Monogenic Disorders Genetic Counselling Noelene Kinsley Genetic Counsellor MSc (Med) Wits 7 June 2017

Outline Monogenic disorders – definitions and associated unique features Use of features to assist with risk prediction and genetic testing Value of the genetic counselling process to facilitate risk prediction and communication

Monogenic Disorder ~ Mendelian Condition, Single Gene Disorder Mutation* in a gene that results in the diagnosis of the disorder. Single gene involvement: Genetic Heterogeneity Genetic mutation complexity Inheritance Definitive patterns * Pathogenic variant

Monogenic vs Complex Rare Pathogenic variant in a single gene - disorder Pathogenic variant in gene Inheritance defined - predictive risk Common Variants in multiple genes - predisposition Interactions gene/gene and gene/environment Empirical risk Gene A PotentialDisorder Gene A Disorder Gene A Gene A

Genetic Heterogeneity Many genes associated with a single genetic disorder

Mutation complexity Multiple mutations in a single gene – same condition (CF)

Mutation complexity Multiple mutations in a single gene – same condition (CF) Different mutations in a single gene – different severity of genetic condition (CF) Different mutations in a single gene – different diagnosis Pleiotrophy (ABCA4 gene/HBB)

Haemaglobinopathies Nature Communications 1, Article number: 104 (2010)

Test complexity: Monogenic Disorders Albinism (AR) Haemophilia (XL) Huntington Disease (AD) Retinitis Pigmentosa (AD,AR,XL) Cystic Fibrosis Population specific Biochemical specificity Inheritance pattern Population specificity OCA2 and TYR F8 and F9 HD1 and HD2 >53 genes CFTR 100% detection Common Unique 100% Confirmation 30% Detection Common 30 mutations - Eur (90%) DNA Sequence DNA Sequence RNA Sequence Microarray NGS But even ‘simple’ Mendelian conditions are complex Genetic heterogeneity based on population, condition Limitation in detection based on technology, cost and interpretive powers AR: Autosomal recessive AD: Autosomal dominant XL: X-linked

Autosomal Dominant Inheritance Affected individuals in each generation Males and females equally affected Parent 50% risk of an affected child Common features: Variable expression Incomplete penetrance Anticipation New mutation Examples: Neurofibromatosis, Hereditary cancer syndrome, Huntington Disease, Polycystic Kidney Disease

Autosomal Recessive Inheritance Parents are clinically normal - obligate carriers Often no family history Males and females equally affected Affected - two faulty genes - one from each parent Carrier parents 25% risk affected child Pseudodominance: Certain populations have common recessive conditions Consanguinity Example: Cystic fibrosis, Sickle cell anaemia Beta-thalassaemia, Albinism

X-linked Inheritance Males affected Females carriers Faulty gene on X-chromosome Carrier mother: 50% carrier daughter 50% affected son Carriers: May display symptoms Examples: Duchenne musclar dystrophy, Haemophilia X-linked mental retardation, Retinitis Pigmentosa

Genetic Counselling Process Referral Agenda Information Gathering Information Sharing Genetic Testing Decision Making Result Giving

Referral & Agenda Confirmation of Clinical Diagnosis Clinical features and symptoms Test results – New Born Screening, Prenatal, Blood profile Determine Risk for a Monogenic Disorder Family history Population risk Prenatal screening test Preconception/premarital 3. What do they want to know?

Resources GeneReview Orphanet National Organisation for Rare Disorder Genetic Home Reference: https://ghr.nlm.nih.gov/condition Support Group and Advocacy Sites Genetic Alliance SA Rare Disease

Information Sharing: Genetic Disorder Details of the Genetic Disorder Basic genetics Symptoms and features Genetic Basis Prevalence Test options Management Support

Information Gathering Construct pedigree Clinical information and test results Births, stillbirths, early deaths, terminations Include carriers (~ obligate) Ethnicity, culture and belief Consanguinity Personal perceptions (assumptions of status) Grief, loss and expectations Family communication and experience

Information Sharing: Inheritance

Recessive Inheritance

Dominant Inheritance

X-linked Inheritance

Information Sharing: Risk Calculation Risk of Occurrence/Recurrence Use of pedigree Types of risk: Mendelian Risk of Recurrence Type of Inheritance Obligate carriers Population Risk Consanguinity

Risk Calculation v = ⅓ x ⅓ = 1/6 Likelihood father is a carrier? Repeated infections as a child Pregnancy Affected No genetic test Lung transplant 23 years old Likelihood father is a carrier? Likelihood mother is a carrier? Diagnosis of deceased brother is CF. ½ ½ RISK OF OCCURRENCE = (½ x A) X (½ x B) = (½ x ⅔) x (½ x ⅔) = ⅓ x ⅓ = 1/6

Genetic Testing Reason for testing: Type of Test Prior knowledge Affected (confirm) Asymptomatic (determine risk) Type of Test Single gene, panel, exome, genome Targeted, NGS Prior knowledge Access and availability Resources Alternative

Genetic Testing and Decision-making Identify who should be tested Clinical diagnosis At-risk individuals (family or population risk) Timing Benefits Limitations Implications Reproductive choices, relatedness, at-risk family members and family/community communication Consent or ascent

Result-giving Preconception/premarital screening Prenatal testing and screening Confirmation of clinical diagnosis or test Referral Support

Summary Monogenic disorders due to mutation(s) in a single gene Complexities include genetic heterogeneity, family history and genetic mutations. Genetic counselling process is a guideline for appropriate communication and support Pedigree provides context to discuss monogenic disorders and associated complexities.