• Familial Retinoblastoma inherited as an AD trait with reduced penetrance
Retinoblastoma: Disease manifestation
• Sporadic/unilateral: -- The probability of two spontaneous mutation events in the same cell in a normal individual is very low, so most sporadic cases are unilateral. -- 'Second hit' can be new mutation or mitotic crossover (LOH)
• Familial/bilateral/multifocal: -- Spontaneous mutations will occur in at least one cell in each retina of both eyes in the heterozygote. -- 90-99% of heterozygotes develop tumors and most are bilateral.
Retinoblastoma: Genetic counseling
Retinoblastoma: Risk Management
• Children at risk need EUA every 3 months until age 5.
• Genetic testing can be useful in hereditary cases.
• Most families have private mutations.
• Initial genetic testing requires sequencing of entire gene
Glaucoma: Causes by Age of onset
Glaucoma: Genetics of Congenital form
Glaucoma: Genetics of Developmental Form
PITX2 FOXC1 PAX6 LMX1B
Glaucoma: Genetics of Primary Open Angle Form
EARLY ONSET: 3-20yo --- AD: MYOC
NORMAL TENSION: >20yo --- Complex: OPTN TBK1 WDR36 CDKN2BAS 8q22
EXFOLIATION: > 50yo --- Complex: LOXL1 Northern latitude
Cataract: Pathogenesis and Genetics
Inherited forms appear at birth or early childhood
Mutations in lens proteins: • Crystallins • Aquaporins • Connexins
Adult Forms: Common and Complex
Macular Degeneration: Basics and Findings
Leading cause of blindness world-wide.
Loss of vision is primarily due to fluid leakage and scarring caused by neovascular membranes.
Macular Degeneration: Main Genes
CFH - Complement Factor H - Serum glycoprotein that regulates the function of the alternative complement pathway in plasma and on cellular surfaces. - The protein has been found in drusen and may play a role in their formation.
ARMS2 - HTRA1 - Protein function is not known. Initial studies suggested the gene could contribute to neovascular membrane formation.