Question 1: What is the definition of a single-gene disorder?
Answer: Single-gene disorders are genetic conditions caused by mutations in a single gene. They can follow autosomal dominant, autosomal recessive, or X-linked inheritance patterns.
Question 2: Name two examples of autosomal dominant single-gene disorders.
Answer: Examples include Huntington’s disease and Marfan syndrome.
Question 3: What type of inheritance pattern is observed in cystic fibrosis?
Answer: Cystic fibrosis follows an autosomal recessive inheritance pattern.
Question 4: How does a mutation in the FGFR3 gene affect individuals with achondroplasia?
Answer: A mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene causes it to become overactive, leading to reduced bone growth, particularly in the long bones. This results in achondroplasia, a form of dwarfism characterized by short stature, disproportionately short limbs, and normal trunk size. The mutation affects cartilage formation and conversion into bone during development.
Question 5: Explain the genetic cause of Huntington’s disease and its effect on the nervous system.
Answer: Huntington’s disease is caused by a mutation in the HTT gene involving the expansion of CAG trinucleotide repeats. It leads to progressive neurodegeneration, causing movement disorders, cognitive decline, and psychiatric symptoms.
Question 6: What is the role of the HBB gene in sickle cell anemia?
Answer: The HBB gene encodes the beta-globin subunit of hemoglobin. A mutation in this gene causes the production of abnormal hemoglobin (HbS), leading to sickle-shaped red blood cells and impaired oxygen transport. Sickle cell anemia is inherited in an autosomal recessive pattern. Individuals with two copies of the mutated HBB gene (homozygous for the mutation) develop sickle cell anemia. Those with one copy (heterozygous) are carriers and may experience milder symptoms, known as sickle cell trait.
In summary, the HBB gene mutation leads to the production of abnormal hemoglobin S, which underpins the pathophysiology of sickle cell anemia.
Question 7: Describe the difference between homozygous and heterozygous states in the context of autosomal recessive disorders.
Answer: In an autosomal recessive disorder, individuals must have two copies of the mutated gene (homozygous) to express the condition. Heterozygous individuals have one normal and one mutated gene, usually making them carriers without symptoms.
Question 8: What is the significance of the BRCA1 and BRCA2 genes in relation to cancer risk?
Answer: The BRCA1 and BRCA2 genes produce proteins responsible for repairing DNA damage. Mutations in these genes impair DNA repair, leading to genomic instability and an increased risk of cancers, especially breast and ovarian cancer.
- BRCA1: ~55–65% breast cancer risk, ~39–44% ovarian cancer risk. Associated with aggressive, triple-negative breast cancer.
- BRCA2: ~45–55% breast cancer risk, ~11–17% ovarian cancer risk. Linked to other cancers like pancreatic, prostate, and male breast cancer.
These mutations guide screening, preventive measures (e.g., surgery), and targeted therapies.
Question 9: Why do X-linked recessive disorders affect males more severely than females?
Answer: Males have only one X chromosome, so a single mutation in an X-linked gene will result in the disorder. Females have two X chromosomes, so the second, normal copy can often compensate for the mutation.
Question 10: What is a missense mutation, and how can it lead to a single-gene disorder?
Answer: Missense mutation is a type of genetic mutation where a single nucleotide change in a DNA sequence results in the substitution of one amino acid for another in the protein product. This occurs due to an alteration in a codon that specifies a different amino acid.
How it Leads to a Single-Gene Disorder:
- Protein Dysfunction:
- The substituted amino acid can alter the protein’s structure, stability, or function.
- For example, the mutation may disrupt the protein’s active site, binding regions, or folding, rendering it ineffective or harmful.
- Disease Example:
- Sickle Cell Anemia: A missense mutation in the HBB gene changes glutamic acid to valine in the beta-globin protein, leading to hemoglobin S. This causes red blood cells to sickle, resulting in anemia and vascular complications.
- Cystic Fibrosis (in some cases): Missense mutations in the CFTR gene can impair chloride ion transport.
Missense mutations can have varying effects, from mild to severe, depending on the role of the altered amino acid in the protein’s function.
Question 11: What is the key feature of an autosomal dominant inheritance pattern that distinguishes it from an autosomal recessive inheritance pattern?
Answer: In an autosomal dominant inheritance pattern, the condition typically does not skip generations. An affected individual usually has at least one affected parent, and the trait is observed in every generation of a family. In contrast, autosomal recessive inheritance often involves skipping generations, as affected individuals can be born to unaffected parents who are carriers of the mutated gene. This distinction helps to identify the inheritance pattern in a pedigree analysis.
Question 12: What are the key differences between X-linked recessive and X-linked dominant inheritance patterns?
Answer:
- Male-to-male transmission: X-linked recessive disorders cannot be transmitted from father to son because fathers contribute a Y chromosome and not an X chromosome to their sons. This is considered a “golden rule” for determining inheritance patterns. In contrast, X-linked dominant disorders can be passed from an affected father to all of his daughters. This is because a father will always pass his X chromosome to his daughters.
- Skipping generations: X-linked recessive disorders can skip generations because the trait can be passed down through unaffected female carriers. X-linked dominant disorders do not skip generations. If a parent carries the dominant allele, they will always show the trait.
- Number of males affected: X-linked recessive disorders affect more males than females. This is because males only have one X chromosome, so they only need to inherit one copy of the disease-producing allele to be affected. Females, on the other hand, have two X chromosomes, so they need to inherit two copies of the disease-producing allele to be affected. X-linked dominant disorders are seen about twice as often in females as in males because females have two X chromosomes and males only have one.
Examples:
- X-linked recessive: Hemophilia A and B, Duchenne and Becker muscular dystrophy, and Lesch-Nyhan syndrome.
- X-linked dominant: Fragile X syndrome, hypophosphatemic rickets, and Alport syndrome.
Summary: X-linked recessive inheritance:
- Males are more frequently affected because they have only one X chromosome.
- Females are typically carriers and are usually unaffected unless they inherit two copies of the mutated gene.
- Affected males cannot pass the disorder to their sons but will pass the mutated gene to all their daughters, making them carriers.
X-linked dominant inheritance:
- Both males and females can be affected, but females are more frequently affected due to having two X chromosomes.
- Affected males will pass the condition to all their daughters but none of their sons.
- Affected females have a 50% chance of passing the disorder to each child, regardless of sex.
Question 13: How can autosomal dominant inheritance be distinguished from X-linked dominant inheritance patterns?
Answer: The key differences are:
Sex distribution: Autosomal dominant inheritance affects males and females equally, while X-linked dominant inheritance may show a higher frequency in females due to the presence of two X chromosomes.
Male-to-male transmission: Autosomal dominant traits can be transmitted from father to son, while X-linked dominant traits cannot be passed from father to son, as sons inherit their X chromosome from their mother.
Pedigree patterns: In X-linked dominant inheritance, all daughters of an affected male will inherit the condition, while in autosomal dominant inheritance, both sons and daughters have an equal 50% chance of inheriting the disorder from an affected parent.
Key Points:
- In X-linked dominant inheritance, an unaffected mother cannot have an affected son because she does not carry the dominant mutation on either of her X chromosomes. Since males inherit their X chromosome only from their mother, a son would receive her unaffected X chromosome and, therefore, cannot inherit the disorder.
- In autosomal dominant inheritance also, an unaffected mother cannot have an affected child, regardless of sex, because she does not carry the dominant mutation. If she were heterozygous (having one affected and one normal copy of the gene), she would be affected herself in autosomal dominant inheritance, not unaffected. In that case, there would be a 50% chance of passing the affected gene to a child of either sex.
Question 14: If both parents are carriers of an autosomal recessive condition, the possible genetic outcomes for each child are as follows:
Outcomes:
- 25% (1 in 4) chance of being affected by the condition: The child inherits one mutated allele from each parent, resulting in the disorder.
- 50% (1 in 2) chance of being a carrier: The child inherits one mutated allele and one normal allele, making them a carrier without symptoms.
- 25% (1 in 4) chance of being unaffected: The child inherits two normal alleles, meaning they neither have the disorder nor are they a carrier.
Key Assumptions:
- The inheritance of each allele is independent.
- These probabilities apply to each pregnancy and are the same regardless of the number or sex of the children.
Question 15: If both parents carry an X-linked recessive condition, what are the possible genetic outcomes for their children, and how do these outcomes differ based on the sex of the child?
Answer: If both parents are carriers or affected by an X-linked recessive condition, the possible outcomes depend on the sex of the child. Here’s the breakdown:
Case 1: Mother is a carrier (X*X) and father is unaffected (XY)
For each child:
- 50% chance of a daughter being a carrier (X*X).
- 50% chance of a daughter being unaffected (XX).
- 50% chance of a son being affected (X*Y).
- 50% chance of a son being unaffected (XY).
Case 2: Mother is a carrier (X*X) and father is affected (X*Y)
For each child:
- 50% chance of a daughter being affected (X*X*).
- 50% chance of a daughter being a carrier (X*X).
- 50% chance of a son being affected (X*Y).
- 50% chance of a son being unaffected (XY).
Case 3: Mother is affected (X*X*) and father is unaffected (XY)
For each child:
- 100% chance of daughters being carriers (X*X).
- 100% chance of sons being affected (X*Y).
Case 4: Both parents are affected (X*X* and X*Y)
For each child:
- 100% chance of daughters being affected (X*X*).
- 100% chance of sons being affected (X*Y).
Key Assumptions:
- X-linked inheritance involves the X chromosome, with males inheriting their X from the mother and females inheriting an X from each parent.
- The probabilities apply to each pregnancy and are the same regardless of the number of children.
Question 16: How does variable expression influence the clinical presentation of single-gene disorders, and what factors can contribute to this variability?
Answer: Variable expression refers to the differences in severity or symptoms of a single-gene disorder among individuals with the same genetic mutation. Factors contributing to this variability include genetic modifiers, environmental influences, and epigenetic changes. For example, in Marfan syndrome, individuals may experience mild or severe symptoms despite having the same mutation in the FBN1 gene.
