The wife of a 48-year-old male patient brings him to the emergency room and says that his memoryhas progressively gotten worse over the last several years. She also says his personality hasbeen changing. The physician notes abnormal writhing movements of the man's limbs andhyperreactive reflexes. MRI reveals a loss of volume in the neostriatum and cortex. This diseaseis inherited via an

A. autosomal dominant trait

B. autosomal recessive trait

C. x-linked dominant trait

D. x-linked recessive trait

Explanation:

The correct answer is A. This patient has Huntington's disease, which has autosomal dominantinheritance. It is characterized by severe degeneration of the caudate nucleus along withdegenerative changes in the putamen and cortex. In addition to chorea, these patients frequentlysuffer from athetoid (writhing) movements, progressive dementia, and behavioral disorders.

Genotype Enzyme Activity Phenotype G/G 100 Normal G/D 75 Normal G/LA 120 Normal G/g 50 NormalD/D 50 Normal D/LA 95 Normal LA/LA 140 Normal LA/g 70 Normal g/g <5 Galactosemia

Galactosemia, an inability to metabolize galactose, results from a deficiency of the enzymegalactose-1-phosphate uridyltransferase. The table above summarizes the genotypes and phenotypesat this locus. Which of the following alleles show less than normal activity of the enzyme?

A. D and G

B. D and g

C. D and LA

D. D only

E. G and g

F. G and LA

G. G only

H. g and LA

I. g only

Explanation:

The correct answer is B. While the phenotype for D/D is normal, the enzyme activity isdecreased. For g/g, the phenotype is affected and the enzyme activity is negligible. If you alsolook at the enzyme activity levels for heterozygotes such as G/g and G/D, their enzyme activityis diminished, even though their phenotype is normal. LA is an allele with enhanced enzymeactivity and the heterozygote LA/D shows almost wild-type enzyme activity. Only the D allele andg allele are consistently associated with decreased enzyme activity.

Tissue from a spontaneous abortion is submitted to the laboratory, where an astute pathologistnotes the presence of mature fetal tissue that contains Barr bodies. The fetus may have hadwhich of the following genotypes?

A. Classic Turner syndrome (45, X)

B. Edward's syndrome (47, XY+18)

C. Klinefelter's syndrome (47, XXY)

D. Normal male (46, XY)

E. XYY syndrome (47, XYY)

Explanation:

The correct answer is C. The Barr body, or X chromatin body, is an inactivated X chromosome seenas a small, perinuclear, dark-staining dot in somatic cells with two or more X chromosomes. Barrbodies are seen in any individual born with at least two X chromosomes, including normalfemales. (47, XXY), the classic karyotype of Klinefelter's syndrome, is defined as malehypogonadism due to the presence of a Y chromosome and two or more X's. As in normal females,one of the X chromosomes becomes a Barr body in Klinefelter's syndrome.

Classic Turner syndrome females (choice A) and genotypically normal males (choice D) have onlyone X chromosome. Thus, no X chromosome is inactivated, and somatic cells do not show any Barrbodies.

(47, XY+18) is the karyotype of an Edward's syndrome (choice B) fetus. Although this trisomicphenotype is associated with a characteristic syndrome of physical abnormalities, there is noprogrammed inactivation of the extra chromosome 18. Thus, no Barr body is produced.

XYY syndrome (choice E) is not associated with inactivation of any X chromosomes, so Barr bodiesare not present. Like a trisomy involving any of the non-sex-linked chromosomes, the duplicatedchromosome is expressed in its entirety.

Karyotypic analysis of a spontaneously aborted fetus demonstrates trisomy of one of thechromosomes. Which chromosome is most likely to be affected?

A. 8

B. 13

C. 16

D. 18

E. 21

Explanation:

The correct answer is C. Approximately half of all spontaneous abortions are of fetuses withmajor chromosomal defects, most commonly trisomy 16, triploidy (due to fertilization of an eggby two sperm), and 45 X,0 (Turner's syndrome). Trisomy 16 and triploidy do not produce viableoffspring, unlike 45 X,0.

Trisomy 8 (choice A) is one of the very rare causes of live birth trisomies.

Trisomy 13 (choice B) is one of the more common live birth trisomy syndromes (Patau syndrome).

Trisomy 18 (choice D) is one of the more common live birth trisomy syndromes (Edwards' syndrome)

Trisomy 21 (choice E) causes Down's syndrome.

On physical examination, a newborn is found to have micrognathia, a prominent occiput, low-setears, and rocker-bottom feet. There is very little mental development during the first months oflife and the infant dies of cardiac complications after 8 months. A complete karyotype of thischild would yield which of the following?

A. XO

B. XXY

C. Trisomy 13

D. Trisomy 18

E. Trisomy 21

Explanation:

The correct choice is D. This chromosomal aberration is also known as Edwards' syndrome, ortrisomy 18. It is characterized by mental deficiency, growth retardation, prominent occiput,micrognathia, low-set ears, rocker-bottom feet, and ventricular septal defect.

XO (choice A) is the karyotype of Turner syndrome. It is characterized by short stature, webbedneck, and hypogonadism.

XXY (choice B) represents Klinefelter syndrome. It is usually undetected at birth but ischaracterized by tall stature, male hypogonadism, and sometimes, mental retardation.

Trisomy 13 (Patau syndrome; choice C) is characterized by mental retardation, nervous systemmalformations, rocker-bottom feet, polydactyly, and cleft lip and palate.

Trisomy 21 (Down syndrome; choice E) is characterized by mental retardation, protruding tongue,simian crease, congenital heart defects, and a flat nasal bridge.

A 15-year-old boy is evaluated by a clinician for failure to develop normal male secondarysexual characteristics. Physical examination reveals small testes, a small penis, andgynecomastia. The boy has had some difficulties in school, and the parents say that the schoolpsychometrist said he had an IQ of 90. This patient's condition is most likely to be related towhich of the following?

A. Deletion

B. Nondisjunction of an autosomal chromosome

C. Nondisjunction of a sex chromosome

D. Non-Robertsonian translocation

E. Robertsonian translocation

Explanation:

The correct answer is C. The boy probably has Klinefelter's syndrome (47, XXY), which has thetypical presentation described in the question. The condition arises as a result of failure ofseparation (nondisjunction) of the sex chromosomes, and can be related to either paternalnondisjunction (slightly more common) or maternal nondisjunction.

Deletions (choice A) are a common form of genetic disease and contribute to many geneticrecessive diseases.

Examples of nondisjunction of autosomes (choice B) include trisomies such as most cases ofDown's syndrome (trisomy 21), Edwards' syndrome (trisomy 18), and Patau syndrome (trisomy 13).

There are two types of translocations: non-Robertsonian (choice D) and Robertsonian (choice E).Non-Robertsonian (reciprocal) translocations result when two non-homologous chromosomes exchangegenetic material. Robertsonian translocations are a special type of translocation that involveexchange of genetic material from the long arms of one acrocentric chromosome to the long armsof another acrocentric chromosome, with fusion of the centromeres. Four percent of cases ofDown's syndrome are caused by this mechanism.

A 20-year-old develops weakness accompanied by difficulty in relaxation that is most pronouncedin the hands and feet. Muscle biopsy demonstrates prominent ring fibers, centrally locatednuclei, chains of nuclei, and disorganized sarcoplasmic masses. This condition has beenassociated with a mutation on which of the following chromosomes?

A. X

B. Y

C. 4

D. 5

E. 19

Explanation:

The correct answer is E. The disease is myotonic dystrophy, which is an autosomal dominantdisease; the affected gene has been localized to chromosome 19. Myotonic dystrophy is relativelycommon and is best thought of as a systemic disease, since it causes cataracts, testicularatrophy, heart disease, dementia, and baldness in addition to muscular weakness.

A mutation on the X chromosome (choice A) causes Duchenne muscular dystrophy.

None of the muscle diseases are known to be related to defects on the Y chromosome (choice B).

Facioscapulohumeral dystrophy is associated with a defective gene on chromosome 4 (choice C).

Infantile hypotonia has been related to defective genes on chromosome 5 (choice D).

Which of the following diseases has an X-linked recessive inheritance pattern?

A. Alpha1-antitrypsin deficiency

B. Cystic fibrosis

C. Duchenne muscular dystrophy

D. Phenylketonuria

E. Tay-Sachs disease

Explanation:

The correct answer is C. Duchenne-type muscular dystrophy is the only disease listed that is X-linked; the other diseases are autosomal recessive. Remembering the genetics of myriads ofdiseases is very problematic, but here are some imperfect rules of thumb that can help you outif you encounter an unfamiliar disease on an examination. Deficiencies of most enzymes arerecessive (either autosomal or X-linked), since each person has at least two copies (from eachof the parents) of each enzyme, and one working gene is usually enough (although carefulevaluation of heterozygotes often shows mildly altered physiology). In contrast, alterations instructural proteins are often autosomal dominant, since having any amount of abnormal protein instructures such as basement membranes or in collagen tends to disturb their function. The numberof common X-linked diseases (almost all recessive) is small, and can be memorized: Duchennemuscular dystrophy, hemophilia A and B, chronic granulomatous disease, glucose-6- phosphatedehydrogenase deficiency, agammaglobulinemia, Wiskott-Aldrich syndrome, diabetes insipidus,Lesch-Nyhan syndrome, fragile-X syndrome, and color blindness.

Alpha1-antitrypsin deficiency (choice A) is a deficiency of an enzyme (alpha1-antitrypsin) thatinhibits the action of various proteolytic enzymes. The two autosomal alleles for alpha1-antitrypsin are codominantly expressed such that they both contribute to the levels ofcirculating alpha1-antitrypsin.

Cystic fibrosis (choice B) is an autosomal recessive disorder. The gene for cystic fibrosis hasbeen localized to chromosome 7.

Phenylketonuria (choice D), in its classical form, is an autosomal recessive deficiency ofphenylalanine hydroxylase.

Tay-Sachs disease (choice E) is an autosomal recessive deficiency of the enzyme hexosaminidaseA.

Microscopic examination of a cancer cell reveals a cell in an abnormal telophase in which threeclusters of chromosomes are seen. An abnormality of which of the following would be most likelyto produce this alteration?

A. Chiasma

B. Mitotic spindle

C. Mosaicism

D. Polar body

E. Synapsis

Explanation:

The correct answer is B. Abnormal mitotic spindles can produce tripolar mitoses. These areclearly abnormal mitoses that, when present, are considered definitive evidence that a tumor is

malignant rather than benign. They are therefore often searched for by pathologists evaluating atumor.

Chiasma (choice A) is the cross-like structure produced when a homologous pair of chromosomesaligns to exchange genetic material.

Mosaicism (choice C) refers to a difference in genetic material in different somatic cells ofthe same organism.

A polar body (choice D) is a daughter cell of a developing oocyte that contains almost nocytoplasm.

Synapsis (choice E) is a formal name for the pairing of homologous chromosomes with whichmeiosis begins.

A 28-year-old woman gives birth to a 1850 gm infant after a difficult pregnancy complicated byoligohydramnios. The infant is placed in the neonatal intensive care unit and tissue from theumbilical cord is sent for cytogenetic analysis. The infant's karyotype is 46, XY with noapparent abnormalities. No biochemical abnormalities are detected. The observed intrauterinegrowth retardation might have been caused by

A. chromosomal deletion

B. confined placental mosaicism

C. expansion of tandem nucleotide repeats

D. fetal trisomy

E. genomic imprinting

Explanation:

The correct answer is B. Confined placental mosaicism is the consequence of a genetic aberrationoccurring in the trophoblast or in extraembryonic progenitor cells in the inner cell mass. Thegenetic abnormality (e.g., a trisomy) leads to abnormal placental development and intrauterinegrowth retardation. Since the genetic abnormality is present only in the placenta, no geneticabnormalities will be detected in the neonate. Genetic mosaicism may also be confined to theembryo, or may be constitutional (affecting both the embryo and the placenta), depending on whenthe mutation occurs.

A chromosomal deletion (choice A) or fetal trisomy (choice D) are ruled out by the normalkaryotype.

Expansion of tandem nucleotide repeats (choice C) is thought to be involved in Fragile Xsyndrome and Huntington disease. Cytogenetic testing would have revealed this abnormality.

Genomic imprinting (choice E) is the phenomenon in which the phenotypic expression of a genediffers if the gene is inherited from the mother, as opposed to the father. Genomic imprintingmay affect expression of the genetic defect in confined placental mosaicism, but it is not thecause of the observed intrauterine growth retardation.

An infant develops tetany on the second day of life. Physical examination is remarkable fordysmorphic facies with low-set ears and micrognathia. Determination of serum electrolytesreveals severe hypocalcemia. Which of the following chromosomal aberrations is most likelyresponsible for this presentation?

A. Deletion in chromosome 22

B. Monosomy of chromosome 5

C. Translocation of chromosome 21

D. Trisomy of chromosome 13

E. Trisomy of X chromosome

Explanation:

The correct answer is A. DiGeorge syndrome is caused by malformation of the third and fourthpharyngeal pouches, leading to absence of the thymus and parathyroid glands, among otherabnormalities. It was originally believed that DiGeorge syndrome was an acquired abnormality,but recent studies suggest that deletions of chromosome 22q11 are frequently involved. Infantsafflicted with this syndrome present as dysmorphic babies who develop convulsions or tetany ashort time after birth due to severe hypocalcemia caused by a lack of parathyroid hormone. Thesepatients are very difficult to manage, and frequently have severe associated cardiac defectsthat may lead to death. Survivors often have at least small amounts of residual thymic tissue,and have a few circulating T cells that tend to slowly increase with age. Antibody production isusually adequate.

A slightly mentally retarded individual with menstrual irregularities is found to have a 47, XXXkaryotype. The average life span for individuals with this condition is

A. 10-20 years

B. 20-30 years

C. 30-40 years

D. 40-50 years

E. normal

Explanation:

The correct answer is E. 47, XXX is a surprisingly benign condition, the incidence of which isunknown because most cases are never diagnosed, as a normal phenotype with normal life span istypical. There is some increase in the incidence of mental retardation and menstrualirregularities in the population, particularly with increasing numbers of supernumerary Xchromosomes. Presumably, the inactivation of the extra X chromosome (forming a second Barr bodythat may be observed on a buccal smear examined for other reasons) limits the expression of theextra genes.

A cloned DNA fragment, when used as a probe, reveals a restriction fragment length polymorphism(RFLP) in the region adjacent to the centromere of chromosome 21. Four haplotypes exist: A, B,C, and D. An AB woman and a CD man have a child with trisomy 21 who is ACC. Nondisjunctionoccurred in

A. the child during the first mitotic division

B. the father during meiosis I

C. the father during meiosis II

D. the mother during meiosis I

E. the mother during meiosis II

Explanation:

The correct answer is C. The RFLP detects a region near the centromere of chromosome 21. Theregion around the centromere exhibits a phenomenon called crossover suppression. Since geneticexchange cannot happen in this area, the probe is a reliable marker for the individualchromosomes. During meiosis II, sister chromatids, which are two identical copies of the samechromosome, should separate. If a nondisjunction event occurs in this division, two copies ofthe same chromosome are passed to the progeny. In this case, both parents are heterozygous forthe probe. The child received an A from the mother and two Cs from the father, leading us toconclude that the problem occurred in the father during meiosis II.

Choice A (the child during the first mitotic division). If a nondisjunction event of chromosome21 occurs early in development, a child that is a mosaic for trisomy 21 is the result. Thisaccounts for approximately 1% of children with trisomy 21. Since some of their cells are normal,these individuals show only a mild expression of the trisomy 21 phenotype.

Choice B (the father during meiosis I). During meiosis I, homologues that carry similar but notidentical information separate. If a failure occurred in this division, we would expect the manto pass CD and the woman to pass A or B, producing a child that was ACD or BCD.

Choice D (the mother during meiosis I). If an AB woman had a failure in meiosis I, an AB gametewould be produced. When fertilized by the man's C or D sperm, a child that was ABC or ABD wouldresult.

Choice E (the mother during meiosis II). If an AB woman's sister chromatids failed to disjoinduring meiosis II, AA or BB gametes would result. When fertilized by the CD male's sperm, achild that was AAC, AAD, BBC, or BBD would result.

Examination of a karyotype taken from a metaphase preparation reveals the presence of an extrachromosome. Which of the following is the most common mechanism of producing this phenomenon?

A. Balanced translocation

B. Chromosomal breakage

C. Fertilization by two sperm

D. Nondisjunction

E. Unbalanced translocation

Explanation:

The correct answer is D. Nondisjunction can occur in both meiosis and mitosis, and refers to afailure of paired chromosomes to separate and go to different daughter cells. When this happens,one daughter cell gets an extra chromosome and the other daughter cell is "short" onechromosome.

A balanced translocation (choice A) is an exchange of genetic material between non-homologouschromosomes that preserves all critical genetic material.

Chromosomal breakage (choice B) produces fragmented chromosomes and can contribute totumorigenesis.

Fertilization by two sperm (choice C) produces triploidy and is seen in many spontaneouslyaborted fetuses.

An unbalanced translocation (choice E) occurs when non-homologous chromosomes exchange geneticmaterial with a net loss or gain of critical genetic material.

A 13-year-old boy is brought to a rural clinic because of poor school performance. His parentsstate that he did not begin talking until after three years of age, and still does not uselanguage as effectively as his sister, who is 6-years-old. A careful family history reveals thata maternal grandfather was mildly retarded. The mother has two sisters, both of whom areapparently normal, but the mother admits that she did not do well in school, and dropped out atthe age of 16. Physical examination of the child reveals large ears, a long, narrow face, andlarge testes. Which of the following genetic mechanisms most likely accounts for the observedfindings in the son?

A. Expanded trinucleotide repeat

B. Genomic imprinting

C. Robertsonian translocation

D. Trisomy 13

E. Trisomy 18

Explanation:

The correct answer is A. The features described are typical of the familial form of mentalretardation known as fragile X syndrome. This disorder is the second most common heritable causeof mental retardation, second only to Down syndrome. Striking features of this disease are thatthe clinical features tend to worsen with each successive generation, and that males are usuallymuch more severely affected than females, although nearly 50% of carrier females are at leastslightly mentally retarded. The explanation appears to involve a region of DNA on the Xchromosome that normally contains 6-54 tandem repeats of the sequence CGG. Carrier females forfragile X syndrome may have up to 200 CGG repeats. Clinically affected individuals have250-4,000 repeats of the CGG sequence. The greater the number of repeats, the more severe theretardation tends to be. Amplification of premutations to full mutations appears much morelikely to occur during oogenesis than spermatogenesis.

Genomic imprinting (choice B) is a phenomenon in which the phenotypic expression of a genediffers if the gene is inherited from the mother, rather than the father. An example of thiseffect is Angelman ("happy puppet") syndrome, caused by a deletion of band q12 in the maternalcopy of chromosome 15. A similar deletion in the paternal chromosome 15 produces a differentdisease called Prader-Willi syndrome.

A Robertsonian translocation (choice C) causes about 5% of cases of Down syndrome. Generally themother [typically with genotype 45, XX, -14, -21, +t(14q; 21q)] has normal mentation, but someof her children may carry the translocation in addition to the normal maternal chromosome 21 andnormal paternal chromosome 21, producing partial trisomy 21. This form of Down syndrome canappear to be a recessive genetic disease.

Trisomy 13 (Patau syndrome; choice D) is characterized by microcephaly, mental retardation,cleft lip and palate, polydactyly, and rocker-bottom feet. Survival is rare beyond one year.

Trisomy 18 (Edwards syndrome; choice E) is characterized by mental retardation, micrognathia,low-set ears, cardiac defects, renal defects, and rocker-bottom feet. Survival is rare beyondone year.

In a certain population, the frequency of color-blind males is 1 in 100. Assuming that thepopulation is in Hardy-Weinberg equilibrium at this locus, the frequency of color-blind femalesis approximately

A. 0.0001

B. 0.0005

C. 0.01

D. 0.02

E. 0.025

Explanation:

The correct answer is A. Color blindness is an X-linked recessive trait. A male is hemizygousfor the X chromosome, and thus has only one copy of each trait. The frequency of an X-linkedrecessive in males is thus equal to the frequency of the allele in the population. From this, weknow that q = 0.01 and p = 0.99. A female has two copies of each gene on the X chromosome, sothe equation for Hardy-Weinberg equilibrium is the same as for the autosomal traits. In thiscase, a homozygous recessive female would occur at a frequency of q2 or 0.0001.

Choice B, 0.0005, is incorrect. If you remembered that color blindness was more frequent inmales, but did not know how to use the equations to get the true estimate, you might haveguessed this answer.

Choice C, 0.01, makes the assumption that the trait is autosomal, and so the frequencies ofaffected males and affected females are equal.

Choice D, 0.02, assumes that q = 0.01, and then calculates the frequency of carrier females(2pq).

Choice E, 0.025 is also incorrect; it is a distracter.

A 3 year-old boy is brought to a physician because the mother notices that the child is engagingin less active play and tires easily. During physical examination, the pediatrician notices thatthe child's thighs are larger than normal for age and that the child cannot stand up withoutusing his arms to help. Further studies demonstrate a defective dystrophin gene in the boy.Which of the following people in the child's family is most likely to also have this disease?

A. Father

B. Father's brother

C. Mother

D. Mother's brother

E. Sister

Explanation:

The correct answer is D. The disease is Duchenne muscular dystrophy, an X-linked recessivemuscular disease usually caused by a deletion involving the dystrophin gene. This defectproduces accelerated muscle breakdown leading initially to proximal muscle weakness, then laterto generalized weakness that typically begins before age 5. A feature of X-linked recessivediseases is that carrier mothers pass the disease to half their sons; affected fathers can havecarrier daughters but not affected sons. Since the mother is presumably normal (because thedisease is X-linked), she must be a carrier to have an affected son, and the grandmother mustalso be a carrier, therefore the mother's brother (maternal uncle) may also have the disease.

The father's (choice A) side of the family, including the father's brother (choice B), mostlikely does not carry the defective gene (since they themselves would be affected, andfurthermore since the father cannot pass the gene on to a son). It would be extremely unlikelyfor a carrier female to marry an affected male (and the question does not mention any similarsymptoms in the father).

The mother (choice C) and possibly the sister (choice E) are carriers of, but not affected by,the defective gene.

A retarded 45-year-old man living in Mexico becomes ill with pneumonia and his family brings himacross the border to the United States. He succumbs to his illness and an autopsy is performed.Neuropathological examination of his brain reveals neuritic plaques and neurofibrillary tangles.Which of the following was the most likely cause of this man's retardation?

A. Down's syndrome

B. Edwards' syndrome

C. Fragile X syndrome

D. Patau syndrome

E. Supernumerary Y syndrome

Explanation:

The correct answer is A. Features of Down's syndrome (trisomy 21) in children include mentalretardation, epicanthal folds, dysplastic ears, hypotonia, a horizontal palmar crease (simiancrease), redundant neck skin, and a short trunk. However, most of these children eventually growto adulthood. At that point, the aging parents may have to deal with a physically strong andhealthy mentally retarded individual who is experiencing a deterioration in mental function.This deterioration may be accompanied by aggressive behavior (as in the elderly with Alzheimer'sdisease) arising out of the patient's diminishing ability to reason or understand hisenvironment.

Edwards' syndrome (choice B), or trisomy 18, causes death in infancy. Characteristics includerocker-bottom feet, low-set ears, micrognathia, congenital heart disease, and mentalretardation.

Fragile X syndrome (choice C) is associated with enlarged testes as well as mental retardation.The condition is unusual in that it is related to expansion of a CGG repeat sequence located onthe X chromosome.

Patau syndrome (choice D), or trisomy 13, is characterized by severe mental retardation,microcephaly, microphthalmia, polydactyly, cleft lip and palate, renal defects, and cardiacabnormalities. Affected infants typically die before the age of 1.

The effects of supernumerary Y chromosomes (choice E; most commonly XYY) include increasedstature, aggressive behavior, and infertility, but a supernumerary Y chromosome is sometimesfound in otherwise normal individuals.

19

A 26-year-old woman and her 29-year-old husband have been trying to have a child for the last 3years. During this time the woman has had 5 spontaneous abortions. The karyotypes of the mother,father, and the most recently aborted fetus all contained 46 chromosomes, and all pairs werenormal except for the pairs shown above. The event that led to the child's abnormal karyotypewas

A. adjacent I segregation

B. adjacent II segregation

C. alternate segregation

D. a recombination event within a paracentric inversion

E. a recombination event within a pericentric inversion

Explanation:

The correct answer is B. The couple is experiencing infertility and a high rate of spontaneousabortions because the father has a reciprocal translocation between chromosome 7 and chromosome12. His karyotype is 46, XY, t(7;12) (12qter &rarr; 12q23::7p13 &rarr; 7qter; 12pter &rarr;12q23::7p13 &rarr; 7pter). During meiosis I, the four chromosomes involved in the translocationwill pair together in a structure called a quadrivalent, which is pictured below.

There are three ways that the quadrivalent can separate during meiosis I. They are calledadjacent I, adjacent II, and alternate segregation. Adjacent II segregation occurs only when thebreakpoint of the translocation is so close to the centromere of a chromosome that the cellcannot distinguish between the centromeres. In this specific case, the fetus received a normalchromosome 7 and a normal chromosome 12 from his mother. From his father, the fetus received anormal chromosome 7 and a chromosome composed of 12qter &rarr; 12q23::7p13 &rarr; 7qter. Thisgives the fetus a total of three copies of the material from 7p13 &rarr; 7qter, and only onecopy of material from 12pter &rarr; 12q23. Note that the zygote has three copies of thecentromere of chromosome 7, the hallmark of adjacent II segregation. Since the zygote isunbalanced, it aborts.

Adjacent I segregation (choice A) produces cells that contain different centromeres, but haveduplication and deletions that lead to spontaneous abortion. In this case, the products ofadjacent I segregation would be 12qter &rarr; 12q23::7p13 &rarr; 7qter and the normal chromosome12, or 12pter &rarr; 12q23::7p13 &rarr; 7pter and the normal chromosome 7.

Alternate segregation (choice C) yields the only outcomes that produce viable progeny. Twoproducts are produced. One contains a normal chromosome 7 and a normal chromosome 12, and thesecond product contains the balanced translocation. This cell has all the information it needs;it is just arranged in a unique order. In this case, 12qter &rarr; 12q23::7p13 &rarr; 7qter and12pter &rarr; 12q23::7p13 &rarr; 7pter.

A recombination event within a paracentric inversion (choice D) leads to the formation of anacentric fragment and a dicentric bridge. This cell will not complete meiosis.

A recombination event within a pericentric inversion (choice E) leads to chromatids that areduplicated for material on one of the arms and deleted for material on the other arm.

A couple is referred to a specialist for evaluation of their two-and-a-half year old son. Thechild has multiple congenital defects including mental retardation, hirsutism, micrognathia, andcardiac and renal abnormalities. Karyotypes are done of both parents and the child, and theresults are shown above. The event that led to the child's abnormal karyotype was

A. adjacent I segregation

B. adjacent II segregation

C. alternate segregation

D. a recombination event within a paracentric inversion

E. a recombination event within a pericentric inversion

Explanation:

The correct answer is E. An inversion is a chromosomal rearrangement in which the centralsegment produced by two breaks is inverted prior to repair of the breaks. Inversions thatinclude the centromere are called pericentric inversions. Those that do not include thecentromere are called paracentric inversions. Examination of the father's karyotype reveals thathe has a pericentric inversion on one of his chromosome 3s - [inv(3) (p25q21)]. To allow pairingof homologous material, his homologues will form a loop structure during meiosis I. If arecombination event occurs with the loop, the chromatids produced by the crossover event will beduplicated for material on one of the arms and deleted for material on the other arm. Anillustration of these events is given below.

Examination of the third chromosomes of the child reveals that he has one normal chromosome anda chromosome that is duplicated for q21 qter (ter = terminal) and deleted for p25 pter.

Adjacent I and II segregation (choices A and B) and alternate segregation (choice C) refer tothe possible segregation events undergone by the quadrivalent during anaphase of meiosis I.

The outcome of a crossover event within a paracentric inversion (choice D) is the formation ofan acentric fragment and a dicentric bridge. This cell will not complete meiosis. A reciprocaltranslocation event involves the exchange of material between nonhomologous chromosomes. Duringmeiosis I, the four chromosomes involved in the translocation will pair together in a structurecalled a quadrivalent.

During the process of meiosis, a single homologous chromosome pair fails to separate during thefirst meiotic division. This failure would be most likely to produce which of the followingconditions if fertilization occurs and an embryo later develops?

A. Balanced translocation

B. Triploidy

C. Trisomy

D. Unbalanced translocation

E. Uniploidy

Explanation:

The correct answer is C. The process described is nondisjunction, which will cause one daughtercell to have 24 chromosomes while the other will have 22 chromosomes. When a gamete with thenormal 23 chromosomes combines at fertilization with a gamete with 22 or 24 chromosomes, theembryo will have 47 chromosomes (trisomy) or 45 chromosomes (monosomy). Nondisjunction can occurin either the first or second meiotic division.

Balanced translocation (choice A) occurs when non-homologous chromosomes exchange geneticmaterial in such a way that no critical genetic material is lost.

Triploidy (choice B) is the term used when a cell has 69 chromosomes (3 of each), and can occurin tumors or when an egg is fertilized by two sperm.

An unbalanced translocation (choice D) occurs when non-homologous chromosomes exchange geneticmaterial with a net loss or gain of critical genetic material.

Uniploidy (choice E) is the state of having 23 chromosomes, seen normally in sperm and eggs.

Physical examination of a neonate demonstrates abnormal facies with a small lower jaw, low-setears, and a prominent occiput. The feet have a rocker-bottom deformation, and the infant ishypertonic. Cardiac evaluation demonstrates a ventricular septal defect. Which of the followingis the average life-span for infants with this neonate's syndrome?

A. 2-3 months

B. 1-2 years

C. 4-7 years

D. 15-25 years

E. Normal life expectancy

Explanation:

The correct answer is A. The syndrome described is Edwards' syndrome (trisomy 18), which istypically characterized by the features noted and additionally causes severe mental retardation,which would not be recognizable in the neonatal period. This disease is relatively common, withan incidence of about 1 in 5000 births (Down syndrome has an incidence of 1 in 2000 births). Theaverage life span is only 2-3 months.

A 6-month-old child with severe mental retardation is brought to a specialty clinic. Physicalexamination is remarkable for microcephaly, a cat-like cry, and an anti-mongoloid slant to thepalpebral fissures. This child should be further evaluated for which of the following disorders?

A. Duodenal atresia

B. Hepatocellular carcinoma

C. Nephroblastoma

D. Renal cysts

E. Ventricular septal defect

Explanation:

The correct answer is E. The presentation is classic for cri-du-chat syndrome, caused by adeletion of the short arm of chromosome 5 (5p-). Approximately one-quarter of such patients havea ventricular septal defect. Other features of the syndrome include short stature, distortedlaryngeal anatomy, profound mental retardation, microcephaly, a wide nasal bridge, and an anti-mongoloid slant to the palpebral fissures. The laryngeal malformation causes feeding andrespiratory difficulties, as well as the cat-like cry, which typically disappears by age 1. Manypatients survive to adulthood, but are usually institutionalized.

Transcription of a prokaryotic gene by RNA polymerase yields an mRNA corresponding to a singlepolypeptide chain containing 64 amino acids. The mRNA has a 5' untranslated region of 120nucleotides and a 3' untranslated region of 240 nucleotides. Approximately how many nucleotidesare in the coding region of the mRNA?

A. 64

B. 128

C. 192

D. 424

E. 552

Explanation:

The correct answer is C. Regardless of how long the untranslated regions are, the number ofnucleotides in the coding region of an mRNA is three times the number of amino acids, sincethree nucleotides are required to code for each amino acid, and 3 X 64 = 192. In reality, threenucleotides code for the first amino acid (formyl-methionine in prokaryotes, methionine ineukaryotes), which may be removed in posttranslational steps, and three nucleotides at the 3'end (are needed to terminate the process (i.e., a STOP codon), so the actual number would likelybe slightly higher.

A 42-year-old woman is pregnant and undergoes amniocentesis. The results of the amniocentesisare consistent with trisomy 21, but the woman wishes to carry the pregnancy to term. Afterbirth, this child will be at increased risk for the development of which of the followingneoplasms?

A. Acute lymphoblastic leukemia

B. Basal cell carcinoma

C. Colon cancer

D. Glioblastoma multiforme

E. Hodgkin's disease

Explanation:

The correct answer is A. In addition to the well-known mental retardation associated with Down'ssyndrome (trisomy 21), affected individuals have an increased incidence of a variety of medicalproblems. Acute myeloblastic leukemia is seen in newborns and acute lymphoblastic leukemia isseen in older children. Epilepsy, which can be very difficult to manage, affects up to 10% ofchildren with Down's. On occasion, the malformed head and neck region can undergo atlantoaxialdislocation, causing a sudden or progressive quadriparesis. Congenital malformations of thecardiac system are common (40% of cases), and include (in decreasing order of frequency) atrialand ventricular septal defects, tetralogy of Fallot, and patent ductus arteriosus. Thedevelopment of the hypopharynx is often poor, predisposing to both aspiration pneumonia andobstruction by enlarged adenoids. Other malformations that occur with lower frequency includeduodenal atresia and imperforate anus. Acquired autoimmune hypothyroidism is frequent. Boys areinfertile; girls are subfertile but can get pregnant. Alzheimer-like changes develop in mid-adulthood. Visual problems related to strabismus, nystagmus, or myopia are common. None of theother neoplasms occur with increased frequency in individuals with trisomy 21.

26

In a rural town, 19-year-old boy and his 16-year-old sister have two children by an incestuousrelationship, as shown in the pedigree above. The girl did not have prenatal care for eitherchild. The second child, a girl, is brought to the emergency room at three months of age becauseof seizures. Physical examination is remarkable for hepatomegaly and growth retardation. Serumchemistries demonstrate severe hypoglycemia and hyperlipidemia. This patient may have a defectinvolving which of the following enzymes?

A. Alpha-L-iduronidase

B. Beta-glucocerebrosidase

C. Glucose-6-phosphatase

D. Hexosaminidase A

E. Muscle phosphorylase

Explanation:

The correct answer is C. The presence of hepatomegaly and hypoglycemic seizures suggests thatthis is probably a glycogen storage disease. Only two of the enzymes listed are related toglycogen storage diseases: glucose-6-phosphatase (deficiency produces von Gierke's disease, fromwhich this patient is suffering) and muscle phosphorylase (choice E; deficiency producesMcArdle's disease). McArdle's disease is relatively mild, causing only muscle weakness beginningin the second or third decades, so this option can be excluded. Von Gierke's disease is aglycogen storage disease caused by a deficiency of glucose-6-phosphatase (type Ia), or theglucose-6-phosphate translocase (type Ib). It typically presents with neonatal hypoglycemia,hyperlipidemia, lactic acidosis, and ketosis. Failure to thrive is common in early life;convulsions may occur due to profound hypoglycemia. The glycogen accumulation in von Gierke'sdisease occurs primarily in the liver and kidneys, accounting for the enlargement of theseorgans. Gout may develop later because of the derangement of glucose metabolism. Von Gierke'sdisease, like most enzyme deficiencies, is inherited as an autosomal recessive disorder.

Alpha-L-iduronidase (choice A) is the defective enzyme in Hurler's syndrome, which is associatedwith hepatosplenomegaly, dwarfism, skeletal abnormalities, mental retardation, and cornealclouding.

Beta-glucocerebrosidase deficiency (choice B) causes Gaucher's disease, which is characterized

by hepatosplenomegaly and glucocerebroside accumulation in phagocytic cells.

Hexosaminidase A (choice D) deficiency is associated with Tay-Sachs disease, which ischaracterized by progressive neurologic deterioration.

The pedigree above illustrates the mode of inheritance for which of the following diseases?

A. Glucose-6-phosphate dehydrogenase deficiency

B. Leber's hereditary optic neuropathy

C. Neurofibromatosis

D. Sickle cell anemia

E. Tay Sachs disease

Explanation:

The correct answer is A. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (choice A) is an X-linked recessive disorder that affects the pentose phosphate pathway. The hallmark of X-linkedrecessive inheritance is an abundance of affected males and an absence of affected females.Males are hemizygous for the X chromosome, so the phenotype is expressed with only one dose ofthe gene. Females have two copies of the X chromosome, so they appear phenotypically normalalthough they may carry the recessive allele. Since a male inherits his X chromosome from hismother, if he is affected, she must carry the trait. Other X-linked recessives include Lesch-Nyhan disease, hemophilia A, and Duchenne's muscular dystrophy.

Leber's hereditary optic neuropathy (choice B) is a relatively common cause of acute or subacutevision loss, especially in young men. It exhibits a mitochondrial inheritance pattern. Thehallmark of this pattern is matrilineal inheritance. All of the children of an affected womanwill be affected since they receive mitochondrial genes only from the female parent. Affectedmales do not contribute mitochondria to progeny, so their children will not receive the trait.

Neurofibromatosis (choice C) shows an autosomal dominant inheritance pattern, so the phenotypewill be expressed if the allele is present in one dose. Deleterious autosomal dominants occur atvery low frequencies, so affected individuals are almost always heterozygous for the trait.Since the gene is located on an autosome, both male and female progeny can be affected. Otherautosomal dominants include Ehlers-Danlos syndrome, Huntington's disease, and osteogenesisimperfecta.

Sickle cell anemia (choice D) and Tay Sachs disease (choice E) are both inherited as autosomalrecessives. For the phenotype of the autosomal recessive to be expressed, the recessive allelemust be present in two doses. Both male and female children can be affected. The hallmarkfeature is that unaffected parents have affected children of both sexes.

A baby is born with a small head, small eyes, and 6 fingers on each hand. Two dimensionalechocardiography reveals congenital heart defects. Which of the following genetic conditions ismost likely to be the cause of this child's presentation?

A. Trisomy 13

B. Trisomy 18

C. Trisomy 21

D. XXY

E. XYY

Explanation:

The correct answer is A. This is Patau syndrome, or trisomy 13. This disorder is also associatedwith severe mental retardation, abnormal forebrain structures, and death within one year ofbirth. Patau syndrome has an incidence of 1:6000 births, making it the second most common formof autosomal trisomy.

Trisomy 18 (choice B) is Edwards syndrome, characterized by severe mental retardation, rockerbottom feet (also sometimes seen in Patau syndrome, so be careful!), low-set ears, micrognathia,clenched hands, prominent occiput, and death within one year. Edwards syndrome has an incidenceof 1:8000, making it the third most common autosomal trisomy.

Trisomy 21 (choice C) is Down syndrome, and is characterized by mental retardation, flat facialprofile, prominent epicanthal folds, simian crease, duodenal atresia, and congenital heartdisease. Down syndrome is the most common autosomal trisomy, with an incidence of 1:700.

XXY (choice D) is Klinefelter syndrome and is associated with male hypogonadism and infertility,eunuchoid body habitus, gynecomastia, and lack of male secondary sexual characteristics.

XYY (choice E) is double Y syndrome. Affected individuals often go undetected, but may be tallerthan average, and may be more likely to exhibit aggressive, antisocial behavior.

A 43-year-old man is brought to the general medicine clinic by his wife. She states that hismemory has progressively deteriorated over the last several years, and that his personality hasbeen changing. On examination, the physician notes abnormal, writhing movements of the man'slimbs and hyperreactive patellar reflexes. An MRI of the head reveals a loss of volume in theneostriatum and cortex. A family history reveals that similar symptoms occurred in severalmembers of the patient's family. Which of the following genetic mechanisms has been implicatedin this disorder?

A. Expanded trinucleotide tandem repeat

B. Genomic imprinting

C. Large deletion in one gene

D. Single amino acid substitution

E. Translocation

Explanation:

The correct answer is A. The disease described is Huntington's disease, which is now known to berelated to an expanded trinucleotide tandem repeat on the short arm of chromosome 4. The numberof trinucleotide repeats frequently increases in succeeding generations during the process ofspermatogenesis.

Prader-Willi and Angelman syndromes are frequently cited examples of genetic diseases involvinggenomic imprinting (choice B).

Duchenne's muscular dystrophy is an example of a disease that is frequently due to a largedeletion in a single gene (choice C).

Single amino acid substitutions (choice D) are common in recessive diseases such as sickle cellanemia.

Translocations (choice E) occur in disorders such as chronic myelogenous leukemia (CML;Philadelphia chromosome) and some cases of Down's syndrome.

A 10-year-old boy with the facies and many other critical features of Down's syndrome has anintelligence quotient (IQ) in the mid-normal range. Which of the following genetic mechanismswould most likely account for the discrepancy between the child's IQ and his appearance?

A. Balanced translocation

B. Chiasma

C. Mosaicism

D. Spermiogenesis

E. Synapsis

Explanation:

The correct answer is C. Mosaicism is the term used when cells with more than one type ofgenetic constitution are present in the same organism. The scenario described in the questionuncommonly occurs when nondisjunction of chromosome 21 occurs during mitosis (rather thanmeiosis) in one of the early cell divisions. The degree to which the individual expresses thecharacteristics of the syndrome depends on the number of cells involved and their distribution.

Balanced translocation (choice A) does not produce features of any syndrome, because criticalgenetic material is not lost, although progeny may be affected when the translocated chromosomeis added to a complement of otherwise normal chromosomes.

Chiasma (choice B) refers to the "X"-shape of chromosomes undergoing exchange of geneticmaterial in crossover.

Spermiogenesis (choice D) refers to the development of sperm precursors into mature sperm.

Synapsis (choice E) refers to the pairing of homologous chromosomes in the first meioticdivision.

A couple has a daughter who is ataxic and has a seizure disorder. She also has a strange affectcharacterized by excessive laughter at inappropriate times. Cytogenetic analysis demonstrates anormal genotype with 46 chromosomes and no apparent deletions. These symptoms are most likelydue to

A. a point mutation in an autosome

B. confined placental mosaicism

C. expansion of a trinucleotide repeat

D. random inactivation of the X chromosome

E. uniparental disomy

Explanation:

The correct answer is E. The child described is exhibiting the features of Angelman (happypuppet) syndrome. This disorder is generally caused by a deletion of band q12 in the maternalcopy of chromosome 15, i.e., [(del (15)(q11q13)]. A similar deletion in the paternal chromosome15 produces Prader-Willi syndrome. The disparate expression of the effects of deletions in thepaternal vs. the maternal chromosomes is called genomic imprinting, and implies that the samegenetic loci are expressed quite differently in maternal and paternal chromosomes. Angelmansyndrome can also occur if uniparental disomy occurs for chromosome 15 such that the embryoreceives two copies of the paternal chromosome 15 without the maternal chromosome 15 to"balance" the paternal contribution.

Point mutation in autosomes (choice A) has not been associated with Angelman syndrome.

Confined placental mosaicism (choice B) is due to a mutation occurring within trophoblast orextraembryonic precursor cells of the inner cell mass and is an important cause of intrauterinegrowth retardation.

Expansion of a trinucleotide repeat (choice C) is associated with Fragile X syndrome andHuntington disease.

Random inactivation of the X chromosome (choice D) occurs normally, as postulated in the Lyonhypothesis.

In the pedigree above, what is the probability that IV.3 is a carrier of this trait?

A. 1/4

B. 1/3

C. 1/2

D. 2/3

E. 1/1

Explanation:

The correct answer is D. Given that both III.1 and III.2 must be carriers since they haveproduced affected offspring and the pedigree is obviously that of an autosomal recessive(multiple affected children from unaffected parents), there is a 2/3 chance that IV.3 is acarrier. In a cross, there would be a 25% chance that they would be normal, 50% chance that theywould be carriers, and 25% chance that they would be affected. Since we know they are notaffected, we can disregard that probability (25%). This means that we are now dealing with theremaining 75%, and that the original 50% chance of being a carrier, divided by the remaining 75%(.50/.75) now equals 66%, or 2/3.

Retinoblastoma is associated with an abnormality in which chromosome?

A. 5

B. 8

C. 13

D. 21

E. X

Explanation:

The correct answer is C. About 20% of patients with chromosome 13 abnormality (13q-syndrome)develop retinoblastoma. There is also a genetic dominant form of retinoblastoma that has an 80%penetrance rate. Retinoblastomas that have a genetic basis are more apt to be bilateral than thespontaneous lesions. Microscopically, retinoblastomas are composed of masses of smallhyperchromatic cells that may form small rosettes composed of radially arranged cellssurrounding a central lumen.

A family is referred to a genetic specialist because of mild mental retardation in several ofthe school-age children. Laboratory evaluation demonstrates a specific chromosomal breakage sitein metaphase studies of lymphocytes cultured with methotrexate. Which of the followingchromosomes is most likely to be specifically affected?

A. X

B. Y

C. 13

D. 18

E. 21

Explanation:

The correct answer is A. The heritable mental retardation condition associated with chromosomalbreakage is fragile X syndrome. The break point is at q27.3 on the X chromosome. The test forthis condition involves culturing lymphocytes in either folate-deficient medium or with chemicalagents such as methotrexate that tend to break chromosomes. To make the diagnosis, at least 4%of metaphase chromosomes must show the specific break-point on the X chromosome. The percentageof defective X-chromosomes above 4% does not correlate well with the degree of mentalretardation. The breakage point is a site of CGG trinucleotide repeats, which tend to expand insuccessive generations, producing the clinical feature of worsening mental retardation in eachgeneration.

Y chromosome (choice B) damage is not part of fragile X syndrome, but loss of this chromosome isone mechanism of producing 45, X0 (Turner syndrome), characterized by mental retardation.

Trisomy 13 (choice C, Patau syndrome), trisomy 18 (choice D, Edward's syndrome) and trisomy 21(choice E, Down's syndrome) are all associated with mental retardation, but not chromosomalbreakage syndromes.

The pregnant mother of a 6-year-old son with glucose&ndash;6-phosphate dehydrogenase deficiencyis very worried that her female fetus will have the disease. The father and mother areclinically normal. Which of the following is true about her baby?

A. The baby has a 25% chance of clinical disease

B. The baby has a 50% chance of being a carrier

C. The baby has a 50% chance of clinical disease

D. The baby will be a carrier

E. The baby will have clinical disease

Explanation:

The correct answer is B. Glucose-6-phosphate dehydrogenase disease is an X-linked condition. Thefather has a normal X chromosome since he does not have clinical disease. The mother has onenormal X chromosome and one defective X chromosome, since her 6-year-old son has the disease andshe does not. Therefore, the female fetus has a 50% chance of having two normal X chromosomesand a 50% chance of having one normal and one abnormal X chromosome, making her a carrier.

Glucose 6-phosphate dehydrogenase deficiency is a defect in the pentose phosphate pathway ofglucose metabolism, leading to defective production of reduced NADPH. Reduced NADPH is used inmany biochemical pathways, and is specifically used to regenerate the reduced form ofglutathione that protects the body against oxidant drugs.

Examination of a late aborted fetus reveals a small head, small eyes, prominent cleft lip andpalate, 6 fingers on each hand, and dextrocardia. The developmental abnormalities noted in thisfetus were probably due to

A. 5p-

B. 45, XO

C. trisomy 13

D. trisomy 18

E. trisomy 21

Explanation:

The correct answer is C. Chromosomal aberrations are common in spontaneously aborted fetuses.This fetus has Patau syndrome (trisomy 13). A convenient way to remember trisomy 13 is to thinkof polydactyly (remembered as 13 fingers) and midline defects including microphthalmia (rarelyjust one central "eye"), cleft lip, palate, or face; arrhinencephalia (failure of development ofolfactory nerves and related brain); and dextrocardia or ventricular septal defect. The head isusually small, with profound mental retardation. In fetuses that survive until birth, deathusually occurs in the neonatal period. Patau syndrome has an incidence of 1 in 6000 births.

Features of Cri du Chat syndrome (5p-; choice A) include a cat-like cry, severe mentalretardation, microcephaly, and epicanthal folds.

Features of Turner's syndrome (45, X0; choice B) include webbed neck, short stature, broadchest, low hairline, primary amenorrhea, coarctation of aorta and streak ovaries.

Features of Edwards' syndrome or trisomy 18 (choice D) include severe mental retardation,ventricular septal defect, micrognathia, rocker-bottom feet, low-set ears, prominent occiput,and hypotonia.

Features of Down syndrome or trisomy 21 (choice E) include mental retardation, flat nasalbridge, epicanthal folds, oblique palpebral fissures, dysplastic ears, horizontal palmar crease,redundant neck skin, short trunk, ventricular septal defect, acute lymphoblastic leukemia, andneurologic changes similar to those of Alzheimer's disease.

A couple has four children, three girls and a boy. The girls are healthy, but the boy developscorneal opacities, painful neuropathies, and multiple, violaceous nodules distributed diffuselyover his skin. Two of the daughters marry and have a total of seven children. As shown in thepedigree above, two of these children develop the same syndrome as did the affected son in theF1 generation. Which of the following is the likely diagnosis?

A. Fabry's disease

B. Gaucher's disease

C. Krabbe's disease

D. Metachromatic leukodystrophy

E. Niemann-Pick disease

Explanation:

The correct answer is A. Even if you do not remember the features of the individual lipidstorage diseases, it is worth remembering that Fabry's disease (described above) is the only onein the group with X-linked genetics. As a general rule, you should associate all of the lipidstorage diseases with severe neurologic deterioration. The exception is Gaucher's disease(choice B), which tends to affect the liver and spares the brain.

Gaucher's disease (choice B), Niemann-Pick disease (choice E), and Type I Tay-Sachs disease arenot X-linked; all occur with greater frequency in Ashkenazi Jews.

You should associate Krabbe's disease (choice C) with the presence of "globoid" cells indegenerating white matter in the brain.

Metachromatic leukodystrophy (choice D) is caused by a deficiency of the enzyme arylsulfatase A.

A 5-year-old mentally retarded boy is brought to the city from a rural community for evaluation.A careful history reveals mental retardation in a number of other family members, especially themales. Physical examination is remarkable for a long face with large ears, a large jaw andbilateral enlargement of the testes. This presentation is suggestive of

A. Down's syndrome

B. Edward's syndrome

C. Fragile X syndrome

D. Klinefelter's syndrome

E. Turner's syndrome

Explanation:

The correct answer is C. Enlarged testes are the most specific phenotypic feature to suggestFragile X syndrome in an individual who appears to have a hereditary mental retardation. Thecondition has unusual genetics as it is related to expansion of a CGG repeat sequence located onthe X chromosome. The larger the number of repeats, the higher the probability of significantretardation, hence the retardation tends to become more severe in successive generations, asmore CGG repeats accumulate. Sisters of affected males tend to show milder retardation thantheir brothers.

Features of Down's syndrome (choice A), or trisomy 21, include mental retardation, epicanthalfolds, dysplastic ears, hypotonia, a horizontal palmar crease (simian crease), redundant neckskin, and a short trunk.

Edwards' syndrome (choice B), or trisomy 18, causes death in infancy. Characteristics includerocker bottom feet, low set ears, micrognathia, congenital heart disease, and mentalretardation.

Klinefelter's syndrome (47, XXY; choice D) is associated with testicular atrophy, a eunuchoidbody shape, long extremities, and a small penis.

Turner's syndrome (45, X; choice E) produces a female phenotype with short stature, ovariandysgenesis and webbing of the neck.

A boy with Duchenne muscular dystrophy (DMD) was born to parents with no family history of thedisease. The most likely explanation for this occurrence is

A. a CGG expansion that resulted in the disruption of the promoter of the dystrophin gene

B. infidelity

C. a point mutation in the dystrophin gene

D. a recombination event in the dystrophin gene that gave rise to a frameshift mutation leadingto an untranslatable mRNA

E. a translocation that resulted in the disruption of the dystrophin gene

Explanation:

The correct answer is D. Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessivedisease affecting approximately 1 in 3300 live male births. The disease becomes symptomatic inearly childhood. Inability to walk occurs by the end of the first decade, and death usuallyoccurs by the second decade. Nearly all patients show the complete absence of the proteindystrophin, which is abundant in skeletal and cardiac muscle. The dystrophin gene (or DMD gene),located at Xp21, is approximately 2300 Kb in size, making it one of the largest known genes ofany species. It contains 24 regions of 109 amino acids that are similar but not identicalrepeats of each other. In women, the similarity of these sequences can lead to the misalignmentof homologous material at meiotic synapsis. In association with a recombination event, thismisalignment gives rise to frameshift mutations, leading to an untranslatable mRNA. This seriesof events occurs at an extremely high rate of about 1 in 10,000. In fact, one third of DMD casesin each generation arise from this mechanism.

Diseases such as fragile X syndrome and Huntington disease are caused by the expansion of atrinucleotide repeat (choice A).

Infidelity (choice B) is not a plausible explanation for the child because the trait is an X-linked recessive condition. A male child must receive the DMD trait on the maternal Xchromosome. The father of the child contributes only a Y chromosome, and the history stated thatthe mother had no family history of the disorder.

DMD in a patient with no family history is not generally due to a point mutation in thedystrophin gene (choice C).

Rare cases of DMD in females have been caused by an X chromosome-autosome translocation (choice

E) with the breakpoint on the X chromosome within the DMD gene. Because of the translocation,only the cells in which the normal X chromosome is inactivated survive in the female zygote.This gives rise to a female who is heterozygous for the DMD gene but phenotypically expressesthe disease.

A 25-year-old man presents with a chief complaint of persistent, high-pitched ringing noises inhis ears. Questioning reveals that he has also been losing his balance lately. CT of the headdemonstrates bilateral tumors involving the vestibulocochlear nerve. Which of the followingchromosomes contains the tumor suppressor gene most likely to be involved in this case?

A. 5q

B. 13q

C. 17q

D. 18q

E. 22q

Explanation:

The correct answer is E. The patient has bilateral acoustic neuromas, probably due toneurofibromatosis type II (over 90% of patients with NF-2 develop bilateral acoustic neuromas).This condition is a associated with the NF-2, gene, located on 22q (note all the 2's). Patientsoften develop meningiomas, gliomas, and schwannomas of cranial and spinal nerves.

5q (choice A) contains the APC tumor suppressor gene, which is associated with familial andsporadic colorectal cancers.

13q (choice B) contains the Rb tumor suppressor gene, which is associated with retinoblastomaand osteosarcoma.

17q (choice C) contains both the NF-1 tumor suppressor gene, which is associated withneurofibromatosis type I, and the p53 tumor suppressor gene, associated with many human cancers.

18q (choice D) contains both the DCC gene, which is associated with colon and gastric carcinomasand the DPC gene, associated with pancreatic cancer.

Tay-Sachs disease, an autosomal recessive disease caused by a deficiency of hexosaminidase A, islethal in childhood. In a population of Ashkenazi Jews, blood testing shows the frequency ofheterozygotes to be 0.1. What is the probability that the first child of two individuals fromthis population with no family history of the disease will have Tay-Sachs?

A. 0.25

B. 0.11

C. 0.0625

D. 0.0025

E. Cannot be calculated from the information given

Explanation:

The correct answer is D. Since Tay-Sachs is lethal in childhood, the only adults carrying thegene are heterozygotes. The only mating that will produce progeny with the disease is the matingbetween two heterozygotes. Using the blood test data, the probability that a random individualis a heterozygote is 0.1. The probability that two heterozygotes will produce a child with Tay-Sachs disease is 0.25. So, the overall probability that two individuals in the population willproduce a child with Tay-Sachs is (0.1)(0.1)(0.25), or 0.0025.

Choice A, 0.25, could be obtained if the parents are carriers, so the probability of a Tay-Sachs child is equal to the probability that two heterozygotes will produce a child with thedisease, or 0.25.

Choice B, 0.11, could be obtained if both of the parents had a sibling with Tay-Sachs. Thiswould mean that the grandparents must have carried the disease, and that their normal childrenhad a 0.67 chance of carrying the allele. This gives the probability that the parent's childwould have Tay-Sachs as (0.67)(0.67)(0.25), or 0.11.

Choice C, 0.0625, is also incorrect. It is the product of (0.25)(0.25).

Choice E incorrectly assumes that because q2, the frequency of the disease, cannot becalculated, and hence the allele frequencies cannot be calculated, that an estimate of thefrequency of heterozygotes cannot be made. The problem can be done, however, because theheterozygote frequency (0.1) was given in the question stem.

A 2-year-old child presents to the pediatrician with hematuria. Examination reveals hypertensionand an abdominal mass. A tumor is localized to the right kidney and biopsy reveals a stromacontaining smooth and striated muscle, bone, cartilage, and fat, with areas of necrosis. Thegene for this disorder has been localized to which of the following chromosomes?

A. 5

B. 11

C. 13

D. 17

E. 22

Explanation:

The correct answer is B. This is a tough two-step style question. You first needed to make thediagnosis, and then you needed to recall the localization of this particular disease to aspecific chromosome. In this case, everything in the vignette leads you to a diagnosis of Wilms'tumor. Wilms' tumor occurs in children and typically presents with an abdominal mass as well aswith hypertension, hematuria, nausea, and intestinal obstruction. Because the tumor is derivedfrom mesonephric mesoderm, it can include mesodermal derivatives such as bone, cartilage, andmuscle. The Wilms' tumor suppressor gene (WT-1) has been localized to chromosome 11 (11p).

The remaining answer choices provide us the opportunity to discuss some other knownrelationships between genes and disease. This is a topic of intense research that is likely tobecome more and more emphasized on the USMLE examinations.

Chromosome 5 (choice A) is the site of the tumor suppressor gene APC, which is involved in thepathogenesis of colon cancer and familial adenomatous polyposis.

Chromosome 13 (choice C) is the site of the tumor suppressor gene for retinoblastoma and

osteosarcoma (Rb) as well as the BRCA-2 gene for breast cancer.

Chromosome 17 (choice D) is the site of p53 (involved in most human cancers), NF-1(neurofibromatosis type I), and BRCA-1 (breast and ovarian cancer).

Chromosome 22 (choice E) is home to the NF-2 gene, which is involved in neurofibromatosis typeII.