An 8-year-old African American girl is brought to the clinic by her mother for her regular blood exchange. They come in every 2–3 months for the procedure. The child is in good health with no symptoms. Her last trip to the emergency department was 6 months ago due to bone pain. She was treated with morphine and oxygen and a blood transfusion. She takes hydroxyurea and folic acid daily. She has an uncle that also has to get blood exchanges. Today, her heart rate is 90/min, respiratory rate is 17/min, blood pressure is 110/65 mm Hg, and temperature is 37.0°C (98.6°F). She calmly waits for the machine to be set up and catheters inserted into both of her arms. She watches a movie as her blood is slowly replaced with 6 L of red blood cells. Based on this history, which of the following mechanisms most likely explains this patient's condition?
Q82
A 34-year-old man comes to the physician because of blurry vision and fatigue for 2 months. During this period, he has also had occasional bleeding from his gums after brushing his teeth. One month ago, he was diagnosed with deep vein thrombosis after returning from an overseas business meeting. His pulse is 118/min, respirations are 19/min, and blood pressure is 149/91 mm Hg. Pulse oximetry on room air shows an oxygen saturation of 97%. Examination shows bluish discoloration of the lips. The tip of the spleen is palpable 1 cm below the left costal margin. Sensory examination of the hands shows paresthesia. Hemoglobin concentration is 18 g/dL, hematocrit is 65%, leukocytes are 15,000/μL, and platelets are 470,000/μL. His serum erythropoietin concentration is decreased. Activation of which of the following is the most likely underlying cause of this patient's condition?
Q83
A 28-year-old woman, gravida 1, para 0, at 20 weeks' gestation comes to the physician for genetic counseling. Her brother and maternal uncle both have anemia that worsens after taking certain medications. Based on the pedigree shown, what is the probability that her son will be affected by the disease?
Q84
A 10-month-old boy is brought to the physician by his mother for evaluation of abnormal growth and skin abnormalities. His mother has also noticed that his eyes do not fully close when sleeping. He is at the 24th percentile for height, 17th percentile for weight, and 29th percentile for head circumference. Physical examination shows wrinkled skin, prominent veins on the scalp and extremities, and circumoral cyanosis. Genetic testing shows a point mutation in a gene that encodes for a scaffold protein of the inner nuclear membrane. The mutation causes a deformed and unstable nuclear membrane, which leads to premature aging. Which of the following is most likely to be the defective protein?
Q85
An 8-year old boy is brought into clinic for evaluation of possible scoliosis that was newly found on a routine exam at school. On exam, he is also noted to be in the 99th percentile for height and 70th percentile for weight. He appears to have abnormally long extremities as well as an upward lens dislocation on ophthalmologic exam. A mutation leading to a defect in which of the following proteins is the most likely cause of his condition?
Q86
A 48-year-old man presents to a physician with complaints of paresthesia of the lower extremities, which he has had for the last 3 months. He has been frequently fatigued for the past 5 months and also experienced an increased frequency of urination over the last few months. There is no history of a known medical condition or of substance abuse. His physical examination does not reveal any specific abnormality, except that he is obese: his body mass index is 34.6 kg/m2. The patient’s detailed laboratory evaluation reveals a fasting plasma glucose of 160 mg/dL and 2-hour plasma glucose of 270 mg/dL. His physician tells him that his laboratory evaluation suggests a diagnosis of diabetes mellitus type 2. The patient, surprised by this news, asks his physician why he has developed diabetes mellitus even though no one else in his family has ever suffered from it. The physician explains to him that genetic factors play an important role in the development of diabetes mellitus, but that their interactions are complex. Apart from neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY), the development of diabetes mellitus cannot be explained by a single genetic mutation. Which of the following options best explains the genetics of the form of diabetes mellitus from which this man is suffering?
Q87
A 33-year-old man presents to his physician with a 3-year history of gradually worsening tics and difficulty walking. He was last seen by the physician 5 years ago for anxiety, and he has been buying anti-anxiety medications from an internet website without a prescription as he cannot afford to pay for doctor’s visits. Now, the patient notes that his anxiety is somewhat controlled, but motor difficulties are making it difficult for him to work and socialize. Family history is unobtainable as his parents died in an accident when he was an infant. He grew up in foster care and was always a bright child. An MRI of the brain is ordered; it shows prominent atrophy of the caudate nucleus. Repeats of which of the following trinucleotides are most likely responsible for this patient’s disorder?
Q88
An 18-month-old boy is brought in by his parents for a routine check-up. The parents state that the patient still has not had any language development, and they are concerned about developmental delay. Of note, they have also noticed that the patient’s facial features have changed significantly in the last year. The patient also seems to have trouble visually focusing on objects or on the television. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 108/72 mmHg, pulse is 86/min, and respirations are 14/min. Of interest, the patient has not increased much in length or weight in the past 3 months. He is now in the 25th percentile for weight but is in the 90th percentile for head circumference. The patient does not appear to have any gross or fine motor deficiencies. Of note, he has coarse facial features that were not previously noted, including a long face, prominent forehead, and protruding eyes. The patient has corneal clouding bilaterally. At rest, the patient keeps his mouth hanging open. After extensive workup, the patient is found to have 2 mutated copies of the IDUA gene, with no production of the protein iduronidase. Which of the following is the likely mutation found in this disease?
Q89
An 11-month-old boy is brought to the physician by his adoptive mother for the evaluation of seizures and musty-smelling urine. His immunizations are up-to-date. His height and weight are both below the 10th percentile. He is pale and has blue eyes. He cannot pull himself up from a seated position to stand and does not crawl. Which of the following genetic principles best explains the variety of phenotypic traits seen in this patient?
Q90
A 4-year-old boy is brought to the pediatrician by his mother for a routine medical examination. His medical history is relevant for delayed gross motor milestones. The mother is concerned about a growth delay because both of his brothers were twice his size at this age. Physical examination reveals a well-groomed and healthy boy with a prominent forehead and short stature, in addition to shortened upper and lower extremities with a normal vertebral column. The patient’s vitals reveal: temperature 36.5°C (97.6°F); pulse 60/min; and respiratory rate 17/min and a normal intelligence quotient (IQ). A mutation in which of the following genes is the most likely cause underlying the patient’s condition?
Molecular Genetics US Medical PG Practice Questions and MCQs
Question 81: An 8-year-old African American girl is brought to the clinic by her mother for her regular blood exchange. They come in every 2–3 months for the procedure. The child is in good health with no symptoms. Her last trip to the emergency department was 6 months ago due to bone pain. She was treated with morphine and oxygen and a blood transfusion. She takes hydroxyurea and folic acid daily. She has an uncle that also has to get blood exchanges. Today, her heart rate is 90/min, respiratory rate is 17/min, blood pressure is 110/65 mm Hg, and temperature is 37.0°C (98.6°F). She calmly waits for the machine to be set up and catheters inserted into both of her arms. She watches a movie as her blood is slowly replaced with 6 L of red blood cells. Based on this history, which of the following mechanisms most likely explains this patient's condition?
A. Nonsense mutation
B. Amino acid substitution (Correct Answer)
C. Enzyme deficiency
D. Amino acid deletion
E. Trinucleotide repeat
Explanation: ***Amino acid substitution***
- This patient's symptoms (bone pain requiring emergency treatment, need for chronic exchange transfusions, hydroxyurea therapy, African American ethnicity, family history) are characteristic of **sickle cell disease**
- Sickle cell disease is caused by a **single point mutation** (GAG → GTG) in the beta-globin gene, resulting in substitution of **glutamic acid with valine at position 6** of the beta-globin chain
- This amino acid substitution causes hemoglobin to polymerize under low oxygen conditions, leading to **sickling of red blood cells** and vaso-occlusive crises
*Nonsense mutation*
- A nonsense mutation creates a **premature stop codon**, resulting in a **truncated, nonfunctional protein**
- This mechanism causes conditions like **beta-thalassemia major** (some cases), but is not the mechanism of sickle cell disease
- Sickle cell involves a missense mutation (amino acid substitution), not a nonsense mutation
*Enzyme deficiency*
- Enzyme deficiencies such as **glucose-6-phosphate dehydrogenase (G6PD) deficiency** or **pyruvate kinase deficiency** can cause hemolytic anemias
- However, these typically present with episodic hemolysis triggered by oxidative stress, not chronic vaso-occlusive crises requiring regular exchange transfusions
- The mechanism in sickle cell disease is a **structural hemoglobin defect**, not an enzyme deficiency
*Amino acid deletion*
- An amino acid deletion involves **removal of one or more amino acids** from the protein sequence
- This mechanism causes conditions like **cystic fibrosis** (ΔF508 deletion in CFTR protein)
- Sickle cell disease involves **substitution**, not deletion of an amino acid
*Trinucleotide repeat*
- Trinucleotide repeat disorders involve **expansion of a three-nucleotide sequence** within a gene, showing anticipation across generations
- Examples include **Huntington disease (CAG repeats)**, **myotonic dystrophy (CTG repeats)**, and **fragile X syndrome (CGG repeats)**
- These affect neurological or muscular function and are unrelated to hemoglobinopathies
Question 82: A 34-year-old man comes to the physician because of blurry vision and fatigue for 2 months. During this period, he has also had occasional bleeding from his gums after brushing his teeth. One month ago, he was diagnosed with deep vein thrombosis after returning from an overseas business meeting. His pulse is 118/min, respirations are 19/min, and blood pressure is 149/91 mm Hg. Pulse oximetry on room air shows an oxygen saturation of 97%. Examination shows bluish discoloration of the lips. The tip of the spleen is palpable 1 cm below the left costal margin. Sensory examination of the hands shows paresthesia. Hemoglobin concentration is 18 g/dL, hematocrit is 65%, leukocytes are 15,000/μL, and platelets are 470,000/μL. His serum erythropoietin concentration is decreased. Activation of which of the following is the most likely underlying cause of this patient's condition?
A. Serine/threonine kinase
B. Antiapoptotic molecule
C. Nonreceptor tyrosine kinase (Correct Answer)
D. Transcription factor
E. Cytokine receptor
Explanation: ***Nonreceptor tyrosine kinase***
- This patient's symptoms (blurry vision, fatigue, gum bleeding, deep vein thrombosis, splenomegaly, **elevated hemoglobin, hematocrit, leukocytes, and platelets**, and **decreased erythropoietin**) are highly suggestive of **polycythemia vera**.
- Polycythemia vera is a myeloproliferative neoplasm characterized by a mutation in the **JAK2 gene**, which encodes a **nonreceptor tyrosine kinase**. This mutation leads to constitutive activation of the JAK-STAT pathway, resulting in uncontrolled proliferation of myeloid cells independent of growth factors.
*Serine/threonine kinase*
- While serine/threonine kinases are involved in various cellular signaling pathways, their constitutive activation is not the primary underlying cause of polycythemia vera.
- Mutations in serine/threonine kinases are more commonly associated with other conditions, such as certain cancers, but not specifically with the **JAK2 V617F mutation** characteristic of PV.
*Antiapoptotic molecule*
- Activation of antiapoptotic molecules plays a role in the survival of cancer cells, but it is a downstream effect rather than the primary initiating event in polycythemia vera.
- The **JAK2 mutation** leads to increased cell proliferation and reduced apoptosis indirectly by enhancing survival signals.
*Transcription factor*
- Transcription factors regulate gene expression, and their dysregulation can contribute to various diseases, including cancers. However, the direct activation of a transcription factor is not the root cause of polycythemia vera.
- The **JAK-STAT pathway** ultimately affects transcription factors, but the initial genetic defect is in the JAK2 kinase.
*Cytokine receptor*
- Cytokine receptors bind cytokines and initiate signaling cascades, often involving JAK kinases. While cytokine receptor signaling is hyperactive in polycythemia vera, the primary defect is not in the receptor itself but in the downstream **JAK2 kinase**.
- The **JAK2 V617F mutation** causes **cytokine-independent activation** of the signaling pathway, meaning the cells don't need external cytokines to proliferate.
Question 83: A 28-year-old woman, gravida 1, para 0, at 20 weeks' gestation comes to the physician for genetic counseling. Her brother and maternal uncle both have anemia that worsens after taking certain medications. Based on the pedigree shown, what is the probability that her son will be affected by the disease?
A. 12.5%
B. 100%
C. 50%
D. 0%
E. 25% (Correct Answer)
Explanation: ***25%***
- This is an **X-linked recessive** disorder, as evidenced by affected males born to unaffected parents, and the skipping of generations in females. The woman (III-2) is the daughter of a carrier mother (II-1) and an unaffected father (II-2), making her a **carrier** with a 50% probability (X<sup>A</sup>X<sup>a</sup>).
- Since her mother (II-1) is a carrier (as her brother IV-1 is affected and her parents (I-1 and I-2) are unaffected), and her father (II-2) is unaffected, the woman (III-2) has a 50% chance of being a **carrier**. If she is a carrier (X<sup>A</sup>X<sup>a</sup>) and her son inherits her affected X chromosome, he will be affected. The probability of her son being affected is (0.5 probability of her being a carrier) * (0.5 probability of passing on the affected X to her son) = **0.25 or 25%**.
*12.5%*
- This value would arise from an incorrect calculation of the woman's carrier status, or the inheritance pattern.
- It does not account for the direct inheritance from a carrier mother to a son in an X-linked recessive pattern.
*100%*
- This would only be possible if the mother was affected (which she is not, as she is female and not shaded) and passing on the affected X to all sons, or if the father was affected in a condition with male-to-male transmission.
- The woman (III-2) herself is not affected, indicating she is at most a carrier, not homozygous for the affected allele, nor is the disorder dominant.
*50%*
- This would be the probability of the son being affected *if* the woman (III-2) was a confirmed carrier, or if the disorder was autosomal dominant if she was affected.
- This option incorrectly assumes that the woman (III-2) is a *confirmed* carrier, ignoring the 50% probability that she might not have inherited the carrier status from her mother.
*0%*
- If the woman (III-2) were not a carrier, or if the disease was autosomal recessive and her partner was unaffected and not a carrier, then the probability would be 0%.
- Given the pattern of inheritance and her family history (affected brother and maternal uncle), there is a definite risk of her being a carrier and passing it on.
Question 84: A 10-month-old boy is brought to the physician by his mother for evaluation of abnormal growth and skin abnormalities. His mother has also noticed that his eyes do not fully close when sleeping. He is at the 24th percentile for height, 17th percentile for weight, and 29th percentile for head circumference. Physical examination shows wrinkled skin, prominent veins on the scalp and extremities, and circumoral cyanosis. Genetic testing shows a point mutation in a gene that encodes for a scaffold protein of the inner nuclear membrane. The mutation causes a deformed and unstable nuclear membrane, which leads to premature aging. Which of the following is most likely to be the defective protein?
A. Vimentin
B. Lamin (Correct Answer)
C. Plectin
D. Nesprin
E. Desmin
Explanation: ***Lamin***
- The clinical presentation with **accelerated aging** symptoms (wrinkled skin, prominent veins, abnormal growth percentiles, lagophthalmos/difficulty closing eyes) combined with a defect in a **scaffold protein** of the **inner nuclear membrane** is diagnostic of **Hutchinson-Gilford Progeria Syndrome (HGPS)**.
- **Lamins** (specifically Lamin A/C) are intermediate filaments that form the **nuclear lamina**, the primary structural scaffold underlying the inner nuclear membrane, and mutations in the **LMNA gene** cause progeria and other laminopathies.
- The mutation typically produces progerin, an abnormal lamin protein that destabilizes the nuclear envelope leading to premature cellular senescence.
*Vimentin*
- **Vimentin** is an intermediate filament primarily found in **mesenchymal cells** and plays a role in cell shape, integrity, and motility within the **cytoplasm**.
- Defects in vimentin are not associated with disorders of the nuclear membrane or premature aging syndromes.
*Plectin*
- **Plectin** is a **cytoskeletal linker protein** that cross-links intermediate filaments to each other, to microtubules, and to actin filaments, reinforcing cellular stability.
- While important for cellular integrity, plectin is a **cytoplasmic protein**, not a component of the inner nuclear membrane scaffold.
*Nesprin*
- **Nesprins** (Nuclear Envelope Spectrin-repeat Proteins) are components of the **Linker of Nucleoskeleton and Cytoskeleton (LINC) complex**, bridging the nuclear lamina to the cytoskeleton at the **outer nuclear membrane**.
- While nesprins interact with the nuclear envelope, they are not the primary scaffold protein of the **inner nuclear membrane** itself (that role belongs to lamins), and mutations in nesprins are associated with muscular dystrophies, not progeria.
*Desmin*
- **Desmin** is an intermediate filament found predominantly in **muscle cells** (cardiac, skeletal, and smooth muscle), forming a scaffold that connects myofibrils to each other and to the sarcolemma.
- Mutations in desmin are associated with **myopathies** and **cardiomyopathies**, not with defects in the inner nuclear membrane or premature aging.
Question 85: An 8-year old boy is brought into clinic for evaluation of possible scoliosis that was newly found on a routine exam at school. On exam, he is also noted to be in the 99th percentile for height and 70th percentile for weight. He appears to have abnormally long extremities as well as an upward lens dislocation on ophthalmologic exam. A mutation leading to a defect in which of the following proteins is the most likely cause of his condition?
A. Type IV collagen
B. Type I collagen
C. Elastin
D. Fibrillin (Correct Answer)
E. ATP7A
Explanation: ***Fibrillin***
- The patient's clinical features, including **scoliosis**, being in the **99th percentile for height**, having **abnormally long extremities** (arachnodactyly), and **upward lens dislocation**, are classic signs of **Marfan syndrome**.
- **Marfan syndrome** is an autosomal dominant disorder caused by a mutation in the *FBN1* gene, which codes for **fibrillin-1**, a glycoprotein essential for the formation of elastic fibers in connective tissue.
*Type I collagen*
- Defects in **Type I collagen** are primarily associated with **osteogenesis imperfecta**, characterized by **bone fragility**, multiple fractures, blue sclera, and hearing loss.
- While it can present with skeletal abnormalities, it does not typically cause the extreme height, arachnodactyly, or lens dislocation seen in this patient.
*Type IV collagen*
- Defects in **Type IV collagen** are linked to conditions like **Alport syndrome**, which primarily affects the kidneys (glomerulonephritis), ears (hearing loss), and eyes (ocular defects including lenticonus), but not typically the skeletal features described.
- It is a major component of **basement membranes**, important for filtration and structural support in various organs.
*Elastin*
- Mutations in **elastin** are associated with conditions like **supravalvular aortic stenosis** (Williams syndrome) or cutis laxa, which affect the skin and cardiovascular system.
- It does not explain the characteristic skeletal and ocular findings of Marfan syndrome.
*ATP7A*
- A mutation in the *ATP7A* gene, which codes for an ATPase involved in copper transport, is responsible for **Menkes disease**.
- **Menkes disease** is characterized by **sparse, kinky hair**, failure to thrive, neurological degeneration, and connective tissue abnormalities due to copper deficiency, which does not align with the patient's presentation.
Question 86: A 48-year-old man presents to a physician with complaints of paresthesia of the lower extremities, which he has had for the last 3 months. He has been frequently fatigued for the past 5 months and also experienced an increased frequency of urination over the last few months. There is no history of a known medical condition or of substance abuse. His physical examination does not reveal any specific abnormality, except that he is obese: his body mass index is 34.6 kg/m2. The patient’s detailed laboratory evaluation reveals a fasting plasma glucose of 160 mg/dL and 2-hour plasma glucose of 270 mg/dL. His physician tells him that his laboratory evaluation suggests a diagnosis of diabetes mellitus type 2. The patient, surprised by this news, asks his physician why he has developed diabetes mellitus even though no one else in his family has ever suffered from it. The physician explains to him that genetic factors play an important role in the development of diabetes mellitus, but that their interactions are complex. Apart from neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY), the development of diabetes mellitus cannot be explained by a single genetic mutation. Which of the following options best explains the genetics of the form of diabetes mellitus from which this man is suffering?
A. Synergistic epistasis
B. Anticipation
C. Natural selection
D. Genomic imprinting
E. Polygenic inheritance (Correct Answer)
Explanation: ***Polygenic inheritance***
- **Type 2 diabetes mellitus** is a classic example of a **polygenic disorder**, where multiple genes interact with environmental factors (like obesity) to increase disease risk.
- The physician's statement that "the development of diabetes mellitus cannot be explained by a single genetic mutation" directly supports a polygenic model.
*Synergistic epistasis*
- This describes a specific type of **gene interaction** where the combined effect of two or more genes is greater than the sum of their individual effects. While epistasis can contribute to complex diseases, it's a specific mechanism within polygenic inheritance, not the overarching genetic mechanism for the described condition.
- The question asks for the best explanation of the *genetics* of the condition (T2DM), and polygenic inheritance provides a broader, more accurate classification for multifactorial diseases.
*Anticipation*
- This phenomenon is observed in certain genetic disorders where the disease onset occurs earlier and/or symptoms become more severe in successive generations.
- **Anticipation** is typically seen in disorders caused by expansion of trinucleotide repeats (e.g., Huntington's disease, myotonic dystrophy), which is not characteristic of Type 2 Diabetes Mellitus.
*Natural selection*
- **Natural selection** is an evolutionary process by which organisms that are better adapted to their environment tend to survive and produce more offspring.
- While evolutionary pressures can influence genetic predispositions to diseases, natural selection is a mechanism of evolution over populations and generations, not the direct genetic inheritance pattern for a disorder in an individual.
*Genomic imprinting*
- This is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin-specific manner, meaning only the allele inherited from either the mother or the father is expressed.
- Conditions like **Prader-Willi** and **Angelman syndromes** are examples of imprinting disorders; it does not explain the inheritance pattern of Type 2 Diabetes Mellitus.
Question 87: A 33-year-old man presents to his physician with a 3-year history of gradually worsening tics and difficulty walking. He was last seen by the physician 5 years ago for anxiety, and he has been buying anti-anxiety medications from an internet website without a prescription as he cannot afford to pay for doctor’s visits. Now, the patient notes that his anxiety is somewhat controlled, but motor difficulties are making it difficult for him to work and socialize. Family history is unobtainable as his parents died in an accident when he was an infant. He grew up in foster care and was always a bright child. An MRI of the brain is ordered; it shows prominent atrophy of the caudate nucleus. Repeats of which of the following trinucleotides are most likely responsible for this patient’s disorder?
A. CCG
B. CTG
C. CGG
D. CAG (Correct Answer)
E. GAA
Explanation: ***CAG***
- The clinical presentation of **worsening tics**, **difficulty walking** (suggesting motor dysfunction), and the MRI finding of **caudate nucleus atrophy** are classic signs of **Huntington's disease**.
- **Huntington's disease** is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of **CAG trinucleotide repeats** within the *HTT* gene.
*CCG*
- Expansions of **CCG repeats** are associated with conditions like **fragile X-associated tremor/ataxia syndrome (FXTAS)**.
- While FXTAS involves neurological symptoms, the specific presentation of prominent tics and caudate atrophy points more strongly to Huntington's.
*CTG*
- **CTG trinucleotide repeat** expansions are characteristic of **myotonic dystrophy type 1 (DM1)**.
- Myotonic dystrophy primarily manifests with muscle weakness, myotonia, and cataracts, which are not the primary presenting symptoms here.
*CGG*
- Expansions of **CGG repeats** are the genetic basis of **Fragile X syndrome**, the most common inherited cause of intellectual disability.
- While Fragile X syndrome can have neurological features, it typically presents with developmental delay and distinctive physical features, rather than adult-onset tics and caudate atrophy.
*GAA*
- An expansion of **GAA trinucleotide repeats** is responsible for **Friedreich's ataxia**.
- Friedreich's ataxia is characterized by progressive ataxia, dysarthria, and loss of proprioception, which differ from the motor tics and specific caudate atrophy seen in this patient.
Question 88: An 18-month-old boy is brought in by his parents for a routine check-up. The parents state that the patient still has not had any language development, and they are concerned about developmental delay. Of note, they have also noticed that the patient’s facial features have changed significantly in the last year. The patient also seems to have trouble visually focusing on objects or on the television. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 108/72 mmHg, pulse is 86/min, and respirations are 14/min. Of interest, the patient has not increased much in length or weight in the past 3 months. He is now in the 25th percentile for weight but is in the 90th percentile for head circumference. The patient does not appear to have any gross or fine motor deficiencies. Of note, he has coarse facial features that were not previously noted, including a long face, prominent forehead, and protruding eyes. The patient has corneal clouding bilaterally. At rest, the patient keeps his mouth hanging open. After extensive workup, the patient is found to have 2 mutated copies of the IDUA gene, with no production of the protein iduronidase. Which of the following is the likely mutation found in this disease?
A. Interstitial deletion
B. Silent mutation
C. Missense mutation
D. Chromosomal translocation
E. Nonsense mutation (Correct Answer)
Explanation: ***Nonsense mutation***
- A **nonsense mutation** leads to the formation of a **premature stop codon**, resulting in a truncated, non-functional protein, which aligns with the total absence of iduronidase.
- This type of mutation can severely impair protein function, leading to the severe phenotype described with **Hurler syndrome**, which is caused by a complete lack of **alpha-L-iduronidase** activity due to mutations in the *IDUA* gene.
*Interstitial deletion*
- An **interstitial deletion** involves the loss of a segment of a chromosome; while it can cause genetic disorders, it typically results in the **complete absence of a gene** or multiple genes, not specific protein truncation from a gene sequence.
- Though a deletion in the *IDUA* gene could cause Hurler syndrome, the specific finding of **no production of the protein iduronidase** suggests a point mutation affecting protein synthesis rather than a large chromosomal deletion.
*Silent mutation*
- A **silent mutation** is a change in a single nucleotide that does not alter the **amino acid sequence** of the protein due to the redundancy of the genetic code.
- This type of mutation would **not cause any change** in protein function or expression, as seen in this patient with complete absence of iduronidase.
*Missense mutation*
- A **missense mutation** involves a change in a single nucleotide that results in a **different amino acid** being incorporated into the protein.
- While a missense mutation can impair protein function, it typically results in a **partially functional** or altered protein, not the complete absence of protein product as described.
*Chromosomal translocation*
- A **chromosomal translocation** involves the rearrangement of parts between non-homologous chromosomes.
- While translocations can lead to genetic disorders by disrupting gene function or dosage, they are less likely to cause a **complete absence of a specific enzyme** unless the translocation directly disrupts the gene's coding region or regulatory elements in a way that prevents any transcription or translation.
Question 89: An 11-month-old boy is brought to the physician by his adoptive mother for the evaluation of seizures and musty-smelling urine. His immunizations are up-to-date. His height and weight are both below the 10th percentile. He is pale and has blue eyes. He cannot pull himself up from a seated position to stand and does not crawl. Which of the following genetic principles best explains the variety of phenotypic traits seen in this patient?
A. Incomplete penetrance
B. Variable expressivity
C. Anticipation
D. Pleiotropy (Correct Answer)
E. Loss of heterozygosity
Explanation: ***Pleiotropy***
- **Pleiotropy** refers to a single gene affecting multiple, seemingly unrelated phenotypic traits, which is the hallmark of **phenylketonuria (PKU)**
- In this patient, a single genetic defect in the **phenylalanine hydroxylase enzyme** leads to: seizures, developmental delay, growth retardation, fair skin/blue eyes (hypopigmentation), and musty-smelling urine (phenylacetic acid)
- This demonstrates how one mutated gene can have widespread effects across multiple organ systems
*Incomplete penetrance*
- **Incomplete penetrance** describes when individuals with a disease-causing genotype do not always express the associated phenotype
- This patient clearly *expresses* the phenotype with multiple manifestations, making incomplete penetrance incorrect
- PKU shows complete penetrance - all untreated homozygotes develop the condition
*Variable expressivity*
- **Variable expressivity** refers to different degrees of severity of the *same* phenotypic feature among individuals with the same genotype
- While PKU can show variable expressivity in symptom *severity*, this concept does not explain the existence of multiple *distinct, unrelated* symptoms from a single gene defect
- The question specifically asks about the *variety* of different traits, not severity variation
*Anticipation*
- **Anticipation** is a phenomenon where genetic disorders become more severe and/or have earlier onset in successive generations
- This occurs primarily in trinucleotide repeat expansion disorders (e.g., Huntington's disease, myotonic dystrophy, fragile X syndrome)
- PKU is an autosomal recessive enzyme deficiency without trinucleotide repeats and does not demonstrate anticipation
*Loss of heterozygosity*
- **Loss of heterozygosity (LOH)** occurs when a heterozygous individual loses the functional copy of a gene in somatic cells, typically affecting tumor suppressor genes
- LOH is a mechanism in cancer development (e.g., retinoblastoma, Li-Fraumeni syndrome), not metabolic disorders
- PKU is a germline autosomal recessive condition requiring two mutated alleles from birth, not a somatic mutation event
Question 90: A 4-year-old boy is brought to the pediatrician by his mother for a routine medical examination. His medical history is relevant for delayed gross motor milestones. The mother is concerned about a growth delay because both of his brothers were twice his size at this age. Physical examination reveals a well-groomed and healthy boy with a prominent forehead and short stature, in addition to shortened upper and lower extremities with a normal vertebral column. The patient’s vitals reveal: temperature 36.5°C (97.6°F); pulse 60/min; and respiratory rate 17/min and a normal intelligence quotient (IQ). A mutation in which of the following genes is the most likely cause underlying the patient’s condition?
A. Runt-related transcription factor 2
B. Alpha-1 type I collagen
C. Fibroblast growth factor receptor 3 (Correct Answer)
D. Insulin-like growth factor 1 receptor
E. Fibrillin-1
Explanation: ***Fibroblast growth factor receptor 3***
- The constellation of **short stature**, prominent forehead, and **shortened upper and lower extremities** with a normal vertebral column in a child with normal intelligence is characteristic of **achondroplasia**.
- Achondroplasia is caused by a gain-of-function mutation in the **fibroblast growth factor receptor 3 (FGFR3)** gene, which inhibits chondrocyte proliferation and differentiation, leading to impaired endochondral ossification.
*Runt-related transcription factor 2*
- Mutations in **Runt-related transcription factor 2 (RUNX2)** are associated with **cleidocranial dysplasia**, a condition characterized by absent or hypoplastic clavicles, delayed closure of fontanelles, and dental abnormalities, which are not described in this patient.
- While it affects bone development, the specific features of achondroplasia, such as rhizomelic dwarfism and a prominent forehead, are not typical of RUNX2 mutations.
*Alpha-1 type I collagen*
- Mutations in **collagen genes**, particularly type I collagen (COL1A1, COL1A2), are linked to **osteogenesis imperfecta**, characterized by **fragile bones**, blue sclera, and hearing loss.
- The patient's presentation does not include these features, and the primary issue is disproportionate short stature due to impaired cartilage growth, not bone fragility.
*Insulin-like growth factor 1 receptor*
- Mutations in the **insulin-like growth factor 1 receptor (IGF1R)** can lead to **pre- and postnatal growth retardation** and microcephaly, often associated with developmental delay and feeding difficulties.
- While IGF1R mutations cause short stature, the specific skeletal dysmorphology (e.g., prominent forehead, shortened limbs) and normal intelligence are much more suggestive of achondroplasia.
*Fibrillin-1*
- Mutations in **fibrillin-1** are responsible for **Marfan syndrome**, which typically presents with **tall stature**, long limbs (dolichostenomelia), joint hypermobility, and cardiovascular abnormalities such as aortic root dilation.
- The patient's short stature and shortened limbs directly contradict the clinical picture of Marfan syndrome.
