KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Part II ● Medical Genetics

Review Questions

Select the ONE best answer.

1.A 26-year-old woman has produced two children with Down syndrome, and she has also had two miscarriages. Which of the following would be the best explanation?

A.Her first cousin has Down syndrome.

B.Her husband is 62 years old.

C. She carries a reciprocal translocation involving chromosomes 14 and 18.

D.She carries a Robertsonian translocation involving chromosomes 14 and 21.

E.She was exposed to multiple x-rays as a child.

2.A 6-year-old boy has a family history of mental retardation and has developmental delay and some unusual facial features. He is being evaluated for possible fragile X syndrome. Which of the following would be most useful in helping establish the diagnosis?

A.Genetic test for a trinucleotide repeat expansion in the fragile X gene

B.IQ test

C.Karyotype of the child’s chromosomes

D.Karyotype of the father’s chromosomes

E.Measurement of testicular volume

3.A couple has one son, who is age 7. Multiple attempts to have a second child have ended in miscarriages and spontaneous abortions. Karyotypes of the mother, the father, and the most recently aborted fetus are represented schematically below. What is the most likely explanation for the most recent pregnancy loss?

A.Aneuploidy in the fetus

B.Fetus identified as a reciprocal translocation carrier

C.Nondisjunction during oogenesis in the mother

D.Partial monosomy and trisomy in the fetus

E.Unbalanced chromosomal material in the father

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4.A woman brings her 16-year-old daughter to a physician because she has not yet begun menstruating. Although her parents are both 1.75 meters, the patient is 1.5 meters and has always been below the 50th percentile in height. Physical examination reveals no breast development. She has no problems in school and is of normal intelligence. What is the most likely underlying basis for her condition?

A.A 45,X karyotype

B.A balanced reciprocal translocation

C.A balanced Robertsonian translocation

D.Two Barr bodies

E.Deletion of an imprinted locus

5.A 38-year-old woman in her 15th week of pregnancy undergoes ultrasonography that reveals an increased area of nuchal transparency. Amniocentesis is recommended and performed at 16 weeks’ gestation. The amniotic karyotype is 46,XYadd(18)(p.11.2), indicating additional chromosomal material on the short arm of one chromosome 18 at band

11.2.All other chromosomes are normal. What is the most likely cause of this fetal karyotype?

A.A balanced reciprocal translocation in one of the parents

B.A balanced Robertsonian translocation in one of the parents

C.An isochromosome 18i(p) in one of the parents

D.Nondisjunction during meiosis 1 in one of the parents

E.Nondisjunction during meiosis 2 in one of the parents

6.A 37-year-old woman is brought to emergency department because of crampy abdominal pain and vaginal bleeding for 3 hours. She is 11 weeks pregnant. This is her first pregnancy. Her pregnancy has been unremarkable until this episode. Her temperature is 36.8 C (98.2 F), pulse is 106/min, blood pressure is 125/70 mm Hg, and respiration rate is 22/min. Speculum examination shows the presence of blood in the vagina and cervical dilatation. Inevitable spontaneous abortion is suspected. After discussing the condition with the patient, she gave her consent for dilatation and curettage. What is the most common cause of spontaneous abortions?

A.Chromosomal abnormality, polyploidy

B.Chromosomal abnormality, monosomy X

C.Chromosomal abnormality, trisomy

D.Effects of environmental chemicals

E.Immunologic rejection

F.Infection

G.Maternal endocrinopathies

H.Physical stresses

I.Teratogenic drugs

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Part II ● Medical Genetics

Answers

1.Answer: D. As a translocation carrier, it is possible that she can transmit the translocated chromosome, containing the long arms of both 14 and 21, to each of her offspring. If she also transmits her normal copy of chromosome 21, then she will effectively transmit two copies of chromosome 21. When this egg cell is fertilized by a sperm cell carrying another copy of chromosome 21, the zygote will receive 3 copies of the long arm of chromosome 21. The miscarriages may represent fetuses that inherited 3 copies of the long arm and were spontaneously aborted during pregnancy.

Although the risk for Down syndrome increases if a woman has had a previous child, there is no evidence that the risk increases if a more distant relative, such as a first cousin, is affected (choice A).

Although there is no conclusive evidence for an increased risk of Down syndrome with advanced maternal age, there is little or no evidence for a paternal age effect on Down syndrome risk (choice B).

An extra copy of material from chromosome 14 or 18 (choice C)could result in a miscarriage, but neither would produce children with Down syndrome, which is caused by an extra copy of the long arm of chromosome 21.

Heavy irradiation has been shown to induce nondisjunction in some experimental animals, but there is no good evidence for a detectable effect on human trisomy (choice E).

2.Answer: A. The presence of an expanded trinucleotide repeat in the 5′ untranslated region of the gene is an accurate test for fragile X syndrome.

An IQ test (choice B)would be useful because the IQ is typically much lower than average in fragile X syndrome patients. However, many other syndromes also include mental retardation as a feature, so this would not be a specific test.

A karyotype of the child’s chromosomes (choice C) might reveal X chromosomes with the decondensed long arm characteristic of this syndrome, but not all chromosomes have this appearance in affected individuals. Thus, the karyotype may yield a false-negative diagnosis.

The father’s chromosomes (choice D) will not be relevant because this is an X-linked disorder.

Testicular volume (choice E) is increased in males with fragile X syndrome, but this is observed in postpubertal males.

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Chapter 3 ● Cytogenetics

3.Answer: D. The fetal karyotype shows a partial trisomy and a partial monosomy.

Fetal tissue

The fetus has 46 chromosomes, indicating euploidy (a multiple of 23), not aneuploidy (choice A). The father is the reciprocal translocation carrier, not the fetus (choice B). Nondisjunction during meiosis (choice C) produces full trisomies and chromosomes have normal structure. Although the father is a translocation carrier, his genetic material is balanced, not unbalanced (choice E). He is diploid for

all loci.

4.Answer: A. The daughter most likely has Turner syndrome, monosomy X, or 45,X. It should be high on the differential diagnosis list for a female adolescent of short stature who presents with primary amenorrhea. Women with Turner syndrome have streak gonads, and the absence of ovarian function is responsible for failure to develop many secondary sex characteristics.

Balanced translocations (choices B and C) have few, if any, consequences on the phenotype, although they may result in pregnancy loss of conceptions with unbalanced chromosome material.

Women with Turner syndrome have no Barr body. Two Barr bodies (choice D) would be consistent with a 47,XXX karyotype or a 48,XXXY karyotype, neither of which produces the phenotype described.

Deletion of a locus subject to imprinting (choice E) is consistent with Prader-Will syndrome or Angelman syndrome but is not associated with the phenotype described.

5.Answer: A. The fetus has unbalanced chromosomal material (additional chromosomal material on one copy of chromosome 18). One of the parents is likely to be a carrier of a reciprocal translocation involving chromosome 18 and one other chromosome (unspecified in stem).

A Robertsonian translocation (choice B) would result in fusion of q arms from two acrocentric chromosomes. This is not what is described in the fetal karyotype.

Isochromosome 18(p) indicates a chromosome 18 with two p arms and no q arms (choice C). This is not the abnormality described in the fetal karyotype.

Nondisjunction during either meiosis 1 or meiosis 2 (choices D and E) would produce a full trisomy.

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Part II ● Medical Genetics

6.Answer: C. Chromosomal abnormalities are responsible for about 50% of first trimester spontaneous abortions, and of these the most common cause is trisomy (52%). The most common trisomy in spontaneous abortion is trisomy 16. Polyploidy (choice A) is seen in 22% and monosomy

(choice B) in 19%.

All other listed causes can also cause miscarriage; however, these problems are less common than chromosomal anomalies.

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Genetics of Common Diseases 4

Learning Objectives

Interpret scenarios about multifactorial inheritance

OVERVIEW

Previous discussion has dealt with diseases caused by an alteration in a single gene or in a specific chromosome. Most common diseases (heart disease, cancer, diabetes, etc.) have substantial genetic components, but their causation is complex. These diseases tend to cluster in families (familial), but they do not conform to mendelian pedigree patterns. This chapter reviews some basic principles of the genetics of common, complex diseases.

MULTIFACTORIAL INHERITANCE

The term multifactorial inheritance refers to the fact that most common diseases are caused by multiple genes (i.e., a polygenic component) and expression is often influenced by environmental factors. The genetic and environmental factors involved are referred to as risk factors, and the summation of these in an individual represents that person’s liability for the disease. Because several genes and influential environmental factors contribute to the liability, its distribution in the population can be represented as a Gaussian (“bell-shaped”) curve. Figure II-4-1A shows an example of a distribution curve for body mass index (BMI), a multifactorial trait, in the U.S. adult population. The mean BMI is 26 ± 6 kg/m2. Because obesity is defined in terms of BMI (BMI ≥30 kg/m2), this graph can also represent a liability curve for obesity.

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