Genetic eye disease the conditions information for patients

Genetic eye disease: the conditions, & information for patients and families Associate Professor Robyn Jamieson Clinical Geneticist Head, Eye Genetics Research Save Sight Institute Children’s Medical Research Institute The Children’s Hospital at Westmead University of Sydney

Genetics of Eye Disease • Human disease genes known in some cases • Research to identify others • Research towards improved treatment Anterior segment dysgenesis and glaucoma Cataract Retinitis pigmentosa Microphthalmia & Anophthalmia (small eyes)

Structure of the eye & disease Anterior segment dysgenesis and glaucoma Cataract Retinitis pigmentosa, Retinal dystrophy, Cone or Rod dystrophy Leber congenital amaurosis

Why identify underlying disease genes? Genetic diagnosis Autosomal recessive <1% ? Autosomal dominant 50% (1: 2)

Why identify underlying disease genes? Mechanisms of disease & treatment • Severe retinal disease, RPE 65 mutations • Gene therapy, some improvement

Cells, chromosomes and genes

Chromosomes - karotype 46, XX (female) Pairs, 1 – 22: autosomes, 23: sex chromosomes

Chromosomes - karotype 46, XY (male)

Autosomal dominant disorder Dominant: Disease manifests when only one gene of a pair carries an abnormality * *

Autosomal dominant disorders • Affected individuals in successive generations • Males and females affected • Recurrence risk 50%, (1: 2) each pregnancy Eg some types of: - Cataracts - Retinitis pigmentosa

Genetic disorders • Variable expression • Check family members ? ? low, ? 1: 4 ? 50% (1: 2)

New autosomal dominant condition • Sporadic case • If new autosomal dominant condition: - Parents – low recurrence risk - Affected individual - 50% (1: 2) recurrence risk for each child New autosomal dominant condition ? 50% eg Some types of: - Cataracts - Retinitis pigmentosa

Autosomal recessive disorder Recessive: Disease manifests when both genes of a pair have an abnormality * *

Autosomal recessive disorder Carrier Parent * * * Affected 25% (1: 4) * * Carrier 50% (1: 2) * * Carrier * * * Normal 25% (1: 4)

Autosomal recessive disorder • Unaffected parents, siblings affected • Males and females equally affected • 25% (1: 4) recurrence risk each pregnancy for parents eg Some types of - Cataracts - Retinitis pigmentosa

Autosomal recessive inheritance • Sporadic case • If autosomal recessive condition: - Parents – 1: 4 recurrence risk - Affected individual - low recurrence risk for each child (if having children with an unrelated person) Autosomal recessive condition eg Some types of - Cataracts - Retinitis pigmentosa

X-linked recessive disorders Disorders due to mutation in X chromosome gene: Males are affected *

X-linked recessive disorders Disorders due to mutation in X chromosome gene: Females are carriers (but can sometimes be affected) **

X-linked recessive inheritance • Affected males born to women (carriers) • No male transmission Eg - X-linked Retinitis Pigmentosa - X-linked Cone Dystrophy - Congenital stationary night blindness

Ways to examine the genome 3 billion base pairs in human genome • ~1. 5% base pairs (45 million bps) in exons of protein-coding genes (23, 000) • previously sequenced each gene one by one • recently can sequence many or all genes at once Next- generation sequencing: • Exome sequencing • Whole genome sequencing

Eye Genetics Research CHW, Sydney Eye, Sydney Children’s, Newcastle, Canberra, Brisbane, Melbourne, Adelaide, Perth, Hobart, New Zealand Patients & families Trials for new treatments - Model systems - Clinical trials Next-generation sequencing - known disease genes - novel disease genes Functional studies in mouse/zebrafish/cells - to confirm that novel gene candidates are disease-causing - to establish model systems for new treatments such as gene therapy

Zebrafish & Mouse Models – Helping With: Diagnosis, how it works & new treatments Lens Retina

Genetics of Eye Disease • Modes of inheritance - Autosomal dominant, recessive, X-linked - family member examination - differences in recurrence risk information for different family members - • Next-generation sequencing - testing for known disease genes - identification of novel disease genes • Research for new treatments - genetic diagnosis - mechanisms of disease, networks - model systems - clinical trials

NSW Centre for Genetics Education http: //www. genetics. edu. au/ Genetic Services in NSW http: //www. genetics. edu. au/Genetics-Services Metropolitan • Children’s Hospital at Westmead • Westmead Adult Hospital • Sydney Children’s Hospital • Royal Prince Alfred Hospital • Royal North Shore Hospital • St George Hospital • Liverpool Hospital • Nepean Hospital • Newcastle - Hunter Genetics Regional Centres