Genetic Imprinting and Associated Inherited Diseases

Definition: Imprinted genes are those whose expression is determined by the parent of origin.
Prevalence: Humans possess approximately $100$ imprinted genes.
Classification:
- Maternally Imprinted: The allele inherited from the mother is silenced or switched off.
- Paternally Imprinted: The allele inherited from the father is silenced or switched off.
Biological Mechanism:
- Imprints are reset during gametogenesis. This ensures an individual passes on the correct imprints according to their biological sex (e.g., a male will reset all imprints to paternal imprints in his sperm).
- Only one functional allele is required for the cell to produce the correct amount of protein. However, if that single active allele is missing or mutated, disease occurs.

Scenario Setup: Consider a maternally imprinted gene where the maternal allele is always inactivated.
Inheritance Patterns in a Three-Generation Family:
- Generation 1: A mother (alleles $1$ and $2$ ) and a father (alleles $3$ and $4$ ). If the mother got allele $1$ from her mother, it is inactivated. If the father got allele $4$ from his mother, it is inactivated. Both express the allele inherited from their respective fathers.
- Generation 2: The parents pass alleles to their children with a $\frac{50}{50}$ chance.
  - If a daughter inherits allele $1$ from her mother, that allele is inactivated in her because it came from a female parent.
  - If a son inherits allele $1$ from his mother, it is also inactivated in him.
- Generation 3: The expression depends on the sex of the parent in Generation 2.
  - If the son from Generation 2 (who carries allele $1$ ) has children, those children will express allele $1$ because it was inherited from their father.
  - If the daughter from Generation 2 (who carries allele $1$ ) has children, those children will inactivate allele $1$ because it was inherited from their mother.

The Pathogenic Mutation ( $m$ ): If an allele (e.g., allele $1$ ) carries a pathogenic mutation such as a stop codon, the phenotype depends entirely on whether that specific allele is the one being expressed.
Case 1: Inherited from Mother (Maternally Imprinted Gene):
- An individual inherits the mutation ( $m$ ) from their mother.
- Because it is a maternally imprinted gene, the maternal allele is switched off.
- The individual expresses the wild-type allele from their father.
- Result: The individual is an unaffected carrier of the mutation.
Case 2: Inherited from Father (Maternally Imprinted Gene):
- An individual (e.g., individual $3.1$ in a pedigree) inherits the mutation ( $m$ ) from their father.
- The maternal allele (inherited from the mother) is silenced by default.
- The individual is forced to rely on the sequence from the paternal allele, which contains the mutation.
- Result: The individual is affected by the disease.
Critical Factors: Whether an individual is affected depends on two questions:
1. Did they inherit the mutation?
2. Which parent did they inherit the mutation from?

Chromosomal Clustering: Imprinted genes often cluster together in the same region on a chromosome. These clusters frequently contain a mixture of both maternally and paternally imprinted genes.
The Wild-Type Expression Balance:
- In a cluster of three genes where genes $1$ and $3$ are paternally imprinted and gene $2$ is maternally imprinted:
  - Gene $1$ is expressed from the maternal chromosome.
  - Gene $2$ is expressed from the paternal chromosome.
  - Gene $3$ is expressed from the maternal chromosome.
- The net result is a sufficient amount of protein for all three genes.
Mechanism of Deletions: Deletions often occur de novo (of new) and involve the removal of the entire cluster of genes on one chromosome.
Outcome of Maternal Deletion:
- The mother's chromosome is missing genes $1, 2, \text{ and } 3$ .
- The father provides a wild-type chromosome, but his imprinting machinery has already silenced genes $1$ and $3$ .
- Result: The individual expresses gene $2$ but has zero expression of genes $1$ and $3$ , leading to Phenotype A.
Outcome of Paternal Deletion:
- The father's chromosome is missing the cluster.
- The mother provides a wild-type chromosome, but her imprinting machinery has already silenced gene $2$ .
- Result: The individual expresses genes $1$ and $3$ but has zero expression of gene $2$ , leading to Phenotype B.

Beckwith Wiedemann Syndrome:
- Location: Chromosome $11$ .
- Scope: Contains at least $8$ imprinted genes.
- Physical Features: Umbilical hernia (incomplete closure of the stomach wall), large tongue, and a cluster of overgrowth features.
- Inheritance: These genes are paternally imprinted. Therefore, the disease phenotype only manifests in children who inherit the deletion from their mother.
Chromosome 15 Cluster:
- Scope: Contains at least $10$ imprinted genes, including a mixture of maternal and paternal imprints.
- Prader Willi Syndrome:
  - Cause: Deletion inherited from the father (paternal chromosome).
  - Features: Obesity, intellectual disability, and diabetes.
- Angelman Syndrome:
  - Cause: Deletion inherited from the mother (maternal chromosome).
  - Features: Growth retardation, intellectual disability, hyperactivity, and affected speech.

Every individual expresses only one allele of an imprinted gene.
Imprints must be reset in gametes to match the parent's biological sex so the opposite sex can provide the complementary imprints at fertilization.
Phenotypic expression of a mutation requires the mutation to be inherited from the parent whose allele is active (not silenced).
The same deletion in a gene cluster can cause two entirely different clinical syndromes (e.g., Prader Willi vs. Angelman) depending solely on which parental chromosome carries the deletion.