Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier

Jamie E. Craig, Paul N. Baird, Danielle L. Healey, Andrew I. McNaught, Paul J. McCartney, Julian L. Rait, Joanne L. Dickinson, Lynne Roe, John H. Fingert, Edwin M. Stone, David A. Mackey

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Abstract

Objective: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). Design: Cross-sectional genetic study. Participants: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. Methods: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. Results: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 ± 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 ± 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 ± 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 ± 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. Conclusions: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

Original languageEnglish
Pages (from-to)1607-1620
Number of pages14
JournalOphthalmology
Volume108
Issue number9
DOIs
Publication statusPublished - 12 Sep 2001
Externally publishedYes

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Genetic Heterogeneity
Glaucoma
Pedigree
Mutation
Ocular Hypertension
Intraocular Pressure
Penetrance
Primary Open Angle Glaucoma
Tasmania
Phenotype
Inheritance Patterns
Trabeculectomy
Age of Onset
Drainage
Cross-Sectional Studies
Mothers

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Craig, Jamie E. ; Baird, Paul N. ; Healey, Danielle L. ; McNaught, Andrew I. ; McCartney, Paul J. ; Rait, Julian L. ; Dickinson, Joanne L. ; Roe, Lynne ; Fingert, John H. ; Stone, Edwin M. ; Mackey, David A. / Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. In: Ophthalmology. 2001 ; Vol. 108, No. 9. pp. 1607-1620.
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title = "Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier",
abstract = "Objective: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). Design: Cross-sectional genetic study. Participants: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. Methods: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. Results: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 ± 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 ± 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 ± 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 ± 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72{\%} at age 40 years and 82{\%} at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. Conclusions: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.",
author = "Craig, {Jamie E.} and Baird, {Paul N.} and Healey, {Danielle L.} and McNaught, {Andrew I.} and McCartney, {Paul J.} and Rait, {Julian L.} and Dickinson, {Joanne L.} and Lynne Roe and Fingert, {John H.} and Stone, {Edwin M.} and Mackey, {David A.}",
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Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. / Craig, Jamie E.; Baird, Paul N.; Healey, Danielle L.; McNaught, Andrew I.; McCartney, Paul J.; Rait, Julian L.; Dickinson, Joanne L.; Roe, Lynne; Fingert, John H.; Stone, Edwin M.; Mackey, David A.

In: Ophthalmology, Vol. 108, No. 9, 12.09.2001, p. 1607-1620.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier

AU - Craig, Jamie E.

AU - Baird, Paul N.

AU - Healey, Danielle L.

AU - McNaught, Andrew I.

AU - McCartney, Paul J.

AU - Rait, Julian L.

AU - Dickinson, Joanne L.

AU - Roe, Lynne

AU - Fingert, John H.

AU - Stone, Edwin M.

AU - Mackey, David A.

PY - 2001/9/12

Y1 - 2001/9/12

N2 - Objective: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). Design: Cross-sectional genetic study. Participants: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. Methods: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. Results: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 ± 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 ± 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 ± 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 ± 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. Conclusions: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

AB - Objective: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). Design: Cross-sectional genetic study. Participants: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. Methods: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. Results: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 ± 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 ± 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 ± 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 ± 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. Conclusions: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

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DO - 10.1016/S0161-6420(01)00654-6

M3 - Article

VL - 108

SP - 1607

EP - 1620

JO - Ophthalmology: journal of the American Academy of Ophthalmology

JF - Ophthalmology: journal of the American Academy of Ophthalmology

SN - 0161-6420

IS - 9

ER -