Chromosomal Disorders — MCQs
All of the following are true about Down syndrome except for one.
Which of the following translocations is not associated with Down syndrome?
Which of the following is not the karyotype of Turner syndrome?
The diagrammatic representation of the karyotype of an individual indicates a specific genetic abnormality. What is the diagnosis?
Syndrome which is characterized by 2X chromosomes and 1Y chromosome is:
A 1-year-old girl born to a 40-year-old woman is undergoing an examination by a pediatric resident in the hospital. The pregnancy was uneventful and there were no complications during the delivery. The physical examination reveals midface hypoplasia with a flat nasal bridge and upslanting palpebral fissures. She has a small mouth and chest auscultation reveals a blowing holosystolic murmur that is heard best along the sternal border. The family history is unremarkable. A karyotype analysis is ordered because the resident suspects a numerical chromosomal disorder. Which of the following phenomena leads to the infant’s condition?
A 16-year-old male presents to an ophthalmologist as a new patient with a complaint of blurry vision. He reports that over the past several months he has had increasing difficulty seeing the board from the back of the classroom at school. The patient is otherwise doing well in school and enjoys playing basketball. His past medical history is otherwise significant for scoliosis which is managed by an orthopedic surgeon. His family history is significant for a mother with type II diabetes mellitus, and a father who underwent aortic valve replacement last year. On physical exam, the patient is tall for his age and has long arms. He has 20 degrees of thoracic scoliosis, which is stable from previous exams. On slit-lamp examination, the patient is found to have bilateral upward lens subluxation and is prescribed corrective lenses. Which of the following is the most likely etiology of this patient’s presentation?
A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?
During evaluation of a child with Down syndrome, the following finding is noted. Identify?
A 25-year-old man with a genetic disorder presents for genetic counseling because he is concerned about the risk that any children he has will have the same disease as himself. Specifically, since childhood he has had difficulty breathing requiring bronchodilators, inhaled corticosteroids, and chest physiotherapy. He has also had diarrhea and malabsorption requiring enzyme replacement therapy. If his wife comes from a population where 1 in 10,000 people are affected by this same disorder, which of the following best represents the likelihood a child would be affected as well?
Chromosomal Disorders US Medical PG Practice Questions and MCQs
Question 1: All of the following are true about Down syndrome except for one.
- A. Incidence of Robertsonian translocation is 1:1000 (Correct Answer)
- B. Most common cause is trisomy 21
- C. Mosaicism 21 has no association with maternal age
- D. Extra chromosome is of maternal origin
- E. Incidence increases with advanced maternal age
Explanation: **Incidence of Robertsonian translocation is 1:1000** - This statement is **not accurate** for Down syndrome. Robertsonian translocation accounts for only about **3-4% of Down syndrome cases**, not a general population incidence of 1:1000. - The vast majority of Down syndrome cases (~95%) are due to trisomy 21 from nondisjunction, not translocation. - This is the **correct answer** as it is the FALSE statement. *Extra chromosome is of maternal origin* - In approximately **90-95% of Down syndrome cases**, the extra copy of chromosome 21 originates from the mother due to **nondisjunction** during meiosis. - This maternal origin is strongly correlated with **advanced maternal age**. *Most common cause is trisomy 21* - **Trisomy 21** (due to meiotic nondisjunction) accounts for about **95% of all Down syndrome cases**, making it the most common genetic mechanism. - This results in three separate copies of chromosome 21 in all body cells. *Mosaicism 21 has no association with maternal age* - **Mosaic Down syndrome** occurs when nondisjunction happens *after fertilization* in early embryonic development, leading to a mixture of cells with normal and trisomic cells. - Because it is a **post-zygotic event**, its incidence is independent of **maternal age**, unlike full trisomy 21. *Incidence increases with advanced maternal age* - **TRUE statement** - The risk of Down syndrome (particularly trisomy 21) increases significantly with **maternal age**. - Risk is approximately 1:1500 at age 20, 1:1000 at age 30, 1:400 at age 35, and 1:100 at age 40. - This is due to increased risk of meiotic nondisjunction in older oocytes.
Question 2: Which of the following translocations is not associated with Down syndrome?
- A. t(21;21)
- B. t(14;21)
- C. t(15;21)
- D. t(11;14) (Correct Answer)
Explanation: ***t (11: 14)*** - The **t(11;14) translocation** is commonly associated with **mantle cell lymphoma**, a B-cell non-Hodgkin lymphoma, and is not a cause of Down syndrome. - This translocation leads to the overexpression of the **cyclin D1 gene**, located on chromosome 11, which promotes cell growth and proliferation. *t (14; 21)* - This is a common **Robertsonian translocation** involving chromosomes 14 and 21, which results in an extra copy of chromosome 21 material [1]. - Individuals with this translocation can have **Down syndrome** because their cells end up with the equivalent of three copies of chromosome 21 [1]. *t (21; 21)* - This translocation is another type of **Robertsonian translocation** where two chromosome 21s fuse. - This specific translocation is rare and results in an extra copy of chromosome 21, leading to **Down syndrome** with a high recurrence risk in offspring. *t (15: 21)* - This is a **Robertsonian translocation** involving chromosomes 15 and 21, resulting in an extra copy of chromosome 21 material. - This translocation is a known cause of **Down syndrome** due to the dosage imbalance of genes on chromosome 21 [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 169-172.
Question 3: Which of the following is not the karyotype of Turner syndrome?
- A. 45 XO
- B. 46,X,r(X)
- C. 46,X,i(Xp) (Correct Answer)
- D. 46,X, i(X) (q10)
Explanation: ***46,X,i(Xp)*** - This karyotype indicates an **isochromosome of the short arm of the X chromosome**, with two copies of Xp and complete loss of Xq. - This results in **duplication of Xp material** (including the critical SHOX gene region), which **prevents the characteristic short stature** of Turner syndrome [1]. - While Xq material is lost, the **presence of two Xp arms protects against the Turner phenotype**, making this karyotype **NOT typically associated with Turner syndrome**. Just as the loss of SHOX is associated with short stature, excess copies are associated with tall stature [1]. - This is an extremely rare karyotype that does not produce the classic Turner syndrome features. *45,XO* - This is the **classic and most common karyotype for Turner syndrome** (about 50-60% of cases), characterized by complete absence of one X chromosome. - Results in characteristic features: **short stature, gonadal dysgenesis, webbed neck, cardiac anomalies**, and lymphedema. *46,X,r(X)* - This karyotype has a **ring X chromosome**, where both ends of the X chromosome have fused together, typically with loss of genetic material from both arms. - The loss of critical genes leads to **Turner syndrome phenotype** due to haploinsufficiency. - Ring X chromosomes account for approximately 5% of Turner syndrome cases. *46,X,i(X)(q10)* - This is an **isochromosome of the long arm of the X chromosome** (i(Xq)), with two copies of Xq and complete loss of Xp [1]. - The **loss of Xp material (including SHOX gene)** causes the characteristic **short stature and skeletal abnormalities** of Turner syndrome [1]. - This is the **second most common structural abnormality** causing Turner syndrome (15-20% of cases). **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 169-177.
Question 4: The diagrammatic representation of the karyotype of an individual indicates a specific genetic abnormality. What is the diagnosis?
- A. Angelman syndrome
- B. Cri du Chat syndrome
- C. DiGeorge syndrome
- D. Prader-Willi syndrome (Correct Answer)
Explanation: ***Prader-Willi syndrome*** - The karyotype shows an abnormality on **chromosome 15**, which is consistent with Prader-Willi syndrome caused by **deletion of 15q11-q13** inherited from the **paternal** chromosome or **maternal uniparental disomy**. - While PWS deletions are typically **submicroscopic**, larger deletions can occasionally be visible on standard karyotyping, particularly when they represent **class I deletions** that are more extensive and involve additional chromosomal material beyond the typical PWS critical region. *Angelman syndrome* - Although Angelman syndrome also involves **chromosome 15q11-q13 deletion**, it results from **maternal** deletion or **paternal uniparental disomy**, and presents with distinctly different clinical features. - Clinical presentation includes **severe intellectual disability**, **ataxia**, **seizures**, **absent speech**, and **inappropriate laughter** (happy demeanor), which differs significantly from the PWS phenotype. *DiGeorge syndrome* - DiGeorge syndrome is caused by **deletion of chromosome 22q11.2**, not chromosome 15 as shown in the karyotype. - Clinical features include **cardiac defects** (conotruncal abnormalities), **thymic hypoplasia**, **parathyroid hypoplasia** (hypocalcemia), **cleft palate**, and characteristic facial features (CATCH-22 syndrome). *Cri du Chat syndrome* - This syndrome results from **deletion of chromosome 5p** (short arm of chromosome 5), not chromosome 15 as indicated in the karyotype. - Characteristic features include **high-pitched cry** resembling a cat's meow in infancy, **intellectual disability**, **microcephaly**, and **distinctive facial features**.
Question 5: Syndrome which is characterized by 2X chromosomes and 1Y chromosome is:
- A. Turner syndrome
- B. Marfan syndrome
- C. Down syndrome
- D. Klinefelter syndrome (Correct Answer)
Explanation: ***Klinefelter syndrome*** - This syndrome is characterized by a **47, XXY karyotype**, meaning individuals have **two X chromosomes** and one Y chromosome [1]. - It affects males, leading to features such as **small testes**, **infertility**, gynecomastia, and often taller stature [1], [3]. *Turner syndrome* - This syndrome is characterized by a **45, X karyotype**, meaning individuals have only **one X chromosome** and no second sex chromosome [2]. - It affects females, leading to features like **short stature**, a **webbed neck**, and ovarian dysgenesis [2]. *Marfan syndrome* - This is an **autosomal dominant genetic disorder** affecting connective tissue, caused by mutations in the **FBN1 gene**. - It is characterized by **tall stature**, long limbs (arachnodactyly), **cardiovascular abnormalities** (e.g., aortic dissection), and ocular problems (e.g., lens dislocation). *Down syndrome* - This syndrome is caused by **trisomy 21**, meaning individuals have an **extra copy of chromosome 21**. - It is characterized by specific **facial features**, intellectual disability, and an increased risk of certain medical conditions like congenital heart defects.
Question 6: A 1-year-old girl born to a 40-year-old woman is undergoing an examination by a pediatric resident in the hospital. The pregnancy was uneventful and there were no complications during the delivery. The physical examination reveals midface hypoplasia with a flat nasal bridge and upslanting palpebral fissures. She has a small mouth and chest auscultation reveals a blowing holosystolic murmur that is heard best along the sternal border. The family history is unremarkable. A karyotype analysis is ordered because the resident suspects a numerical chromosomal disorder. Which of the following phenomena leads to the infant’s condition?
- A. Meiotic non-disjunction (Correct Answer)
- B. Uniparental disomy
- C. Genomic imprinting
- D. Partial deletion
- E. Trinucleotide repeat
Explanation: ***Meiotic non-disjunction*** - The combination of **midface hypoplasia**, **upslanting palpebral fissures**, **flat nasal bridge**, and a **holosystolic murmur** (suggesting a **ventricular septal defect**) in an infant born to an older mother is highly characteristic of **Down syndrome (Trisomy 21)**. - **Trisomy 21** is most commonly caused by **meiotic non-disjunction**, where homologous chromosomes fail to separate during meiosis I or sister chromatids fail to separate during meiosis II, resulting in a gamete with an extra chromosome 21. *Uniparental disomy* - **Uniparental disomy** occurs when an individual receives both copies of a chromosome from a single parent, rather than one from each parent. - While it can lead to various genetic disorders, it does not typically cause **Trisomy 21** or the specific constellation of features described. *Genomic imprinting* - **Genomic imprinting** is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin specific manner. - While relevant to conditions like Prader-Willi or Angelman syndromes, it is not the mechanism responsible for **Trisomy 21**. *Partial deletion* - A **partial deletion** refers to the loss of a segment of a chromosome. - While chromosomal deletions cause various syndromes (e.g., Cri-du-chat syndrome), they would result in a **monosomy or partial monosomy**, not the extra chromosome seen in Trisomy 21. *Trinucleotide repeat* - **Trinucleotide repeat disorders** involve an abnormal expansion of a three-nucleotide sequence within a gene, leading to conditions like Huntington's disease or fragile X syndrome. - This mechanism is not associated with the etiology of **Down syndrome**.
Question 7: A 16-year-old male presents to an ophthalmologist as a new patient with a complaint of blurry vision. He reports that over the past several months he has had increasing difficulty seeing the board from the back of the classroom at school. The patient is otherwise doing well in school and enjoys playing basketball. His past medical history is otherwise significant for scoliosis which is managed by an orthopedic surgeon. His family history is significant for a mother with type II diabetes mellitus, and a father who underwent aortic valve replacement last year. On physical exam, the patient is tall for his age and has long arms. He has 20 degrees of thoracic scoliosis, which is stable from previous exams. On slit-lamp examination, the patient is found to have bilateral upward lens subluxation and is prescribed corrective lenses. Which of the following is the most likely etiology of this patient’s presentation?
- A. Extra copy of sex chromosome
- B. Mutation of gene on chromosome 15 (Correct Answer)
- C. Mutation of COL5A1 or COL5A2
- D. Defective metabolism of methionine
- E. Mutation of RET proto-oncogene
Explanation: ***Mutation of gene on chromosome 15*** - The patient's presentation with **tall stature**, **long arms** (dolichostenomelia), **scoliosis**, and **bilateral upward lens subluxation** are classic features of **Marfan syndrome**. - Marfan syndrome is an autosomal dominant disorder caused by a mutation in the *FBN1* gene located on **chromosome 15**, which encodes for **fibrillin-1**, a glycoprotein essential for connective tissue formation. *Extra copy of sex chromosome* - An extra copy of a sex chromosome, such as in **Klinefelter syndrome (XXY)**, is associated with tall stature and disproportionately long limbs, but it typically presents with **hypogonadism**, infertility, and learning difficulties, not lens subluxation or significant scoliosis as the primary features. - Patients with Klinefelter syndrome often have a **eunuchoid body habitus** and gynecomastia, which are not described in this patient. *Mutation of COL5A1 or COL5A2* - Mutations in *COL5A1* or *COL5A2* are associated with **Ehlers-Danlos syndrome (classical type)**, which primarily features **skin hyperextensibility**, delayed wound healing, and **joint hypermobility**. - While some forms of Ehlers-Danlos can have ocular involvement (e.g., easy bruising, scleral fragility), **lens subluxation** and the specific tall, slender build with scoliosis are not characteristic clinical features. *Defective metabolism of methionine* - A defective metabolism of methionine is characteristic of **homocystinuria**, an autosomal recessive disorder. - Homocystinuria also causes **tall stature**, **scoliosis**, and **lens subluxation**, but the subluxation is typically **downward and inward**, differentiating it from the upward subluxation seen in Marfan syndrome. Patients also have an increased risk of **thromboembolic events** and **intellectual disability**. *Mutation of RET proto-oncogene* - Mutations of the *RET* proto-oncogene are associated with **Multiple Endocrine Neoplasia type 2 (MEN2)**. - MEN2 presents with specific endocrine tumors such as **medullary thyroid carcinoma**, **pheochromocytoma**, and **parathyroid hyperplasia**, and does not involve the skeletal or ocular abnormalities described in this patient.
Question 8: A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?
- A. Abnormally increased expression of the gene from the maternal chromosome
- B. Abnormally decreased expression of the gene from the maternal chromosome (Correct Answer)
- C. Abnormally decreased expression of the gene from both chromosomes
- D. Abnormally decreased expression of the gene from the paternal chromosome
- E. Abnormally increased expression of the gene from the paternal chromosome
Explanation: ***Abnormally decreased expression of the gene from the maternal chromosome*** - This patient's symptoms (non-verbal, severe developmental delays, cognitive disability, seizures, uncoordinated movements, wide-based gait, inappropriate laughter, and an abnormality in an E3 ubiquitin ligase gene) are characteristic of **Angelman syndrome**. - Angelman syndrome is typically caused by a deletion or mutation on the **maternally inherited copy of chromosome 15q11-q13**, specifically affecting the *UBE3A* gene, which is an E3 ubiquitin ligase. This leads to reduced or absent expression of the *UBE3A* gene in critical brain regions where only the maternal allele is expressed. *Abnormally increased expression of the gene from the maternal chromosome* - Angelman syndrome is caused by a **loss of function** of the maternally inherited *UBE3A* gene, not an increase in its expression. - Increased expression would not lead to the neurodevelopmental deficits seen in Angelman syndrome. *Abnormally decreased expression of the gene from both chromosomes* - While there is decreased expression of the functional *UBE3A* gene, the paternal allele is normally **silenced** in specific brain regions relevant to Angelman syndrome pathogenesis due to **genomic imprinting**. Therefore, the issue is with the maternal allele. - If both chromosomes had decreased expression, it would imply a different genetic mechanism or a more severe, potentially lethal, condition. *Abnormally decreased expression of the gene from the paternal chromosome* - In the brain regions relevant to Angelman syndrome, the paternal *UBE3A* allele is normally **silenced** due to genomic imprinting. Therefore, its decreased expression would not be an abnormal finding or contribute to the pathology. - Problems with the paternal allele in this region are associated with **Prader-Willi syndrome**, which has a different clinical presentation (e.g., hypotonia, hyperphagia, obesity). *Abnormally increased expression of the gene from the paternal chromosome* - The paternal *UBE3A* allele is normally **silenced** in the relevant brain regions; therefore, an increased expression would be abnormal but is not the genetic basis of Angelman syndrome. - Angelman syndrome is caused by the **loss or absence of functional maternal *UBE3A*** expression, not altered paternal expression.
Question 9: During evaluation of a child with Down syndrome, the following finding is noted. Identify?
- A. Simian crease (Correct Answer)
- B. Kennedy crease
- C. Sydney line
- D. Sandal gap
Explanation: ***Simian crease*** - The image displays a **single palmar crease** (also known as a simian crease or transverse palmar crease), which is a common physical finding in individuals with **Down syndrome (Trisomy 21)**. - This crease runs straight across the palm, often replacing the usual two major palmar creases. *Kennedy crease* - This is **not a recognized medical term** for a palmar crease or any specific dermatological finding. - The feature shown in the image is a clearly defined, single transverse palmar crease. *Sydney line* - A **Sydney line** is another type of palmar crease abnormality where the proximal transverse crease extends across the entire palm, reaching the ulnar edge. - While it is a variation of palmar creases, the crease in the image appears as a single, bold transverse crease, more consistent with a **simian crease**. *Sandal gap* - A **sandal gap** refers to a wide space between the first and second toes, sometimes seen in newborns, including those with Down syndrome. - This finding relates to the **foot**, not the hand, and is not depicted in the provided image.
Question 10: A 25-year-old man with a genetic disorder presents for genetic counseling because he is concerned about the risk that any children he has will have the same disease as himself. Specifically, since childhood he has had difficulty breathing requiring bronchodilators, inhaled corticosteroids, and chest physiotherapy. He has also had diarrhea and malabsorption requiring enzyme replacement therapy. If his wife comes from a population where 1 in 10,000 people are affected by this same disorder, which of the following best represents the likelihood a child would be affected as well?
- A. 0.01%
- B. 2%
- C. 0.5%
- D. 1% (Correct Answer)
- E. 50%
Explanation: ***Correct Option: 1%*** - The patient's symptoms (difficulty breathing requiring bronchodilators, inhaled corticosteroids, and chest physiotherapy; diarrhea and malabsorption requiring enzyme replacement therapy) are classic for **cystic fibrosis (CF)**, an **autosomal recessive disorder**. - For an autosomal recessive disorder with a prevalence of 1 in 10,000 in the general population, **q² = 1/10,000**, so **q = 1/100 = 0.01**. The carrier frequency **(2pq)** is approximately **2q = 2 × (1/100) = 1/50 = 0.02**. - The affected man is **homozygous recessive (aa)** and will always pass on the recessive allele. His wife has a **1/50 chance of being a carrier (Aa)**. If she is a carrier, she has a **1/2 chance of passing on the recessive allele**. - Therefore, the probability of an affected child = **(Probability wife is a carrier) × (Probability wife passes recessive allele) = 1/50 × 1/2 = 1/100 = 1%**. *Incorrect Option: 0.01%* - This percentage is too low and does not correctly account for the carrier frequency in the population and the probability of transmission from a carrier mother. *Incorrect Option: 2%* - This represents approximately the carrier frequency (1/50 ≈ 2%), but does not account for the additional 1/2 probability that a carrier mother would pass on the recessive allele. *Incorrect Option: 0.5%* - This value would be correct if the carrier frequency were 1/100 instead of 1/50, which does not match the given population prevalence. *Incorrect Option: 50%* - **50%** would be the risk if both parents were carriers of an autosomal recessive disorder (1/4 chance = 25% for affected, but if we know one parent passes the allele, conditional probability changes). More accurately, 50% would apply if the disorder were **autosomal dominant** with one affected parent, which is not the case here.
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