle, {Jonathan B.} and Graham, {Stuart L.} and Healey, {Paul R.} and Ivan Goldberg and David Mackey and Hewitt, {Alex W.} and Burdon, {Kathryn P.} and Craig, {Jamie E.}",
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Souzeau, E, Tram, KH, Witney, M, Ruddle, JB, Graham, SL, Healey, PR, Goldberg, I, Mackey, D, Hewitt, AW, Burdon, KP & Craig, JE 2017, 'Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma leads to early identification of at-risk individuals' Ophthalmology, vol. 124, no. 3, pp. 303-309. https://doi.org/10.1016/j.ophtha.2016.11.011

Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma leads to early identification of at-risk individuals. / Souzeau, Emmanuelle; Tram, Kien Hou; Witney, Martin; Ruddle, Jonathan B.; Graham, Stuart L.; Healey, Paul R.; Goldberg, Ivan; Mackey, David; Hewitt, Alex W.; Burdon, Kathryn P.; Craig, Jamie E.

In: Ophthalmology, Vol. 124, No. 3, 01.03.2017, p. 303-309.

Research output: Contribution to journalArticle

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T1 - Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma leads to early identification of at-risk individuals

AU - Souzeau, Emmanuelle

AU - Tram, Kien Hou

AU - Witney, Martin

AU - Ruddle, Jonathan B.

AU - Graham, Stuart L.

AU - Healey, Paul R.

AU - Goldberg, Ivan

AU - Mackey, David

AU - Hewitt, Alex W.

AU - Burdon, Kathryn P.

AU - Craig, Jamie E.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Purpose To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). Design Retrospective clinical and molecular study. Participants Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. Methods Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. Main Outcome Measures Glaucoma clinical parameters and age at presentation. Results At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (−10.0±10.3 vs. −1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. Conclusions Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.

AB - Purpose To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). Design Retrospective clinical and molecular study. Participants Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. Methods Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. Main Outcome Measures Glaucoma clinical parameters and age at presentation. Results At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (−10.0±10.3 vs. −1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. Conclusions Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.

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