- Which of the following most likely accounts for the infant's condition?
Answer: A de novo mutation in a paternal gamete
Achondroplasia is an autosomal dominant disorder. In approximately 80% of cases, it arises from a new (de novo) mutation in a child of unaffected parents. These spontaneous mutations are strongly associated with advanced paternal age, as is seen in this case. Autosomal recessive inheritance is incorrect as the disease is dominant. While germline mosaicism is possible, a single de novo mutation is the most common explanation for a sporadic case.
- The fact that mutations in different genes can cause the same phenotype is an example of which of the following?
Answer: Locus heterogeneity
Locus heterogeneity describes a situation where mutations at two or more different genetic loci can produce the same or similar phenotypes. In this case, both the GJB2 and MYO7A genes can cause deafness. The children have normal hearing because they are heterozygous at both loci, inheriting one normal and one mutant allele for each gene from their parents. This phenomenon, where the normal phenotype is restored, is called complementation, and it is possible because of locus heterogeneity.
- What is the most likely pattern of inheritance for this disorder?
Answer: X-linked dominant
The key finding that points to X-linked dominant (XLD) inheritance is that the affected father transmits the disease to all of his daughters and none of his sons. This is because daughters inherit their father's only X chromosome, while sons inherit his Y chromosome. While it can resemble autosomal dominant inheritance in some ways (e.g., affecting both sexes, not skipping generations), this specific parent-offspring transmission pattern is unique to XLD.
- Which of the following is the most likely explanation for the recurrence of this dominant disorder in the siblings?
Answer: Germline mosaicism in one parent
Germline mosaicism occurs when a mutation arises in a precursor germ cell of one parent. This parent is phenotypically normal because the mutation is not in their somatic cells, but a proportion of their gametes (sperm or eggs) carries the mutation. This explains how unaffected parents can have multiple children with a new autosomal dominant disorder. A single de novo mutation is less likely to explain two affected children. Incomplete penetrance would imply the parents have the gene but are asymptomatic, which is contradicted by the negative genetic test on their somatic cells.
- This patient's condition is most likely inherited in which of the following patterns?
Answer: Autosomal recessive
Cystic fibrosis is a classic example of an autosomal recessive (AR) disorder. The key features in the vignette are that the parents are unaffected but have an affected child, indicating that the condition skips a generation. This pattern occurs when both parents are heterozygous carriers. AR disorders affect males and females with equal frequency. The parents being from the same village increases the likelihood they share a common ancestor and thus carry the same recessive allele (consanguinity).
- What is the probability that this young man has inherited the gene for Huntington disease?
Answer: 50%
Huntington disease is an autosomal dominant condition. An affected individual has a 50% chance of passing the causative allele to each of their children, regardless of the child's sex. The son's current asymptomatic status does not alter his baseline Mendelian risk of having inherited the gene from his affected mother. Therefore, his a priori risk is 50%.
- What is the probability that their next male child will be affected with hemophilia A?
Answer: 50%
The question specifically asks for the probability that a male child will be affected. A male child inherits his X chromosome from his mother and his Y chromosome from his father. Since the mother is a carrier (X'X), she has one normal X and one affected X' chromosome. There is a 50% chance she will pass on the affected X' chromosome to her son. Therefore, the probability that any given son will have hemophilia A is 50%. The 25% probability would apply to the risk for any child (male or female) to be an affected male.
- The phenomenon of a single gene mutation causing a wide range of effects in different organ systems is known as which of the following?
Answer: Pleiotropy
Pleiotropy is the genetic principle where a single gene influences multiple, often seemingly unrelated, phenotypic traits. In Marfan syndrome, the defective fibrillin-1 protein affects connective tissue throughout the body, leading to the diverse skeletal, ocular, and cardiovascular manifestations described. Variable expressivity refers to differences in the severity of a phenotype, whereas pleiotropy refers to the variety of different phenotypes.
- Based on the family history and clinical presentation, which of the following is the most likely mode of inheritance?
Answer: X-linked recessive
Duchenne muscular dystrophy is an X-linked recessive disorder. The pedigree pattern described is characteristic: the disorder affects males almost exclusively and is transmitted through unaffected female carriers (the mother). The presence of an affected maternal uncle is a strong clue. There is no male-to-male transmission, as fathers pass their Y chromosome to their sons.
- What is the probability that this man is a heterozygous carrier of the Wilson disease mutation?
Answer: 2/3
The man's parents are both heterozygous carriers (Ww). The possible genotypes of their offspring are WW, Ww, wW, and ww. Since the man is phenotypically normal, he cannot have the 'ww' genotype (which corresponds to the disease). Therefore, we must consider only the three possible non-affected genotypes: WW (homozygous normal), Ww (carrier), and wW (carrier). Among these three possibilities, two result in him being a carrier. Thus, his probability of being a carrier is 2/3.
- What is the probability that their child will have the PKU phenotype?
Answer: 0%
The woman is affected with an autosomal recessive disorder, so her genotype is homozygous recessive (aa). Her partner is not a carrier, so his genotype is homozygous dominant (AA). All of their offspring will have the genotype Aa, making them obligate heterozygous carriers. Since PKU is a recessive disorder, heterozygous individuals are phenotypically normal. Therefore, there is a 0% chance their child will have the PKU phenotype. Note: The child could be affected by maternal PKU syndrome if the mother's diet is not controlled during pregnancy, but the child's genotype will not cause the disease.
- Which of the following genetic concepts best explains the finding in the maternal grandfather?
Answer: Incomplete penetrance
Incomplete penetrance is the term used when an individual has a disease-causing genotype but does not develop the disease phenotype. The grandfather has the pathogenic MSH2 mutation but did not develop cancer, demonstrating incomplete penetrance. This is common in hereditary cancer syndromes. Pleiotropy refers to a single gene affecting multiple organ systems. Allelic heterogeneity refers to different mutations at the same locus causing the same disease. Anticipation is when a disease becomes more severe in successive generations.
- Which of the following is the most likely mode of inheritance for this condition?
Answer: Autosomal dominant
The pedigree described is classic for autosomal dominant (AD) inheritance. Key features include the disease appearing in every generation (no skipping), affected individuals transmitting the trait to about half their children, and the presence of male-to-male transmission (father to son), which rules out X-linked inheritance. Both males and females are affected, which is also consistent with AD inheritance. Mitochondrial inheritance is passed from a mother to all offspring, which is not the case here.
- What is the probability that their first child will be phenotypically normal?
Answer: 75%
When two heterozygous carriers (e.g., Aa) for an autosomal recessive condition have a child, the possible genotypes for the offspring are AA, Aa, aA, and aa, each with a 25% probability. The child will be affected only with the genotype 'aa' (25% chance). The child will be phenotypically normal with genotypes 'AA' (homozygous normal) or 'Aa'/'aA' (heterozygous carrier). The total probability of being phenotypically normal is the sum of these possibilities: 25% (AA) + 50% (Aa/aA) = 75%.
- The existence of many different disease-causing mutations at a single genetic locus is an example of which of the following?
Answer: Allelic heterogeneity
Allelic heterogeneity is the phenomenon where different mutations (alleles) at the same gene locus can cause the same disease. This is a key feature of many genetic disorders, including cystic fibrosis (CFTR), beta-thalassemia (HBB), and phenylketonuria (PAH). This is distinct from locus heterogeneity, where mutations in different genes cause the same disease.
- Which of the following modes of inheritance is ruled out by the finding that an affected female has an unaffected father?
Answer: X-linked dominant
In X-linked dominant inheritance, an affected male passes his only X chromosome to all of his daughters. Therefore, all daughters of an affected male must be affected. The observation that an affected female has an unaffected father definitively rules out X-linked dominant inheritance. The male-to-male transmission already ruled out X-linked recessive inheritance. The overall pattern is consistent with autosomal dominant inheritance.
- The observation of increasing disease severity and earlier age of onset in successive generations of this family is best described by which of the following terms?
Answer: Anticipation
Anticipation is a genetic phenomenon where the signs and symptoms of a genetic condition become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next. This is a classic feature of trinucleotide repeat expansion disorders, such as myotonic dystrophy, Huntington disease, and fragile X syndrome. The expansion of the repeat from one generation to the next underlies the worsening phenotype.
- What is the probability that their child will be affected by the disorder?
Answer: 35%
This problem requires two steps. First, determine the probability that the child inherits the disease-causing allele. Since the mother is affected by an autosomal dominant disorder, there is a 50% (0.5) chance she will pass the allele to her child. Second, account for the incomplete penetrance. If the child inherits the allele, there is a 70% (0.7) chance they will express the phenotype. The overall probability is the product of these two probabilities: 0.5 * 0.7 = 0.35, or 35%.
- Which genetic principle best explains the different clinical presentations among these affected family members?
Answer: Variable expressivity
Variable expressivity describes the phenomenon where individuals with the same genotype exhibit different phenotypes in terms of severity or combination of symptoms. In this family, all three affected members have the genotype for neurofibromatosis type 1, but the type and severity of their symptoms vary widely. Incomplete penetrance would mean an individual with the genotype shows no signs of the disease at all. Locus heterogeneity means mutations in different genes cause the same disease. Germline mosaicism explains how unaffected parents can have an affected child with a dominant disorder.
- The consanguineous relationship of this couple most significantly increases their risk of having a child with what type of condition?
Answer: Autosomal recessive
Consanguinity, or mating between related individuals, increases the likelihood that both partners carry the same rare recessive alleles inherited from a common ancestor. This significantly elevates the risk for their offspring to be affected by an autosomal recessive disorder compared to the general population. The risk for autosomal dominant disorders (which usually require an affected parent), X-linked disorders, or chromosomal abnormalities like trisomies is not directly increased by consanguinity.
