Genetics: Autosomal & X-linked Recessive Inheritance

Autosomal Recessive Inheritance

• Both parents of an affected child are carriers and do not show symptoms.
• Each parent has a 50% chance of passing on the mutated allele.
• A child has a 25% chance of inheriting the disease if both parents pass on the mutated allele.
• In test questions, unaffected patients with a family history of autosomal recessive disease have a 2/3 chance of being carriers.
• Cystic Fibrosis (CF) is an example of autosomal recessive inheritance.

X-linked Recessive Diseases

• Affect males more frequently because they have only one X chromosome.
• Females are usually carriers unless they inherit the mutated allele from both parents.
• Red-green color blindness is an example of an X-linked recessive disease.
• If the mother is a carrier and the father is unaffected, daughters will be carriers, and half of the sons will be affected.
• If the mother is homozygous for the mutant allele, all daughters will be carriers, and all sons will be affected.
• If the father is affected, all daughters will be carriers, and none of the sons will be affected.
• Duchenne Muscular Dystrophy (DMD) is an example of X-linked recessive inheritance
• An unaffected mother has a 50% chance of being a carrier if her brother is affected by DMD.
• If the mother is a carrier, there is a 1/4 chance her child will inherit the disease

Homozygous vs. Heterozygous in X-linked Recessive Inheritance

• Homozygous: Having two identical alleles for a gene.
• Heterozygous: Having two different alleles for a gene.
• Males are hemizygous for X-linked genes, having only one allele (either normal or mutated).
• They cannot be heterozygous or homozygous.
• Females can be homozygous (both X chromosomes have the mutated allele) or heterozygous (one X chromosome has the mutated allele, the other is normal).

X-linked Dominant Diseases

• Both males and females can be affected.
• The disease is usually more severe in males.
• Rett syndrome is an example of an X-linked dominant disease.
• If the mother is heterozygous and the father is unaffected, their children will have a 50% chance of being affected.
• If the father is affected, all daughters will be affected because they will inherit his affected X chromosome.
• In Rett syndrome, if the mother is heterozygous and the father is unaffected, all daughters will inherit the disease, and 50% of sons will be affected.

Mitochondrial Inheritance

• Mitochondrial DNA is inherited only from the mother.
• Leber hereditary optic neuropathy is a mitochondrial disease.
• If the mother is affected, all her children will inherit the disease.
• If the mother is unaffected, none of her children will inherit the disease, regardless of the father's status.
• In Leber hereditary optic neuropathy, all children will inherit the disease from the mother if she is affected.

Genetic Risk Assessment Scenarios

• To determine the probability of a child inheriting an autosomal recessive disorder:
  • If both parents have an affected sibling:
    • There is a 2/3 chance that each parent is a carrier.
    • The probability of their child being affected is 2/3 * 2/3 * 1/4 = 1/9.
• To determine the probability of a son being affected by an X-linked recessive disorder:
  • If a phenotypically normal woman has an affected brother:
    • She has a 1/2 chance of being a carrier.
    • Each son has a 1/2 chance of inheriting the affected X chromosome if she is a carrier.
    • The overall probability is 1/2 * 1/2 = 1/4.
• To determine the probability of a daughter inheriting an X-linked dominant disorder:
  • If the man's mother has an X-linked dominant disorder, and the woman is unaffected:
    • The father will pass on his X chromosome, which carries the mutated allele, to all of his daughters.
    • The probability of their daughter inheriting the disorder is 100%.

Conditions with a Genetic Origin

• A condition runs in the family
• An individual presents with developmental delays or intellectual disability
  • Pathogenic genetic abnormalities can be detected in 50-64% of individuals with developmental delays or intellectual disability
• Infertility and repeated pregnancy loss
  • Half of infertility cases and repeated pregnancy losses are associated with genetic conditions, including structural abnormalities like deletions, duplications, inversions, translocations, and insertions
  • Single gene disorders, like mutations in the F5 gene, which is associated with Factor V clotting factor disorders, can also contribute to these issues
• Adult-Onset Diseases
  • A classic example of genetic diseases discovered later in life are inherited cancer disorders
  • If a patient reports that multiple family members have been diagnosed with the same type of cancer, it is likely the family carries an inherited cancer mutation
  • Hypertrophic cardiomyopathy, often caused by mutations in the MYBPC3 gene, is another genetic disease that is typically diagnosed in adulthood
• Rare Diseases
  • While rare individually, collectively, rare diseases are quite common
  • If a patient presents with a condition that doesn’t fit any known pattern, it might be due to a genetic condition.

When to Use Genetic Testing

• When trying to find a diagnosis for complex diseases, especially in cases of rare diseases
• Identifying a genetic cause often leads to an official diagnosis, which can influence treatments
• Some patients spend much of their lives trying to understand the cause of their condition or how they could have prevented it, finding a true genetic cause can offer relief
• Once the specific genetic cause is identified, genetic counseling becomes easier, helping to determine the risk of passing the disease on to future offspring
• For inherited cancer disorders, testing can help identify family members at increased risk, enabling earlier screening and intervention

When Genetic Testing May Not Be Useful

• If a condition is already diagnosed and there's no treatment that could be altered by knowing the genetic cause, genetic testing wouldn't be helpful
• In the case of adult-onset diseases such as Alzheimer’s or Parkinson’s, genetic testing after the disease has already been diagnosed does not alter the treatment or diagnosis

Ethical Implications of Genetic Testing

• Discovering a genetic predisposition can have a major impact on family members
• This psychological impact should be considered before proceeding with genetic testing.

When Not to Perform Genetic Testing

• Genetic testing should not be performed on individuals under 18 years old unless they already have a disease or the screening could lead to interventions in the short term
• In cases where knowing about a genetic predisposition would not change diagnosis, treatment, or screening protocols (e.g., inherited cancer in adolescents), it is better to delay genetic testing

Differences between Enzyme and Structural Genetic Abnormalities

• Understanding differences between disorders caused by enzyme deficiencies those caused by abnormalities in structural proteins
• Majority of these disorders are inborn errors of metabolism, which refer to genetic conditions where an enzyme defect causes a buildup of harmful substances or a failure to break down substances properly
• Disorders in genetic abnormalities in non-enzyme proteins include structural proteins and tumor suppressor genes
• Inheritance Patterns of Enzyme Disorders
• Most enzyme-related diseases are autosomal recessive, while familial Hypercholesterolemia is autosomal dominant.
• Diseases related to enzymes involved in metabolism are generally autosomal recessive because a single functional enzyme is usually sufficient for normal metabolism.
• Inheritance Patterns of Structural Proteins:
• Structural protein disorders and diseases related to tumor suppressor genes tend to follow an autosomal dominant inheritance pattern
• Autosomal recessive: This indicates a metabolic block causing the buildup of a metabolite, which is typical of autosomal recessive disorders
• Autosomal dominant. This indicated genetic predisposition passed down through the family, as multiple relatives are affected by the same condition
• Haploinsufficiency: The key term haploinsufficiency indicates that having only one functional copy of the gene is insufficient for proper function, leading to dominant inheritance