Chromosomal Disorders - USMLE Step 1

1. This patient's condition is most likely caused by a microdeletion on which of the following chromosomes?
   Answer: Chromosome 7 The combination of distinctive 'elfin' facial features, an unusually friendly personality, intellectual disability, and supravalvular aortic stenosis is characteristic of Williams syndrome. This condition is caused by a microdeletion on the long arm of chromosome 7 (7q11.23), which includes the gene for elastin.
2. This patient's condition most likely resulted from a nondisjunction event during which of the following processes?
   Answer: Paternal meiosis II The patient's presentation of tall stature, severe acne, and behavioral problems suggests a 47,XYY karyotype. This aneuploidy results from the fertilization of a normal ovum (X) by a sperm carrying two Y chromosomes (YY). A YY sperm is formed as a result of nondisjunction of the sister chromatids of the Y chromosome during paternal meiosis II.
3. This infant's condition is most likely caused by which chromosomal abnormality?
   Answer: Trisomy 18 The clinical presentation, particularly the clenched fists with overlapping fingers, rocker-bottom feet, micrognathia, and prominent occiput, is highly characteristic of Edwards syndrome, which is caused by Trisomy 18. Trisomy 13 (Patau syndrome) has midline defects, while cri-du-chat (5p deletion) has a cat-like cry. 22q11 deletion syndrome has features like cardiac defects, abnormal facies, and hypocalcemia.
4. Which of the following genetic mechanisms best describes the cause of this patient's condition?
   Answer: Maternal uniparental disomy Prader-Willi syndrome results from the loss of function of genes on the paternal chromosome 15, which are normally expressed while the maternal copies are silenced (imprinted). While the most common cause is a paternal deletion, this patient's case is caused by maternal uniparental disomy, where both copies of chromosome 15 are inherited from the mother. With no paternal chromosome 15 present, the necessary genes are not expressed, leading to the syndrome.
5. The chromosomal abnormality in this man increases the risk of abnormal offspring due to the potential for producing which of the following?
   Answer: Gametes with duplication and deletion of chromosome 3 segments The man has a pericentric inversion, which involves a segment of a chromosome that includes the centromere. During meiosis, if a crossover event occurs within the inverted segment, it can lead to the formation of recombinant chromosomes that have a duplication of one end and a deletion of the other. Fertilization with such a gamete results in an unbalanced karyotype and is often lethal or causes severe congenital anomalies.
6. Deletion of which of the following genes is the most likely cause of this infant's failure to develop normal male external genitalia?
   Answer: SRY The SRY (Sex-determining Region on Y) gene, located on the short arm of the Y chromosome, is the primary genetic switch for male development. It encodes a transcription factor that initiates the differentiation of the gonads into testes. A deletion or mutation in the SRY gene in a 46,XY individual leads to gonadal dysgenesis, where the gonads fail to develop properly into testes. Without functional testes, there is insufficient testosterone and anti-Müllerian hormone production, resulting in the development of female or ambiguous external genitalia.
7. Which of the following is the most likely underlying genetic mechanism responsible for this infant's condition?
   Answer: Maternal meiotic I nondisjunction The infant's features are classic for Down syndrome (Trisomy 21). The most common cause of trisomy 21, accounting for over 90% of cases, is nondisjunction of chromosome 21 during maternal meiosis I. This risk increases significantly with advanced maternal age due to the prolonged arrest of primary oocytes in prophase I.
8. Which of the following terms best describes this woman's chromosomal rearrangement?
   Answer: Robertsonian translocation A Robertsonian translocation is a specific type of non-reciprocal translocation that involves the fusion of two acrocentric chromosomes (13, 14, 15, 21, and 22). The fusion occurs at the centromeres, and the small, short arms (p arms), which typically contain non-essential ribosomal RNA genes, are lost. Carriers have 45 chromosomes but are usually phenotypically normal because all essential genetic material is present. However, they have a higher risk of producing offspring with aneuploidy, such as translocation Down syndrome, which explains the family history.
9. Karyotyping of this infant would most likely reveal which of the following?
   Answer: Trisomy 13 This constellation of findings, including midline defects (cleft lip/palate), microcephaly, cutis aplasia, polydactyly, and micropthalmia, is classic for Patau syndrome, which is caused by Trisomy 13. Trisomy 18 presents with clenched hands and rocker-bottom feet, while Trisomy 21 has characteristic facial features and often congenital heart disease.
10. The presence of two distinct cell lines in this patient is best explained by which of the following events?
    Answer: Nondisjunction during an early mitotic division of the zygote The 45,X/46,XX karyotype indicates mosaicism, meaning the patient has two different cell populations derived from a single zygote. This typically occurs due to a post-zygotic error, specifically nondisjunction of the X chromosome during an early mitotic division after fertilization. This event creates a 45,X cell line and a 47,XXX cell line (which is often lost), alongside the original 46,XX cell line. The resulting mix of normal and abnormal cells often leads to a milder phenotype.
11. Which of the following sets of laboratory findings is most consistent with the underlying chromosomal disorder?
    Answer: Low testosterone, high LH, high FSH The patient's phenotype is classic for Klinefelter syndrome (47,XXY). The extra X chromosome leads to testicular dysgenesis, resulting in primary hypogonadism. The damaged Leydig cells produce insufficient testosterone (low testosterone), and the damaged seminiferous tubules produce insufficient inhibin. The lack of negative feedback from testosterone and inhibin on the pituitary and hypothalamus leads to elevated levels of both LH and FSH (hypergonadotropic hypogonadism).
12. This characteristic chromosomal abnormality is the result of which of the following types of mutation?
    Answer: Reciprocal translocation The Philadelphia chromosome is the hallmark of chronic myelogenous leukemia (CML). It is created by a reciprocal translocation between the long arms of chromosome 9 and chromosome 22, denoted as t(9;22)(q34;q11). This translocation fuses the ABL1 gene from chromosome 9 with the BCR gene on chromosome 22, creating a BCR-ABL1 fusion gene that encodes a constitutively active tyrosine kinase.
13. This pattern of serum markers is most suggestive of a fetus with which of the following chromosomal abnormalities?
    Answer: Trisomy 21 The classic quadruple screen pattern for Down syndrome (Trisomy 21) is low MSAFP, low uE3, high hCG, and high inhibin A. In contrast, Trisomy 18 is associated with low levels of all four markers. An open neural tube defect would cause a significantly elevated MSAFP.
14. The formation of the abnormal chromosome in this woman is best explained by which of the following mechanisms?
    Answer: Transverse division of the centromere during meiosis The notation i(Xq) indicates an isochromosome of the long arm of the X chromosome. An isochromosome is a mirror-image chromosome consisting of two copies of either the short arm (p) or the long arm (q). It forms when the centromere divides transversely (horizontally) instead of longitudinally (vertically) during meiosis II or mitosis, leading to loss of one arm and duplication of the other.
15. A 1-month-old infant has a high-pitched cry, microcephaly, and hypotonia. Karyotype shows 46,XY,del(5)(p15). The parents ask what type of chromosomal change this represents compared with trisomy 21. Which statement best explains the difference?
    Answer: This disorder is due to a structural deletion, whereas trisomy 21 is usually a numerical gain This question tests understanding of chromosomal disorders and their genetic mechanisms on the USMLE Step 1. Chromosomal disorders arise from numerical or structural abnormalities, such as trisomies or deletions, leading to various phenotypic manifestations. In this vignette, the patient's symptoms and lab findings suggest cri-du-chat syndrome, supported by the karyotype showing 46,XY,del(5)(p15). The correct choice is A, as it aligns with the clinical and genetic data provided, demonstrating understanding of chromosomal mechanisms. Choice B fails because it inaccurately associates symptoms with monosomy X, a common error when phenotypic traits overlap. To prepare, focus on understanding the genetic basis of common chromosomal disorders and recognize the clinical presentations they typically cause. Practice analyzing karyotypes and relating lab data to clinical findings.
16. This patient's condition is most commonly associated with which of the following karyotypes?
    Answer: 45,X The patient's presentation of short stature, primary amenorrhea, webbed neck, and coarctation of the aorta (indicated by the blood pressure differential between arms and legs) is characteristic of Turner syndrome. The most common karyotype for Turner syndrome is 45,X, resulting from the absence of one X chromosome.
17. Which of the following karyotypes is most likely in this patient?
    Answer: 47,XXX A Barr body is an inactivated X chromosome. The number of Barr bodies in a cell is equal to the number of X chromosomes minus one (n-1 rule). A normal female (46,XX) has one Barr body. A patient with two Barr bodies per cell would have three X chromosomes. The karyotype is therefore 47,XXX (Triple X syndrome). Many individuals with this condition have a normal phenotype or mild features like tall stature and learning disabilities.
18. Which of the following genetic tests is most appropriate to identify a potential microdeletion or microduplication syndrome in this patient?
    Answer: Chromosomal microarray analysis Chromosomal microarray analysis (CMA), also known as array comparative genomic hybridization (aCGH), is a high-resolution method for detecting copy number variants (CNVs), which are submicroscopic deletions and duplications of DNA segments. It is the recommended first-tier test for patients with unexplained developmental delay, intellectual disability, or multiple congenital anomalies when a standard karyotype is normal.
19. The formation of the abnormal chromosome seen in this patient most directly involves which of the following events?
    Answer: Breaks in both arms of a chromosome with fusion of the ends The notation r(14) indicates a ring chromosome 14. A ring chromosome is a structural abnormality that forms when a chromosome undergoes breaks on both its short (p) and long (q) arms, leading to loss of the terminal segments (including telomeres). The newly exposed sticky ends then fuse together, forming a ring structure. This can lead to genetic instability and is associated with various clinical syndromes.
20. Which of the following techniques was most likely used for this rapid diagnosis?
    Answer: Fluorescence in situ hybridization (FISH) Fluorescence in situ hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes to detect the presence or absence of specific DNA sequences on chromosomes. It can be performed on interphase cells, does not require cell culture, and provides rapid results (typically within 24-48 hours), making it ideal for the rapid diagnosis of common aneuploidies like trisomy 21, 13, and 18 in newborns.

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