Inheritance and Disease Genes

Pre-lecture Videos

Links to videos on solving pedigrees and Hardy-Weinberg problems are provided.

How to Solve ALL PEDIGREES
How To Solve ANY Pedigree Without Reading the Question (USMLE)
Solving Hardy Weinberg Problems

Clinical Molecular Genetics

Topics covered include:

Clinical genetics & disease genes
Inheritance and disease genes
Genetic mapping and finding mutations
From genotype to phenotype

Today's Topics

Fundamentals of Genetic Counselling:

Drawing a pedigree
Risk estimation for inherited diseases (Hardy-Weinberg equilibrium)

Spectrum of Characters

Most human traits are determined by a combination of genetic and environmental factors.

single variant versus environment
single variant versus multiple variants
multiple variants versus environment components

Genetic Diseases

Rare diseases: Affect less than 1/2,000 people.
Approximately 8,000 rare diseases are known.
More than 80% have a genetic basis.
About 5% of live-born babies have a significant medical disorder (congenital diseases).
Most common diseases seen later in life also have a genetic component.
Single-gene diseases.

Mendel’s Principles

The principle of uniformity
- All F1 offspring of homozygous parents with different alleles will be identical and heterozygous.
- If tall (T) is dominant over short (t), all F1 offspring will be tall.
- There is no intermediate phenotype.
The principle of segregation
- Only one allele will be transmitted from parent to offspring.
- The distribution of phenotypes will be 3 (dominant allele) to 1 (recessive allele).
- Example: $P: TT \times tt$ , $F1: Tt, Tt, Tt, Tt$ (all tall), $F2: TT, Tt, tT, tt$ (3 tall : 1 short)
The principle of independent assortment
- Separate loci segregate to offspring independently of one another.
- The distribution of two phenotypes will be 9 (dominant allele each) to 3 (one dominant, one recessive allele) to 3 (one recessive, one dominant allele) to 1 (recessive alleles each).
- Example: $P:$ round, yellow (homozygous) $X$ wrinkled, green (homozygous), $F1:$ round, yellow (heterozygous), $F2:$ 9 round, yellow : 3 wrinkled, yellow : 3 round, green : 1 wrinkled, green

Inheritance: Mode of Inheritance?

Example pedigree illustrating X-linked recessive inheritance, referencing European royalty.

Pedigree Symbols

Key symbols used in pedigrees:

male, female, sex unknown/not stated
unaffected, affected
miscarriage
mating, consanguineous mating
dead
brothers, twin brothers
6 offspring, sex unknown/not stated
heterozygous
proband

Genetic Counselling

A pedigree is drafted in the clinic to document family history, including dates of birth/death and diseases/causes of death. The “Proband” is the individual presenting the family.

Genetic Diseases: Huntington Disease

Example of Huntington's disease, showing involuntary movements and brain tissue loss.

Genetic Counselling: Reading a Pedigree

How to read a pedigree, using the Ashton family as an example.

Molecular Diagnostics

Molecular genetic diagnostics relies on preceding clinical findings and is used for:

confirmation of the clinical diagnosis
carrier testing
prenatal diagnostics
predictive testing

Pedigrees: Mode of Inheritance

Determining the mode of inheritance:

autosomal dominant, autosomal recessive
X-linked (recessive), X-linked (dominant)
Y-linked
phenocopy

Autosomal Dominant and X-linked Dominant Inheritance

Key Questions:

Are the parents affected? NO
M to M? YES
Dominant

Autosomal Dominant Inheritance

An affected person usually has one affected parent.
Unaffected parents usually have unaffected children.
Affects either sex.
A child of an affected parent has a 50% risk of being affected (a priori risk).
Example: Huntington’s disease (heterozygous).

Autosomal Recessive Inheritance

An affected person usually has unaffected parents.
Both parents are usually carriers.
Affects either sex.
Recurrence risk for further children after the birth of an affected child is 25% for each child.
Homozygous.

X-linked Recessive Inheritance

No transmission from father to son.
Mothers are usually asymptomatic.
Mainly males affected; 50% risk of being affected for males if the mother is a carrier.
Example: Duchenne muscular dystrophy (DMD) (hemizygous).

X-linked Dominant Inheritance

Affected males:
- all his sons unaffected
- all his daughters affected
Affected females:
- 50% risk of being affected (heterozygous or hemizygous).

Disease Frequency

Incidence: The number of new cases of a certain disease in a defined time period.
- Example: Spinal muscular atrophy (SMA): approximately 100 new cases per year in the UK, incidence of SMA approximately 1/7,500 newborns.
Prevalence: The number of all cases of a certain disease at any one time. For SMA: prevalence of SMA approximately 2,000 – 2,500 in the UK.

Population Frequencies

Hardy-Weinberg distribution: describes the distribution of traits/alleles in a specific population.

Calculate a recurrence risk in a family.
1. How would you determine the frequency of heterozygotes?

Recurrence Risk

Assume:

normal allele CFTR: A
defective allele CFTR: a
$p + q = 1$
$AA$ or $Aa/aA$ or $aa = p^2 + 2pq + q^2 = 1$
incidence: 1/2,500

Hardy-Weinberg Law

$p$ = frequency of one allele at one locus (i.e., dominant allele 'A')
$q$ = frequency of another allele at the same locus on the homologous chromosome (i.e., recessive allele 'a')
$p^2$ = frequency of homozygotes for dominant allele (i.e., 'AA' genotype)
$q^2$ = frequency of homozygotes for recessive allele (i.e., 'aa' genotype)
$2pq$ = frequency of heterozygotes (i.e., 'Aa' genotype)
$(p+q)^2 = p^2 + 2pq + q^2$

Recurrence Risk Calculation

$p^2$ >> probability for $AA$ >> homozygous, unaffected
$q^2$ >> probability for $aa$ >> affected, 1/2,500 for CF
$2pq$ >> probability for $Aa$ >> heterozygous, carrier
$p + q = 1$
$q = \sqrt{\frac{1}{2500}} = \frac{1}{50}$
$p = 1 - q = 1 - \frac{1}{50} = \frac{49}{50}$
Carrier: $2pq = 2 \cdot \frac{49}{50} \cdot \frac{1}{50} = \frac{98}{2500} \approx \frac{1}{25}$
Frequency of heterozygotes is approximately 1/25.

Recurrence Risk: Robert and Maureen

Carrier risk parent 1 $\times$ Probability of inheriting the mutant allele to the child, parent 1 $\times$ Carrier risk parent 2 $\times$ Probability of inheriting the mutant allele to the child, parent 2

What is the risk of Robert and Maureen to have a child with cystic fibrosis?
$\frac{1}{25} \times \frac{1}{2} \times \frac{1}{2} = \frac{1}{100} = 1\%$ . Frequency of heterozygotes in the population

Assumptions Behind Hardy-Weinberg Equilibrium

Large Population Size
Random Mating
No Mutation
No Migration

Tutorial: Tay-Sachs Disease

The genetic counsellor wants to determine the risk of a couple to have a child with Tay-Sachs disease, which is caused by mutations in the gene HEXA. The woman is a known carrier (heterozygous mutation in HEXA). The partner, who is of Ashkenazi Jewish descent, has not been analyzed. The incidence of Tay-Sachs disease in Ashkenazi Jews is approximately 1 / 2,000. Question: What is the estimated frequency of heterozygotes?

Recurrence Risk Calculation: Tay-Sachs Disease

$p^2$ >> probability for $AA$ >> homozygous/unaffected
$q^2$ >> probability for $aa$ >> affected, 1/2,000 for TSD in Ashkenazi Jews
$2pq$ >> probability for $Aa$ >> heterozygous, carrier
$p + q = 1$
$q = \sqrt{\frac{1}{2000}} \approx \frac{1}{45}$
$p = 1 - q = 1 - \frac{1}{45} = \frac{44}{45}$
$2pq = 2 \cdot \frac{44}{45} \cdot \frac{1}{45} = \frac{88}{2025} \approx \frac{1}{23}$
Frequency of heterozygotes is approximately 1/23.

Summary

Most rare diseases have a strong genetic basis and are mainly monogenic. Most common diseases have a genetic component.
The mode of inheritance of ‘Mendelian’ diseases can be determined by reading the pedigree.
The recurrence risk for a monogenic disease and the frequency of heterozygotes can be calculated in a family and population, respectively.