Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma

Owen M. Siggs, Emmanuelle Souzeau, Francesca Pasutto, Andrew Dubowsky, James E.H. Smith, Deepa Taranath, John Pater, Julian L. Rait, Andrew Narita, Lucia Mauri, Alessandra Del Longo, André Reis, Angela Chappell, Lisa S. Kearns, Sandra E. Staffieri, James E. Elder, Jonathan B. Ruddle, Alex W. Hewitt, Kathryn P. Burdon, David A. Mackey & 1 others Jamie E. Craig

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Importance: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

Original languageEnglish
Pages (from-to)348-355
Number of pages8
JournalJAMA Ophthalmology
Volume137
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

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Glaucoma
Exome
Genetic Heterogeneity
Multiplex Polymerase Chain Reaction
Ophthalmology
New Zealand
Italy
Genes
Registries
Nucleotides
Outcome Assessment (Health Care)
Phenotype
Axenfeld-Rieger syndrome

Cite this

Siggs, O. M., Souzeau, E., Pasutto, F., Dubowsky, A., Smith, J. E. H., Taranath, D., ... Craig, J. E. (2019). Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma. JAMA Ophthalmology, 137(4), 348-355. https://doi.org/10.1001/jamaophthalmol.2018.5646
Siggs, Owen M. ; Souzeau, Emmanuelle ; Pasutto, Francesca ; Dubowsky, Andrew ; Smith, James E.H. ; Taranath, Deepa ; Pater, John ; Rait, Julian L. ; Narita, Andrew ; Mauri, Lucia ; Del Longo, Alessandra ; Reis, André ; Chappell, Angela ; Kearns, Lisa S. ; Staffieri, Sandra E. ; Elder, James E. ; Ruddle, Jonathan B. ; Hewitt, Alex W. ; Burdon, Kathryn P. ; Mackey, David A. ; Craig, Jamie E. / Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma. In: JAMA Ophthalmology. 2019 ; Vol. 137, No. 4. pp. 348-355.
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title = "Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma",
abstract = "Importance: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0{\%}) were female, and 71 of 84 (84.5{\%}) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7{\%}) were female, and 45 of 47 (95.7{\%}) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1{\%}), or 8 of 166 participants (4.8{\%}) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.",
author = "Siggs, {Owen M.} and Emmanuelle Souzeau and Francesca Pasutto and Andrew Dubowsky and Smith, {James E.H.} and Deepa Taranath and John Pater and Rait, {Julian L.} and Andrew Narita and Lucia Mauri and {Del Longo}, Alessandra and Andr{\'e} Reis and Angela Chappell and Kearns, {Lisa S.} and Staffieri, {Sandra E.} and Elder, {James E.} and Ruddle, {Jonathan B.} and Hewitt, {Alex W.} and Burdon, {Kathryn P.} and Mackey, {David A.} and Craig, {Jamie E.}",
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Siggs, OM, Souzeau, E, Pasutto, F, Dubowsky, A, Smith, JEH, Taranath, D, Pater, J, Rait, JL, Narita, A, Mauri, L, Del Longo, A, Reis, A, Chappell, A, Kearns, LS, Staffieri, SE, Elder, JE, Ruddle, JB, Hewitt, AW, Burdon, KP, Mackey, DA & Craig, JE 2019, 'Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma' JAMA Ophthalmology, vol. 137, no. 4, pp. 348-355. https://doi.org/10.1001/jamaophthalmol.2018.5646

Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma. / Siggs, Owen M.; Souzeau, Emmanuelle; Pasutto, Francesca; Dubowsky, Andrew; Smith, James E.H.; Taranath, Deepa; Pater, John; Rait, Julian L.; Narita, Andrew; Mauri, Lucia; Del Longo, Alessandra; Reis, André; Chappell, Angela; Kearns, Lisa S.; Staffieri, Sandra E.; Elder, James E.; Ruddle, Jonathan B.; Hewitt, Alex W.; Burdon, Kathryn P.; Mackey, David A.; Craig, Jamie E.

In: JAMA Ophthalmology, Vol. 137, No. 4, 01.04.2019, p. 348-355.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Prevalence of FOXC1 Variants in Individuals with a Suspected Diagnosis of Primary Congenital Glaucoma

AU - Siggs, Owen M.

AU - Souzeau, Emmanuelle

AU - Pasutto, Francesca

AU - Dubowsky, Andrew

AU - Smith, James E.H.

AU - Taranath, Deepa

AU - Pater, John

AU - Rait, Julian L.

AU - Narita, Andrew

AU - Mauri, Lucia

AU - Del Longo, Alessandra

AU - Reis, André

AU - Chappell, Angela

AU - Kearns, Lisa S.

AU - Staffieri, Sandra E.

AU - Elder, James E.

AU - Ruddle, Jonathan B.

AU - Hewitt, Alex W.

AU - Burdon, Kathryn P.

AU - Mackey, David A.

AU - Craig, Jamie E.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Importance: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

AB - Importance: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

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DO - 10.1001/jamaophthalmol.2018.5646

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JO - Archives of Ophthalmology

JF - Archives of Ophthalmology

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