Inheritance Patterns

Mendelian Disorders

Disorders caused by a mutation in a single gene(monogenic). One mutation is sufficient to cause disease.

They are rare compared to non- Mendelian disorders

Non-Mendelian disorders

Multifactorial (caused by many variants in multiple genes + environmental factors e.g diabetes, heart disease), common, and don’t follow simple inheritance rules.

What genotype is needed for autosomal dominant disorders to manifest?

Heterozygous genotype(one mutated allele is enough)

What are the main Mendelian modes of inheritance?

Autosomal dominant

Autosomal recessive

X-linked dominant

X-linked recessive

Y-linked

What is meant by homozygous and heterozygous?

Homozygous: Two identical alleles at a locus (e.g. AA or aa).

Heterozygous: Two different alleles at a locus (e.g. Aa).

What are the key pedigree features of autosomal dominant inheritance?

Disease manifests with heterozygous genotype.

Both sexes affected.

Male-to-female and female-to-male transmission possible.

Often an affected parent present.

50% risk to offspring of affected parent.

Multiple generations affected

What are the features of autosomal recessive inheritance?

Manifests in homozygous or compound heterozygous form.

Carriers (heterozygous) not affected.

Both sexes affected.

Transmission male ↔ female equally.

Usually one generation affected.

25% risk to offspring of two carriers.

Suggests consanguinity(descended from the same ancestor) if more common in population.

Often seen in clusters of siblings with healthy parents.

All children of affected individuals are obligate carriers(must carry at least 1 mutated allele)

Probability of being a carrier in unaffected siblings = 2/3:

If an unaffected sibling of an affected person is tested, their chance of being a carrier is 2/3 

Parents are both carriers (Aa x Aa), so each child has 3 possibilities:

• ¼ (25%) AA= unaffected, not a carrier

• 2/4 (50%) Aa= unaffected carrier

• ¼ (25%) aa= affected

If you have a healthy sibling of an affected person that sibling cannot be ‘‘aa’’(affected)

So they are either AA or Aa

Calculation: 

• Out of the 3 possible ‘‘unaffected outcomes(Aa, Aa, AA):

• 2 are carriers(Aa) and 1 is non-carrier (AA)

So the chance of being a carrier is 2/3

What’s the difference between homozygous and compound heterozygous in autosomal recessive disease?

Homozygous: Two identical mutations in same gene (e.g. CF delF508/delF508).

Compound heterozygous: Two different mutations in same gene, one on each parental allele (e.g. CF delF508/G542X).

What are the features of X-linked inheritance?

Females (XX): Can be homozygous, heterozygous (carrier), or affected (dominant).

Males (XY): Hemizygous → one copy of X-linked gene only.

X-linked recessive:

Females usually carriers and unaffected.

No male-to-male transmission.

All daughters of affected males = obligate carriers.

X-linked dominant:

Females affected.

Males more severely affected (sometimes lethal).

All daughters of affected males are affected because:

• Fathers give sons their Y chromosome, not their X

• Fathers give daughters their X chromosome

• So in x linked dominant disorders all daughters of affected fathers are affected but not the sons

In contrast, mothers who are affected can pass either the mutant X or the normal X to both sons and daughters but fathers can only pass it to their daughters 

Skewed X-inactivation:

Normally, one X chromosome is randomly inactivated in females but sometimes inactivation is skewed, causing some female carriers of the X-linked recessive disorders to show symptoms(manifesting carriers) ~10% of females may show symptoms.

In X linked recessive disorders, females are usually carriers without symptoms(X^A X^a) but if the  X chromosome carrying the normal allele is the one inactivated then more cells will use the mutant allele which leads to symptoms even though shes just a carrier

Manifesting carriers:

Some females show mild symptoms (e.g. cardiomyopathy in Duchenne muscular dystrophy).

What are the features of Y-linked inheritance?

Always passed father → son only.

Examples:

• Y-linked infertility

• Hypertrichosis (hairy ears)

• Swyer syndrome

What are the main complications in Mendelian inheritance?

1. Incomplete/Reduced penetrance: Mutation present but no disease phenotype so some people with the disease-causing mutation dont show symptoms (e.g. Huntington’s).

2. Variable expressivity: Individuals with the same mutation show different severity or symptoms

3. De novo mutations: New mutation arises spontaneously; affected child without affected parent which explains why some affected individuals have no family history

4. Mosaicism: Mutation present in only some cells of the body(can lead to milder or unusual inheritance patterns)

5. Anticipation: Severity increases in successive generations (e.g. triplet repeat disorders).

What is penetrance?

The percentage of people with a disease-causing genotype who develop symptoms.

Can be age-related (e.g. cancers, Huntington’s, polycystic kidney disease).

Types of mutations/variants that cause Mendelian disorders?

Substitutions (point mutations)

Deletions/Insertions(inDels lead to frame shift)

Splice site mutations

Found in coding or non-coding DNA (promoters, introns, etc).

What are synonymous vs non-synonymous variants?

Synonymous variant: Base change does not alter amino acid(silent)

Non-synonymous variant: Base change alters amino acid.(missense, nonsense)

Impact depends on:

Similarity of amino acids.

Functional role of domain in protein.

Evolutionary conservation of residue.

What mutations are most likely to be pathogenic(causing a disease)?

Nonsense(premature stop codon)

Frame shift(disrupts reading frame)

Splice site variants

Missense can be pathogenic, but harder to predict

What are nonsense and missense mutations?

Nonsense:

Base change introduces premature stop codon.

Consequences:

Truncated protein.

No protein (if destroyed by nonsense-mediated decay).

Missense:

A single base change(point mutation) in DNA that causes one amino acid in the protein to be swapped for another

What are splice site variants and their impact?

Mutation at splicing site.

Consequences:

Intron retention.

Exon skipping.

Truncated or dysfunctional protein.

What are InDels (insertions and deletions) and their effects?

Frameshift insertion/deletion → alters reading frame.

Produces completely different amino acid chain.

Often creates premature stop codon → truncated protein.

How do genotypes relate to inheritance patterns?

If one healthy allele is enough → recessive disease (carriers healthy, homozygotes affected).

If one healthy allele is not enough → dominant disease (heterozygotes affected).

What’s the overall summary of Mendelian inheritance?

Mendelian inheritance = autosomal dominant/recessive + sex-linked.

Use pedigrees to identify inheritance patterns.

Mendelian disorders are monogenic and rare.

Usually caused by rare variants with large effect.

Most pathogenic: nonsense, frameshift, splice-site (but missense can too).