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

2. 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

3. 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

4. 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

5. Genetic Heterogeneity
Many genes associated with a single genetic disorder

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

7. 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)

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

9. 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

10. 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

11. 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

12. 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

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

14. 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?

15. Resources GeneReview Orphanet National Organisation for Rare Disorder
Genetic Home Reference:
Support Group and Advocacy Sites
Genetic Alliance SA
Rare Disease

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

17. 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

18. Information Sharing: Inheritance

19. Recessive Inheritance

20. Dominant Inheritance

21. X-linked Inheritance

22. 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

23. 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.
RISK OF OCCURRENCE = (½ x A) X (½ x B)
= (½ x ⅔) x (½ x ⅔)
= ⅓ x ⅓ = 1/6

24. 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

25. 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

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

27. 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.