Genetics and Disease Practice Questions

Q: A 25-year-old man presents for a routine physical examination. The patient is tall (6 ft. 5 in) and on examination he was found to have an early diastolic murmur. His family pedigree is as given below. Which of the following is the mode of inheritance by which the disease is likely to be transmitted?

Autosomal dominant. ***Autosomal dominant*** - The pedigree shows **affected individuals in every generation**, and transmission from an affected parent to approximately half of their children, which is characteristic of **autosomal dominant inheritance**. - The disease affects both males and females, and **affected fathers transmit the disease to both sons and daughters** (e.g., I-1 to II-1 and II-5), ruling out X-linked inheritance. *X linked dominant disorder* - This pattern would show affected fathers transmitting the trait to **all their daughters but no sons**, which is not seen here (e.g., father I-1 has an affected son II-1). - Also, affected mothers would transmit to half their sons and daughters, but the key discriminatory factor is the father-to-son transmission. *X-linked recessive* - X-linked recessive traits usually show **more males affected than females**, and affected sons are typically born to carrier mothers. - An affected father would **not transmit the disease to his sons**, but the pedigree clearly shows affected father I-1 transmitting to son II-1. *Autosomal recessive* - Autosomal recessive disorders typically **skip generations**, with affected individuals often born to unaffected carriers. - The pedigree shows **direct transmission** from affected parents to offspring in every generation, which is inconsistent with recessive inheritance.

Q: A patient with hemochromatosis experiences joint pain and fatigue. Which genetic test would confirm the diagnosis?

HFE gene mutation test. ***HFE gene mutation test*** - **Hemochromatosis** is an iron overload disorder, and the most common hereditary form is caused by mutations in the **HFE gene**. - A positive **HFE gene mutation test**, particularly for C282Y and H63D mutations, is diagnostic for hereditary hemochromatosis in patients with compatible clinical findings [1]. *BRCA1 gene test* - The **BRCA1 gene test** is used to identify mutations associated with an increased risk of developing **breast cancer** and **ovarian cancer**, not hemochromatosis [2]. - This gene is a **tumor suppressor gene** involved in DNA repair [2]. *Lynch syndrome genetic test* - **Lynch syndrome genetic testing** identifies mutations in mismatch repair genes (like MLH1, MSH2, MSH6, PMS2) that predispose individuals to various cancers, particularly **colorectal cancer** and **endometrial cancer**. - It is not related to iron metabolism or hemochromatosis. *MLH1 gene test* - The **MLH1 gene test** is a specific component of **Lynch syndrome genetic testing**, looking for mutations in the **MLH1 gene**, which is a DNA mismatch repair gene. - Mutations in MLH1 are linked to increased cancer risk, not the iron overload seen in hemochromatosis.

Q: A 35-year-old woman presents with hepatomegaly and arthritis. Laboratory results show high serum ferritin and transferrin saturation. Which genetic defect is likely?

Hemochromatosis. ***Hemochromatosis*** - **Hepatomegaly** and **arthritis** are classic clinical manifestations of hemochromatosis, caused by **excessive iron deposition** in various organs. - **High serum ferritin** (reflecting total body iron stores) and **high transferrin saturation** (indicating increased iron absorption) are key laboratory findings for diagnosing hemochromatosis, which is predominantly caused by genetic defects in the **HFE gene** [1]. *Wilson's disease* - Characterized by impaired copper metabolism, leading to **copper accumulation** in the liver, brain, and other organs [2]. - Laboratory findings typically include **low serum ceruloplasmin** and high urinary copper excretion, rather than high ferritin and transferrin saturation [2]. *α1-antitrypsin deficiency* - This genetic disorder primarily affects the lungs (leading to **emphysema**) and liver (causing **cirrhosis** or **hepatitis**) due to a deficiency of protective α1-antitrypsin. - It would not explain the high serum ferritin or transferrin saturation, nor is arthritis a common primary symptom. *Gaucher disease* - A lysosomal storage disorder resulting from a deficiency of the **glucocerebrosidase enzyme**, leading to accumulation of **glucocerebroside** in macrophages. - Clinically presents with **hepatosplenomegaly**, bone pain, and cytopenias, but not typically with high ferritin or transferrin saturation, nor inflammatory arthritis as a primary feature.

Q: Which genetic syndrome is associated with hundreds of colorectal polyps and almost certain progression to colorectal cancer if left untreated?

Familial adenomatous polyposis. ***Familial adenomatous polyposis*** - Characterized by the presence of **hundreds to thousands of colorectal polyps** [1], which invariably progress to **colorectal cancer** if untreated [1]. - Caused by mutations in the **APC gene** [1] and requires regular surveillance and early intervention. *Peutz-Jeghers syndrome* - Presents with **hamartomatous polyps** [1] and associated mucocutaneous pigmentations, but the polyp burden is typically much less than in familial adenomatous polyposis. - Although there is a **cancer risk** [1], it does not have the same near-certain progression to colorectal cancer as familial adenomatous polyposis. *Juvenile polyposis syndrome* - Involves multiple **juvenile polyps** [1], mostly in childhood, but they have a lower risk of cancer compared to familial adenomatous polyposis. - The associated cancer risk is not as high [1], with polyp formation typically seen as **benign**. *Lynch syndrome* - A hereditary condition associated with **non-polyposis colorectal cancer** [2] and endometrial cancer, but does not lead to numerous polyps. - Caused by mutations in **mismatch repair genes** [2] and includes a different cancer risk profile than familial adenomatous polyposis.

Q: A 25-year-old with Gaucher disease type 1 and a GBA mutation, exhibiting significant residual β-glucocerebrosidase activity, what is the best initial treatment?

SRT with eliglustat. **SRT with eliglustat** - *Eliglustat* is a **substrate reduction therapy (SRT)** that inhibits glucosylceramide synthase, reducing the production of glucocerebroside. - It is particularly effective for patients with **Gaucher disease type 1 (GD1)** who have certain *GBA mutations* and **residual β-glucocerebrosidase activity**, as indicated in the patient scenario. *ERT with imiglucerase* - **Enzyme replacement therapy (ERT)** using *imiglucerase* replaces the deficient enzyme, β-glucocerebrosidase. - While effective for GD1, *SRT* is often preferred as a first-line oral treatment for patients with an eligible genotype and **residual enzyme activity**, avoiding intravenous infusions. *Chaperone tx with miglustat* - *Miglustat* is another *SRT*, but it is typically used for patients with **Gaucher disease type 1** who cannot receive *ERT* or as an adjunct. - It has a less favorable side effect profile, including *gastrointestinal disturbances* and *peripheral neuropathy*, compared to *eliglustat*. *BMT* - **Bone marrow transplantation (BMT)** is a curative, but highly invasive and risky, treatment option for Gaucher disease. - It is generally reserved for severe cases, especially those with **neuropathic forms (type 2 or 3)**, or in patients unresponsive to other therapies, given its significant *morbidity and mortality risks*.

Q: Which of the following is NOT a feature of Abetalipoproteinemia?

Elevated plasma apolipoprotein B levels. Elevated plasma apolipoprotein B levels - **Abetalipoproteinemia** is characterized by the **absence** or extremely **low levels** of apolipoprotein B due to a defect in microsomal triglyceride transfer protein (MTP). - This genetic disorder prevents the assembly and secretion of **chylomicrons**, **VLDL**, and **LDL**, all of which contain apolipoprotein B. *Plasma levels of cholesterol and triglyceride are extremely low* - This is a direct consequence of the inability to form and secrete lipoproteins such as **chylomicrons** (transport dietary triglycerides) and **VLDL/LDL** (transport endogenous lipids and cholesterol). - The lack of these lipoproteins results in **malabsorption of fats** and fat-soluble vitamins, contributing to the low plasma lipid levels. *Manifest in early childhood with diarrhea* - **Fat malabsorption** due to the absence of chylomicrons leads to **steatorrhea** (fatty stools), which is often observed as chronic diarrhea in infancy. - Failure to thrive and abdominal distension are also common early GI symptoms. *Progressive pigmented retinopathy seen* - This is a neurological and ocular manifestation resulting from severe **deficiency of fat-soluble vitamins**, particularly **vitamin A and E** [1]. - **Vitamin A deficiency** contributes to poor vision and **retinopathy**, while **vitamin E deficiency** leads to progressive neurological symptoms like ataxia and peripheral neuropathy [1].

Q: Following genetic counselling in a family for Familial polyposis coli (FPC), what is the next appropriate screening test for at-risk individuals?

Colonoscopy. Colonoscopy - **Colonoscopy** is the gold standard for screening individuals at risk for **Familial Adenomatous Polyposis (FAP)**, also known as Familial Polyposis Coli (FPC), as it allows for visualization of the entire colon and removal of polyps [1]. - Screening typically begins in **early adolescence (10-12 years)** due to the high risk of developing multiple adenomatous polyps and subsequent colorectal cancer [1]. Flexible sigmoidoscopy - While useful for inspecting the lower colon, a **flexible sigmoidoscopy** does not visualize the entire colon, which is essential for FAP given that polyps can occur throughout the large bowel [3]. - It would miss polyps in the **proximal colon**, leading to an inadequate assessment of cancer risk in FAP patients [1]. Occult blood in stools - Testing for **occult blood in stools** is a general screening tool for colorectal cancer but is not sensitive enough for FAP, where the goal is to detect and remove polyps before they become malignant. - A negative result does not rule out the presence of **adenomatous polyps**, which are the hallmark of FAP. APC gene - **APC gene** testing is used for **genetic diagnosis** to identify individuals who carry the FAP mutation, but it is not a screening test for adenomatous polyps or cancer themselves [2]. - Once a family member is identified with the APC gene mutation, subsequent surveillance for polyps requires direct visualization methods like colonoscopy [1].

Q: Which karyotype is commonly associated with true hermaphroditism?

46,XX. ***46,XX*** - While various karyotypes can be associated with **true hermaphroditism**, the majority of cases (approximately 60-70%) present with a **46,XX karyotype** [1]. - This karyotype indicates the presence of **XX chromosomes**, typically associated with females, but in true hermaphroditism, both ovarian and testicular tissue are present [1]. *45,X (Turner syndrome)* - This karyotype is classically associated with **Turner syndrome**, characterized by the absence of one X chromosome [2]. - Individuals with Turner syndrome are typically phenotypically female but experience **gonadal dysgenesis**, leading to streak gonads and infertility, not the presence of both ovarian and testicular tissue [2]. *47,XY,+9* - This karyotype indicates an extra copy of chromosome 9 in an individual who is otherwise karyotypically male (XY). - This is a rare chromosomal abnormality that can lead to a variety of developmental issues and birth defects, but it is **not typically associated with true hermaphroditism**. *47,XXX* - This karyotype is known as **Triple X syndrome** or **Trisomy X**, where an individual has three X chromosomes [3]. - Individuals with Triple X syndrome are phenotypically female and often have mild or no clinical symptoms, though some may experience learning difficulties or fertility issues; it does **not involve the development of both ovarian and testicular tissue** [3].

Q: A 25-year-old man presents for a routine physical examination. He is tall and has an early diastolic murmur on examination. Based on the clinical findings, which of the following is the most likely mode of inheritance for the condition?

AD. ### AD - The combination of **tall stature** and an **early diastolic murmur** is highly suggestive of **Marfan syndrome**, which is inherited in an **autosomal dominant** pattern [1]. - This mode of inheritance means that only one copy of the mutated gene (FBN1) is sufficient to cause the disorder [1]. ### AR - **Autosomal recessive** disorders typically require two copies of a mutated gene for the condition to manifest, and patients are often born to unaffected carriers. - Marfan syndrome does not follow this inheritance pattern [1]. ### XLR - **X-linked recessive** disorders primarily affect males, with females usually being carriers or less severely affected. - While Marfan syndrome can affect both sexes, its inheritance pattern is not linked to the X chromosome. ### XLD - **X-linked dominant** disorders are passed from fathers to all daughters but not to sons, and from mothers to half of their children regardless of sex. - This pattern is not consistent with the genetic transmission of Marfan syndrome.

Q: Which one of the following is an autosomal recessive disorder?

Cystic fibrosis. ***Cystic fibrosis*** - **Cystic fibrosis** is caused by mutations in the **CFTR gene**, leading to defective **chloride channel** function. - It is an **autosomal recessive disorder**, meaning an individual must inherit two copies of the mutated gene (one from each parent) to be affected. *Huntington's disease* - **Huntington's disease** is an **autosomal dominant disorder** caused by a mutation in the HTT gene. - Only one copy of the mutated gene is sufficient to cause the disease, resulting in progressive neurodegeneration. *Marfan syndrome* - **Marfan syndrome** is an **autosomal dominant disorder** affecting connective tissue, caused by mutations in the FBN1 gene. - It results in skeletal, ocular, and cardiovascular abnormalities due to defective **fibrillin-1**. *Neurofibromatosis type 1* - **Neurofibromatosis type 1** is an **autosomal dominant disorder** caused by mutations in the NF1 gene. - It is characterized by multiple neurofibromas, café-au-lait macules, and Lisch nodules.

Question 1

A 25-year-old man presents for a routine physical examination. The patient is tall (6 ft. 5 in) and on examination he was found to have an early diastolic murmur. His family pedigree is as given below. Which of the following is the mode of inheritance by which the disease is likely to be transmitted?

Accepted Answer

Autosomal dominant

Answer

X linked dominant disorder

Answer

X-linked recessive

Answer

Autosomal recessive

Question 2

A patient with hemochromatosis experiences joint pain and fatigue. Which genetic test would confirm the diagnosis?

Accepted Answer

HFE gene mutation test

Answer

BRCA1 gene test

Answer

Lynch syndrome genetic test

Answer

MLH1 gene test

Question 3

A 35-year-old woman presents with hepatomegaly and arthritis. Laboratory results show high serum ferritin and transferrin saturation. Which genetic defect is likely?

Accepted Answer

Hemochromatosis

Answer

Wilson's disease

Answer

α1-antitrypsin deficiency

Answer

Gaucher disease

Question 4

Which genetic syndrome is associated with hundreds of colorectal polyps and almost certain progression to colorectal cancer if left untreated?

Accepted Answer

Familial adenomatous polyposis

Answer

Lynch syndrome

Answer

Peutz-Jeghers syndrome

Answer

Juvenile polyposis syndrome

Question 5

A 25-year-old with Gaucher disease type 1 and a GBA mutation, exhibiting significant residual β-glucocerebrosidase activity, what is the best initial treatment?

Accepted Answer

SRT with eliglustat

Answer

BMT

Answer

Chaperone tx with miglustat

Answer

ERT with imiglucerase

Question 6

Which of the following is NOT a feature of Abetalipoproteinemia?

Accepted Answer

Elevated plasma apolipoprotein B levels

Answer

Plasma levels of cholesterol and triglyceride are extremely low

Answer

Manifest in early childhood with diarrhea

Answer

Progressive pigmented retinopathy seen

Question 7

Following genetic counselling in a family for Familial polyposis coli (FPC), what is the next appropriate screening test for at-risk individuals?

Accepted Answer

Colonoscopy

Answer

Flexible sigmoidoscopy

Answer

Occult blood in stools

Answer

APC gene

Question 8

Which karyotype is commonly associated with true hermaphroditism?

Accepted Answer

46,XX

Answer

47,XY,+9

Answer

45,X (Turner syndrome)

Answer

47,XXX

Question 9

A 25-year-old man presents for a routine physical examination. He is tall and has an early diastolic murmur on examination. Based on the clinical findings, which of the following is the most likely mode of inheritance for the condition?

Accepted Answer

AD

Answer

AR

Answer

XLR

Answer

XLD

Question 10

Which one of the following is an autosomal recessive disorder?

Accepted Answer

Cystic fibrosis

Answer

Huntington's disease

Answer

Marfan syndrome

Answer

Neurofibromatosis type 1

Genetics and Disease — MCQs

Genetics and Disease — MCQs

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