Week 1 - L4 - Autosomal Recessive Inheritance

Genetic Composition: The human cell contains approximately $3,000,000,000$ base pairs of DNA.
Chromosomal Organization:
- DNA is located within chromosomes, which are organized into $23$ pairs.
- Autosomes: These comprise the first $22$ pairs of chromosomes.
- Sex Chromosomes: The $23^{rd}$ pair consists of the $X$ and $Y$ chromosomes.
Autosomal Inheritance: This refers to the inheritance of genes located on any of the $22$ pairs of autosomes.

Allele Representation:
- Dominant Alleles: Typically denoted by a capital letter. In a dominant inherited condition, an individual is affected if they have two copies (homozygous dominant) or even one copy (heterozygous) of the dominant allele.
- Recessive Alleles: Typically denoted by a lowercase letter.
Expression of Disease: In autosomal recessive inheritance, the phenotype (the disease) is expressed only in individuals who are homozygous for the recessive allele.
- Individuals with two dominant alleles or those who are heterozygous are healthy.
- Healthy heterozygotes are known as asymptomatic carriers; they carry the variant without showing symptoms.
Loss of Function Variants: Autosomal recessive conditions are typically caused by loss of function variants.
- Definition: A genetic alteration that reduces the biological activity of a gene or the protein it encodes, preventing it from working properly.
- In a recessive state, having one functional copy of the gene is sufficient to prevent the disease; both copies must be mutated or have variants for the disease to manifest.

Parental Phenotypes: Affected individuals are usually born to unaffected parents who are both carriers.
Sex Distribution: The condition appears with equal frequency in both males and females because the genes are not sex-linked.
Generational Pattern: The disease tends to skip generations.
Recurrence Risk: After the birth of an affected child to two carrier parents, each subsequent child has a $25\%$ (one in four) chance of being affected.
Obligate Carriers: By analyzing pedigrees, specific individuals (parents and sometimes grandparents or children) can be identified as "obligate carriers" based on the presence of affected descendants and ancestors.

Definition: Consanguinity refers to reproductive unions between individuals who are related by blood, such as first or second cousins.
Genetic Impact:
- Consanguinity increases the probability that both parents will carry the same disease-causing variant inherited from a common ancestor (e.g., a grandparent).
- Autosomal recessive traits are significantly more likely to appear among the progeny of related parents.
Prevalence in Rare Diseases: While common recessive diseases may find carriers randomly in the general population, rare recessive diseases are most frequently seen in pedigrees involving consanguinity.
Population Effects: At a population level, consanguinity increases the frequency of genetic diseases and mortality rates. The closer the biological relationship, the higher the frequency of genetic disease.
Geographic Trends:
- Consanguinity is not common in Australia.
- It is common in rural India, other parts of Asia, and the Middle East.
- In these locations, approximately $20\%$ to $60\%$ of all marriages are between cousins.

Punnett Square for Two Carriers: If two heterozygotes ( $Aa$ and $Aa$ ) have children:
- $25\%$ chance of homozygous dominant ( $AA$ ) - healthy.
- $50\%$ chance of heterozygous ( $Aa$ ) - healthy asymptomatic carrier.
- $25\%$ chance of homozygous recessive ( $aa$ ) - affected.
Probability Summary: Total probability of a healthy child (either carrier or non-carrier) is $0.75$ .

Genetic Basis: Caused by variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.
Pathology: Results in progressive pulmonary (lung) disease.
Australian Statistics:
- Prevalence: Approximately $1$ in $3,700$ cases.
- Carrier Rate: Approximately $1$ in $25$ Australians carry a variant in the CFTR gene.
Academic Note: At Monash University (implied), students in the third-year genetics unit GEN3051 can undergo anonymized carrier status testing.
Medical Policy: Cystic Fibrosis testing is now covered by Medicare rebates in Australia for individuals planning pregnancies.

Definition: A type of motor neuron disease affecting the Survival Motor Neuron 1 (SMN1) gene.
Genetic Basis: Approximately $95\%$ of affected individuals have a complete absence of the SMN1 gene, meaning the gene is so disrupted that no protein is produced.
Function: The gene is essential for motor neurons that control muscle movement.
Symptoms: Lack of SMN1 leads to progressive muscle weakness and wasting (atrophy). This impacts movement, breathing, coughing, and swallowing.
Australian Statistics: Approximately $1$ in $40$ Australians are carriers.
Screening: SMA is included in the new Medicare rebates to allow couples to identify carrier status and receive genetic counseling before making informed decisions.

Genetic Basis: At least four different genes have been identified as causes.
Nomenclature Note: Historically, the term "mutant" was used; modern genetics uses the term "variant."
Carrier Rates by Ancestry:
- African Ancestry: $1$ in $85$ .
- European Ancestry: $1$ in $100$ .
- Australia (Prevalence): $1$ in $17,000$ .
Biological Mechanism:
- Typical Gene: Produces melanin, resulting in pigmented cells.
- One Variant (Carrier): Still produces enough melanin for typical pigmentation.
- Two Variants (Affected): No melanin is produced, resulting in cells with no pigment and the albino phenotype.