All questions
Question 1
A 4-year-old boy presents with progressive muscle weakness. His mother notes he has difficulty climbing stairs and frequently falls. On examination, he demonstrates a Gower sign, using his hands to push on his legs to stand up. His serum creatine kinase is significantly elevated. His mother reports that her brother is wheelchair-bound with a similar condition, Duchenne muscular dystrophy. The boy's father is healthy.
Based on the family history and clinical presentation, which of the following is the most likely mode of inheritance?
- Autosomal dominant
- Autosomal recessive
- X-linked recessive (correct answer)
- X-linked dominant
Explanation: 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.
Question 2
A 2-year-old boy is evaluated for recurrent pulmonary infections and failure to thrive. A sweat chloride test is markedly elevated, confirming a diagnosis of cystic fibrosis. His parents are both healthy and asymptomatic. They have an older daughter, age 4, who is also healthy. The parents deny any known family history of the disorder, but mention they are from the same small, isolated village.
This patient's condition is most likely inherited in which of the following patterns?
- Autosomal dominant
- Autosomal recessive (correct answer)
- X-linked dominant
- Y-linked
Explanation: 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).
Question 3
A healthy couple seeks preconception counseling. They are both confirmed heterozygous carriers for an autosomal recessive condition. They understand the genetic basis of the disease and are concerned about the health of their future children.
What is the probability that their first child will be phenotypically normal?
- 0%
- 25%
- 50%
- 75% (correct answer)
Explanation: 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%.
Question 4
A 30-year-old woman is diagnosed with an autosomal dominant disorder that has a known penetrance of 70%. Her father is also affected. She and her partner, who is unaffected and has no family history of the disorder, are planning to have a child.
What is the probability that their child will be affected by the disorder?
- 35% (correct answer)
- 50%
- 70%
- 100%
Explanation: 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%.
Question 5
A geneticist sees a family affected by neurofibromatosis type 1, an autosomal dominant condition. The 40-year-old father has numerous café-au-lait macules, axillary freckling, and hundreds of cutaneous neurofibromas. His 15-year-old daughter has several café-au-lait macules and an optic glioma. His 10-year-old son has only mild learning disabilities and Lisch nodules, with very few skin findings. All three individuals have the same pathogenic mutation in the NF1 gene.
Which genetic principle best explains the different clinical presentations among these affected family members?
- Incomplete penetrance
- Variable expressivity (correct answer)
- Locus heterogeneity
- Germline mosaicism
Explanation: 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.
Question 6
A 16-year-old boy is diagnosed with Marfan syndrome due to a mutation in the FBN1 gene. His clinical evaluation reveals a constellation of findings, including tall stature with long limbs (skeletal system), upward dislocation of the lenses (ocular system), and dilation of the aortic root (cardiovascular system).
The phenomenon of a single gene mutation causing a wide range of effects in different organ systems is known as which of the following?
- Epistasis
- Locus heterogeneity
- Pleiotropy (correct answer)
- Variable expressivity
Explanation: 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.
Question 7
A healthy couple with no family history of skeletal disorders has two children, a 4-year-old son and a 2-year-old daughter. Both children are diagnosed with achondroplasia, a condition that is typically inherited in an autosomal dominant pattern. Genetic testing of the parents' somatic cells (from blood samples) fails to detect the causative mutation found in the children.
Which of the following is the most likely explanation for the recurrence of this dominant disorder in the siblings?
- Germline mosaicism in one parent (correct answer)
- Uniparental disomy
- Incomplete penetrance in the parents
- Autosomal recessive inheritance
Explanation: 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.
Question 8
A 26-year-old woman is a known carrier of the mutation for hemophilia A, an X-linked recessive disorder. Her partner is unaffected. They are seeking counseling regarding the risk to their future children.
What is the probability that their next male child will be affected with hemophilia A?
- 0%
- 25%
- 50% (correct answer)
- 100%
Explanation: 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.
Question 9
A 28-year-old woman with phenylketonuria (PKU), an autosomal recessive disorder, is planning a pregnancy. She has been on a strict phenylalanine-restricted diet her entire life and is healthy. Her partner has been tested and is not a carrier for PKU.
What is the probability that their child will have the PKU phenotype?
- 0% (correct answer)
- 25%
- 50%
- 100%
Explanation: 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.
Question 10
A 30-year-old man seeks genetic counseling. His sister was recently diagnosed with Wilson disease, an autosomal recessive disorder of copper metabolism. Their parents are confirmed to be heterozygous carriers. The man is healthy and phenotypically normal.
What is the probability that this man is a heterozygous carrier of the Wilson disease mutation?
- 1/4
- 1/2
- 2/3 (correct answer)
- 1
Explanation: 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.
Question 11
A male infant is born to healthy, unrelated parents of average height. The infant has rhizomelic shortening of the limbs, a large head with frontal bossing, and midface hypoplasia. The findings are characteristic of achondroplasia. There is no family history of this condition on either side. The father is 48 years old.
Which of the following most likely accounts for the infant's condition?
- A de novo mutation in a paternal gamete (correct answer)
- Autosomal recessive inheritance
- Maternal germline mosaicism
- Uniparental disomy
Explanation: 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.
Question 12
A pedigree is analyzed for a family with a rare genetic disorder. The pedigree shows several notable features. First, an affected male has an affected son. Second, the disorder is present in every generation of one branch of the family. Finally, an affected female in this branch has an unaffected father.
Which of the following modes of inheritance is ruled out by the finding that an affected female has an unaffected father?
- Autosomal dominant
- Autosomal recessive
- X-linked recessive
- X-linked dominant (correct answer)
Explanation: 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.
Question 13
A healthy man and woman who are first cousins are planning to start a family. They are concerned about genetic risks. The woman's brother has a rare metabolic disorder that is known to be autosomal recessive. There is no other family history of the condition.
The consanguineous relationship of this couple most significantly increases their risk of having a child with what type of condition?
- Autosomal dominant
- Autosomal recessive (correct answer)
- X-linked dominant
- Trisomy
Explanation: 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.
Question 14
A 40-year-old man is diagnosed with myotonic dystrophy. He has moderate muscle weakness, myotonia, and early cataracts. He recalls that his 65-year-old mother had only mild cataracts later in life and was considered largely asymptomatic. The man's 15-year-old daughter was diagnosed as an infant with a severe, congenital form of the disease, including profound hypotonia and respiratory difficulties.
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?
- Pleiotropy
- Incomplete penetrance
- Anticipation (correct answer)
- Founder effect
Explanation: 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.
Question 15
A genetic counselor is reviewing test results for a large cohort of patients with cystic fibrosis. The report shows that while the ΔF508 mutation is the most common, there are over 2,000 other known mutations within the CFTR gene that can lead to the disease. These different mutations can result in varying levels of disease severity.
The existence of many different disease-causing mutations at a single genetic locus is an example of which of the following?
- Allelic heterogeneity (correct answer)
- Locus heterogeneity
- Variable expressivity
- Incomplete penetrance
Explanation: 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.
Question 16
A couple, both of whom have congenital deafness due to autosomal recessive mutations, have four children together, all of whom have normal hearing. Genetic analysis reveals that the father has a homozygous mutation in the GJB2 gene, while the mother has a homozygous mutation in the MYO7A gene. Both genes are known to cause deafness independently.
The fact that mutations in different genes can cause the same phenotype is an example of which of the following?
- Allelic heterogeneity
- Locus heterogeneity (correct answer)
- Pleiotropy
- Epistasis
Explanation: 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.
Question 17
A geneticist evaluates a family with hypophosphatemic rickets, a condition that causes bone deformities. The pedigree reveals that an affected father has two daughters, both of whom have the condition, and a son, who is unaffected. In the previous generation, an affected mother passed the condition to half of her children, both male and female.
What is the most likely pattern of inheritance for this disorder?
- Autosomal dominant
- Autosomal recessive
- X-linked recessive
- X-linked dominant (correct answer)
Explanation: 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.
Question 18
A 25-year-old man seeks genetic counseling. His father, age 52, and his paternal grandfather both developed progressive chorea and dementia in their 40s, consistent with Huntington disease. The man is concerned about his own risk and that of his future children. His mother and her entire family are unaffected. A review of his family's medical records shows that the condition has been passed from father to son and affects both males and females in every generation on his father's side.
Which of the following is the most likely mode of inheritance for this condition?
- Autosomal dominant (correct answer)
- Autosomal recessive
- X-linked recessive
- Mitochondrial
Explanation: 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.
Question 19
A 22-year-old man is distraught after his 50-year-old mother was diagnosed with Huntington disease, an autosomal dominant neurodegenerative disorder. The disease shows complete penetrance, although the age of onset varies. The young man is currently asymptomatic and wishes to know his risk.
What is the probability that this young man has inherited the gene for Huntington disease?
- 0%
- 25%
- 50% (correct answer)
- 100%
Explanation: 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%.
Question 20
A 40-year-old woman undergoes genetic testing due to a strong family history of early-onset colon cancer. She is found to carry a pathogenic mutation in the MSH2 gene, which causes Lynch syndrome, an autosomal dominant condition. Her mother and two brothers, who carry the same mutation, all developed colon cancer before age 50. However, her 80-year-old maternal grandfather, who was confirmed to carry the same mutation, lived his entire life without developing any associated cancers.
Which of the following genetic concepts best explains the finding in the maternal grandfather?
- Incomplete penetrance (correct answer)
- Pleiotropy
- Allelic heterogeneity
- Anticipation
Explanation: 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.