Chapter 5 Genetic Disorders

1) Multiple members of a family have a disease that is associated with a genetic change that involves substitution of adenine for thymine involving one base pair on homologous chromosomes. What is the best term to describe this finding? A Copy number variation B Deletion C Epigenetic change D Single nucleotide polymorphism E Trinucleotide repeat mutation F RNA alteratio

1) D Single nucleotide polymorphisms (SNPs) are found in less than 0.5% of the genome, and only 1% of these are found in coding regions that affect protein synthesis. Some of these account for point mutations that may be associated with disease conditions. C number variations (CNVs) involve variations in large contiguous regions of DNA from 1000 to a million base pairs. Epigenetic changes involve modulation of gene expression without any change in the DNA. Trinucleotide repeats involve increased numbers of base pairs. RNA alterations may modulate DNA expression, such as noncoding micro RNAs. PBD9 138 BP9 216-218 PBD8 150-152 BP8 235-237

10) A 1-year-old female infant has failure to thrive, poor neurologic development, and poor motor function. Physical examination shows a "cherry red" spot on the macula of the retina. The infant's muscle tone is poor. Both parents and a brother and sister are healthy, with no apparent abnormalities. One brother with a similar condition died at the age of 18 months. This genetic disorder most likely resulted from a mutation involving a gene encoding for which of the following? A Mitochondrial enzyme B Lysosomal enzyme C Cell surface receptor protein D Structural protein

10) B The findings listed suggest a severe inherited neurologic disease, and the pattern of inheritance (e.g., normal parents, an affected sibling) is consistent with an autosomal recessive disorder. This inheritance pattern and the cherry red spot in the retina are characteristic of Tay-Sachs disease, caused by mutations in the gene that encodes a lysosomal enzyme hexosaminidase A. Mitochondrial genes have a maternal pattern of transmission. Mutations in genes affecting receptor proteins and structural proteins typically give rise to an autosomal dominant pattern of inheritance. PBD9 149-152 BP9 229-230 PBD8 150-152 BP8 235-23

12) A 22-year-old woman delivers an apparently healthy female infant after an uncomplicated pregnancy. By 4 years of age, the girl has progressive, severe neurologic deterioration. Physical examination shows marked hepatosplenomegaly. A bone marrow biopsy specimen shows numerous foamy vacuolated macrophages. Analysis of which of the following factors is most likely to aid in the diagnosis of this condition? A Level of α1-antitrypsin in the serum B Level of glucose-6-phosphatase in hepatocytes C Level of sphingomyelinase in splenic macrophages D Number of LDL receptors on hepatocytes E Rate of synthesis of collagen in skin fibroblasts

12) C The clinical features of this child—neurologic involvement, hepatosplenomegaly, and accumulation of foamy macrophages—suggest a lysosomal storage disorder. One such disorder, with which the clinical history is quite compatible, is Niemann-Pick disease type A. It is characterized by lysosomal accumulation of sphingomyelin owing to a severe deficiency of sphingomyelinase. Globules of α1-antitrypsin are seen in the liver cells of individuals with inherited deficiency of α1-antitrypsin. The glycogen storage disease known as von Gierke disease results from glucose-6-phosphatase deficiency. In familial hypercholesterolemia, there are fewer LDL receptors on hepatocytes, leading to early and accelerated atherosclerosis by young adulthood. Collagen synthesis is impaired in individuals with Ehlers-Danlos syndrome. PBD9 152-153 BP9 230-231 PBD8 152-153 BP8 237

13) A 2-year-old child has had failure to thrive since birth, with progressive neurologic deterioration. On physical examination, the child has hepatosplenomegaly and lymphadenopathy. Laboratory studies show pancytopenia. A bone marrow biopsy is obtained and microscopically shows numerous pale phagocytic cells filled with fine vacuoles (secondary lysosomes). An abnormality in genetic encoding for which of the following types of protein is most likely causing this child's disease? A Enzyme B Growth regulation C Ion channel D Receptor E Structural support

13) A This child has Niemann-Pick disease type A, the worst form. Death typically ensues by age 3 years. This inborn error of metabolism occurs in a degradation pathway for sphingomyelin, and accumulation of the abnormal lipid intermediate leads to lysosomal storage disease, mainly affecting tissues of the mononuclear phagocyte system, as well as the central nervous system. Genes involved in growth regulation are typically proto-oncogenes and tumor suppressor genes, and mutations may underlie development of malignancies. Cystic fibrosis results from mutations in the CFTR gene that encodes chloride ion channels. Familial hypercholesterolemia is an example of a disease resulting from an abnormal LDL receptor. Many autosomal dominant conditions, such as Marfan syndrome from fibrillin-1 gene mutations, involve structural protein abnormalities. PBD9 152-153 BP9 230-231 PBD8 150-152 BP8 235-237

15) The parents of a male infant report that male children over three generations in the mother's family have been affected by a progressive disorder involving multiple organ systems. These children have had coarse facial features, corneal clouding, joint stiffness, hepatosplenomegaly, and mental retardation, and many died in childhood. At autopsy, some of the children had subendothelial coronary arterial deposits that caused myocardial infarction. Laboratory testing of the infant now shows increased urinary excretion of mucopolysaccharides. Bone marrow biopsy is performed, and the accumulated mucopolysaccharides are found in macrophages ("balloon cells" filled with minute vacuoles). Which of the following enzyme deficiencies is most likely to be seen in this infant? A Adenosine deaminase B α-l-Iduronidase C Glucocerebrosidase D Glucose-6-phosphatase E Hexosaminidase A F Lysosomal glucosidase G Sphingomyelinase

15) B Hunter syndrome, one of the mucopolysaccharidoses (MPS), results from deficiency of the lysosomal enzyme α-liduronidase. The glycosaminoglycans that accumulate in MPS include dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. All of the MPS variants are autosomal recessive except for Hunter syndrome, which is X-linked recessive. Adenosine deaminase deficiency is a cause of severe combined immunodeficiency (SCID), an immunodeficiency state in which multiple recurrent infections occur after birth. Glucocerebrosidase deficiency is seen in Gaucher disease; in the most common form of the disease, there is no neurologic impairment, and patients have splenomegaly and skeletal disease as a consequence of increased lysosomal glucocerebrosides in cells of the mononuclear phagocyte system. Glucose-6-phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Hexosaminidase A deficiency occurs in Tay-Sachs disease; affected individuals manifest severe neurologic impairment, poor motor development, and blindness beginning in infancy. Lysosomal glucosidase deficiency, seen in Pompe disease, is associated with marked cardiomegaly and heart failure beginning in infancy. Sphingomyelinase deficiency occurs in Niemann-Pick disease type A, characterized by hepatosplenomegaly, lymphadenopathy, and severe motor and mental impairment. PBD9 154-155 BP9 232 PBD8 154-155 BP8 238-239

16) A 2-year-old child with failure to thrive since infancy now exhibits a seizure. Physical examination shows hepatomegaly and ecchymoses of the skin. Laboratory studies show a blood glucose level of 31 mg/dL. A liver biopsy specimen shows cells filled with clear vacuoles that stain positive for glycogen. Which of the following conditions is most likely to produce these findings? A Hurler syndrome B McArdle disease C Pompe disease D Tay-Sachs disease E Von Gierke disease

16) E With von Gierke disease, from deficiency of glucose6-phosphatase, stored glycogen is not metabolized readily to glucose. Affected individuals have severe hypoglycemia, which leads to convulsions. Intracytoplasmic accumulations of glycogen occur mainly in the liver and kidney. In Hurler syndrome, the enzyme α-l-iduronidase is deficient. Affected children have skeletal deformities and a buildup of mucopolysaccharides in endocardium and coronary arteries, leading to heart failure. Another form of glycogen storage disease, McArdle disease, results from a deficiency of muscle phosphorylase and leads to muscle cramping. Cardiomegaly and heart failure mark Pompe disease, the type II form of glycogen storage disease. Tay-Sachs disease is characterized by a deficiency in hexosaminidase A and results in severe neurologic deterioration. PBD9 155-157 BP9 232-233 PBD8 155, 157 BP8 239-240

17) A 25-year-old woman stops going to her aerobic exercise class because of severe muscle cramps that have occurred during every session for the past 2 months. Four hours after each session, she notices that her urine is a brown color. On physical examination, she has normal muscle development and strength. An inherited defect in which of the following substances is most likely to explain her findings? A Dystrophin B Fibrillin C Glucose-6-phosphatase D Lysosomal glucosidase E Muscle phosphorylase F Spectrin

17) E McArdle disease is a form of glycogen storage disease in which a deficiency of muscle phosphorylase enzyme causes glycogen to accumulate in skeletal muscle. Onset is in young adulthood. Because strenuous exercise requires glycogenolysis and use of anaerobic metabolism, muscle cramps ensue, but the blood lactate level does not rise. Myoglobinuria is seen in about half of cases. A lack of dystrophin, a protein that stabilizes muscle membrane, characterizes Duchenne muscular dystrophy. A fibrillin gene mutation can lead to Marfan syndrome. Glucose-6-phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Lysosomal glucosidase deficiency is seen in Pompe disease, characterized by marked cardiomegaly and heart failure beginning in infancy. Abnormal spectrin, a RBC membrane cytoskeletal protein, leads to a condition known as hereditary spherocytosis. PBD9 156-157 BP9 232-233 PBD8 157 BP8 239-240

19) A 13-year-old boy has been drinking large quantities of fluids and has an insatiable appetite. He is losing weight and has become more tired and listless for the past month. Laboratory findings include normal CBC and fasting serum glucose of 175 mg/dL. His parents, two brothers, and one sister are healthy. A maternal uncle is also affected. Which of the following is the probable inheritance pattern of his disease? A Autosomal dominant B Autosomal recessive C Mitochondrial DNA D Multifactorial E X-linked recessive

19) D Type 1 diabetes mellitus has an increased frequency in some families, but the exact mechanism of inheritance is unknown. The risk is increased for offspring when first-order relatives are affected. HLA-linked genes and other genetic loci and environmental factors are considered important. This pattern of inheritance is multifactorial. The other listed inheritance patterns are not seen with most cases of diabetes mellitus. PBD9 158 BP9 234 PBD8 138, 157 BP8 241, 255

2) A 15-year-old girl has developed multiple nodules on her skin over the past 10 years. On physical examination, there are 20 scattered, 0.3-cm to 1-cm, firm nodules on the patient's trunk and extremities. There are 12 light brown macules averaging 2 to 5 cm in diameter on the skin of the trunk. Slit-lamp examination shows pigmented nodules in the iris. A sibling and a parent are similarly affected. Genetic analysis shows a loss-of-function mutation. Which of the following inheritance patterns is most likely to be present in this family? A Autosomal dominant B Autosomal recessive C Mitochondrial D Multifactorial E X-linked recessive

2) A Neurofibromatosis type 1 (NF-1) is characterized by the development of multiple neurofibromas and pigmented skin lesions. Neurofibromas are most numerous in the dermis but also may occur in visceral organs. Patients with NF-1 also may develop a type of sarcomatous neoplasm known as a malignant peripheral nerve sheath tumor (MPNST). NF-1 is a tumor suppressor that appears with an autosomal dominant pattern of inheritance, though some cases result from spontaneous new mutations (no prior family members with the mutation). NF-1 exhibits variable expressivity, because the manifestations (location and types of neoplasms) are not the same in all patients. The other forms of inheritance listed are not associated with tumor suppressor genes. PBD9 140-141 BP9 219 PBD8 140 BP8 229, 231

20) A healthy 20-year-old woman, G3, P2, Ab1, has previously given birth to a liveborn infant and a stillborn infant, both with the same karyotypic abnormality. On physical examination, she is at the 50th percentile for height and weight. She has no physical abnormalities noted. Which of the following karyotypic abnormalities is most likely to be present in this woman? A Deletion of q arm - del(22q) B Isochromosome - 46,X,i C Paracentric inversion - inv(18) D Ring chromosome - r(13) E Robertsonian translocation - t(14;21)

20) E Almost all of the normal genetic material is present in the case of a Robertsonian translocation because only a small amount of the p arm from each translocated chromosome is lost. The maternal karyotype is 45,XX,t(14;21). Statistically, one of six fetuses in a mother who carries a Robertsonian translocation will also be a carrier. In balanced reciprocal translocation, the same possibility of inheriting the defect exists. The other listed structural abnormalities are likely to result in loss of significant genetic material, reducing survivability, or to interfere with meiosis. PBD9 160-161 BP9 236-237 PBD8 160-161 BP8 243-244

21) An 11-year-old mentally retarded boy is able to carry out activities of daily living, including feeding and dressing himself. On physical examination, he has brachycephaly and oblique palpebral fissures with prominent epicanthal folds. A transverse crease is seen on the palm of each hand. On auscultation of the chest, there is a grade III/VI systolic murmur. Which of the following diseases is he most likely to develop by age 20 years? A Acute leukemia B Acute myocardial infarction C Aortic dissection D Chronic renal failure E Hepatic cirrhosis

21) A Down syndrome (trisomy 21) is one of the trisomies that can result in a live-born infant. Although children with Down syndrome can function well, they often have many associated congenital anomalies. Among the more common is congenital heart disease, including ventricular septal defect. There is also a tenfold to twentyfold increased risk of acute leukemia. Virtually all individuals with Down syndrome who live to age 40 years have evidence of Alzheimer disease. Myocardial infarction at a young age suggests familial hypercholesterolemia. Aortic dissection is seen in individuals with Marfan syndrome. Chronic renal failure may be seen in genetic disorders that produce polycystic kidneys. Hepatic cirrhosis is a feature of galactosemia. PBD9 161-163 BP9 237-238 PBD8 161-163 BP8 244-245

23) A 39-year-old woman gives birth to a term infant with an umbilical hernia, Brushfield spots on the iris, macroglossia, low-set ears, oblique palpebral fissures, and a heart murmur. The infant survives to childhood and exhibits only mild mental retardation. Which of the following chromosomal abnormalities, affecting autosomes, is most likely to be present in the somatic cells of this child? A Haploidy B Monosomy C Mosaicism D Tetraploidy E Triploidy

23) C Though these features are characteristic of trisomy 21, the child is not severely affected, which suggests mosaicism. In mosaic individuals, greater numbers of potentially normal cells having the proper chromosomal complement are present, which may allow infants with abnormalities of chromosome number to survive to term and beyond. Haploidy is present in gametes. Loss of an autosomal chromosome is devastating; the only monosomy associated with possible survival to term is Turner syndrome (monosomy X). Most aneuploid conditions (trisomies and monosomies) lead to fetal demise; fetuses with trisomy 21 are the most likely to survive to term. Triploid fetuses rarely survive beyond the second trimester and are virtually never live-born. Likewise, tetraploidy accounts for many first-trimester fetal losses and is not survivable. PBD9 161-163 BP9 237-238 PBD8 161-163 BP8 244-245

27) A 12-year-old boy has a cough and earache for the past 2 days. He has a history of recurrent infections, including otitis media, diarrhea, and pneumonia. Physical examination shows an erythematous right tympanic membrane, a cleft palate, and murmur suggestive of congenital heart disease. A thoracic CT scan shows a small thymus. Results of laboratory studies suggest mild hypoparathyroidism. Which of the following diagnostic studies is most likely to be helpful in diagnosing this patient's condition? A Adenosine deaminase assay in lymphocytes B Branched DNA assay for HIV-1 RNA level C FISH analysis with a probe for chromosome 22q11.2 D Lymph node biopsy E PCR analysis for trinucleotide repeats on the X chromosome

27) C DiGeorge syndrome is an immunodeficiency characterized by infection, a small thymus, congenital malformations, and hypoparathyroidism. This cluster is characteristic of the 22q11.2 deletion syndrome, readily diagnosed by FISH. Adenosine deaminase deficiency can cause immunodeficiency, but it is not associated with congenital malformations. Branched DNA assay can detect HIV infection that can lead to AIDS, but no congenital anomalies are associated with this condition. A lymph node biopsy may show a reduction in T cells or B cells associated with various forms of immunodeficiency, but this is not a specific test that can aid in confirming a specific diagnosis. Trinucleotide repeats of the X chromosome, detected by PCR, are seen in fragile X syndrome, which manifests with mental retardation in males. PBD9 163-164 BP9 237, 239 PBD8 162, 164 BP8 244, 246

29) A 27-year-old man and his 24-year-old wife have been trying to conceive a child for 6 years. Physical examination shows he has bilateral gynecomastia, reduced testicular size, reduced body hair, and increased length between the soles of his feet and the pubic bone. A semen analysis indicates oligospermia. Laboratory studies show increased follicle-stimulating hormone level and slightly decreased testosterone level. Which of the following karyotypes is this man most likely to have? A 46,X,i(Xq) B 47,XYY C 47,XXY D 46,XX/47,XX,+21 E 46,XY,del(22q11)

29) C Klinefelter syndrome is a relatively common chromosomal abnormality that occurs in about 1 of 660 live-born males. The findings can be subtle. The 46,X,i(Xq) karyotype is a variant of Turner syndrome (seen only in females), caused by a defective second X chromosome. The 47,XYY karyotype occurs in about 1 in 1000 live-born males and is associated with taller-than-average stature. A person with a mosaic such as 46,XX/47,XX,+21 has milder features of Down syndrome than a person with the more typical 47,XX,+21 karyotype. The 22q11 deletion syndrome is associated with congenital defects affecting the palate, face, and heart and, in some cases, with T cell immunodeficiency. PBD9 165 BP9 239 PBD8 165 BP8 246-247

3) A female infant born at term shows failure to thrive and failure to achieve developmental milestones. A pedigree reveals only this child is affected out of four generations on both sides of the family. Tissue fibroblasts obtained from this child shows a 46,XX karyotype. Cultured fibroblasts show accumulation of an intermediate product in a metabolic pathway in which multiple enzymes are involved. What is the most likely recurrence risk for this condition in siblings of this infant? A 3% B 8% C 15% D 25% E 50% F 100%

3) D Most inborn errors of metabolism involve mutations in genes encoding for enzymes. Because one active allele produces half the needed enzyme, this is likely sufficient to avoid disease. Inheritance of two mutant alleles, one from each parent, is required for appearance of disease, so the pattern is autosomal recessive, and the recurrence risk is 25%. Most autosomal recessive genes are infrequent in the population, so a family history is unlikely. Even if 1 in 10 persons carries the mutant recessive gene, a homozygote will be 1 in 400. The standard recurrence risk for any pregnancy is 3%. The recurrence risk is increased to 7% in diseases such as diabetes mellitus, or when a syndrome is identified without a defined inheritance pattern, or with multifactorial inheritance. Autosomal dominant conditions usually result from mutations in genes encoding for structural genes and have a recurrence risk of 50%. PBD9 140-141 BP9 219-220 PBD8 142 BP8 229

30) A 25-year-old woman with amenorrhea has never had menarche. On physical examination, she is 145 cm (4 ft 9 in) tall. She has a webbed neck, a broad chest, and widely spaced nipples. Strong pulses are palpable in the upper extremities, but there are only weak pulses in the lower extremities. On abdominal MR imaging, her ovaries are small, elongated, and tubular. Which of the following karyotypes is she most likely to have? A 45,X/46,XX B 46,X,X(fra) C 47,XXY D 47,XXX E 47,XX,+16

30) A The features described are those of classic Turner syndrome. Individuals who reach adulthood may have mosaic cell lines, with some 45,X cells and some 46,XX cells. A female carrier of the fragile X syndrome, X(fra), is less likely to manifest the disease than a male, but the number of triple repeat sequences (CGG) increases in her male offspring. The 47,XXY karyotype occurs in Klinefelter syndrome; affected individuals appear as phenotypic males. The "superfemale" karyotype (XXX) leads to mild mental retardation. Trisomy 16 is a cause of fetal loss early in pregnancy. PBD9 166-167 BP9 240 PBD8 165-166 BP8 247-248

31) A 22-year-old primigravida notes absent fetal movement for 2 days. The fetus is delivered stillborn at 19 weeks' gestation. The macerated fetus shows marked hydrops fetalis and a large posterior cystic hygroma of the neck. At autopsy, internal anomalies include aortic coarctation and a horseshoe kidney. Which of the following karyotypes is most likely to be present in cells obtained from this fetus? A 45,X B 47,XX,+18 C 47,XX,+21 D 47,XYY E 69,XXX

31) A The findings listed are characteristic of Turner syndrome (monosomy X), which accounts for many first trimester fetal losses. The hygroma is quite suggestive of this disorder. Fetuses with this finding are rarely live-born. Trisomy 18 can be marked by multiple anomalies, but overlapping fingers and a short neck are more typical features. Down syndrome (47,XX,+21) may be accompanied by a hygroma and hydrops, but ventricular septal defect is more frequent than coarctation, and horseshoe kidney is uncommon. The 47,XXY karyotype (Klinefelter syndrome) does not result in stillbirth, and these males have no major congenital defects. Triploidy with 69 chromosomes typically leads to fetal loss, but hydrops and hygroma are not features of this condition. PBD9 166-167 BP9 240 PBD8 165-166 BP8 247-248

32) A 23-year-old woman gives birth to a term infant after an uncomplicated pregnancy. On physical examination, the infant has ambiguous external genitalia. The parents want to know the infant's sex, but the physician is hesitant to assign a sex without further information. A chromosomal analysis indicates a karyotype of 46,XX. An abdominal CT scan shows bilaterally enlarged adrenal glands, and the internal genitalia appear to consist of uterus, fallopian tubes, and ovaries. This clinical picture is most consistent with which of the following conditions? A Androgen insensitivity syndrome B Excessive trinucleotide repeats C Female pseudohermaphroditism D Mitochondrial DNA mutation E Nondisjunctional event with loss of Y chromosome

32) C Physicians must be cautious in assigning sex to an infant with ambiguous genitalia; changing one's opinion is about as popular as an umpire changing the call. True hermaphroditism, with ovarian and testicular tissue present, is very rare. This infant has female pseudohermaphroditism, resulting from exposure of the fetus to excessive androgenic stimulation, which in this case is due to congenital adrenal hyperplasia. The gonadal and the karyotypic sex are female. Male pseudohermaphroditism has various forms, but the most common is androgen insensitivity; affected individuals are phenotypically females, but have testes and a 46,XY karyotype. Nondisjunctional events lead to monosomies or trisomies, and most result in fetal loss. Trinucleotide repeats are seen in males with fragile X syndrome. Abnormalities of mitochondrial DNA have a maternal transmission pattern and do not involve sex chromosomes or sexual characteristics. PBD9 167 BP9 239 PBD8 167

33) Mental retardation has affected several generations of a family, and most of the affected individuals have been males. The severity of mental retardation has increased with each passing generation. Genetic testing is performed, and about 20% of the males who have the genetic abnormality are unaffected. Which of the following mechanisms is most likely to produce this genetic condition? A Frameshift mutation B Missense mutation C Mitochondrial DNA mutation D Point mutation E Trinucleotide repeat mutation

33) E Fragile X syndrome is a condition in which there are 250 to 4000 tandem repeats of the trinucleotide sequence CGG. Generally, as the number of trinucleotide repeats increases, the manifestations of the associated conditions worsen or have an earlier onset. The trinucleotide mutations are dynamic; because their number increases during oogenesis, subsequent male offspring have more severe disease compared with earlier generations. With a frameshift mutation, one, two, or three nucleotide base pairs are inserted or deleted. As a result, the protein transcribed is abnormal. A missense mutation results from a single nucleotide base substitution, and it leads to elaboration of an abnormal protein. Abnormalities of mitochondrial DNA, typically involving genes associated with oxidative phosphorylation, are transmitted on the maternal side. A point mutation of a single base pair may affect a single protein. PBD9 168-171 BP9 241-242 PBD8 169-171 BP8 248-250

34) A pregnant woman with a family history of fragile X syndrome undergoes prenatal testing of her fetus. PCR analysis to amplify the appropriate region of the FMR1 gene is attempted using DNA from amniotic fluid cells, but no amplified products are obtained. Which of the following is the most appropriate next step? A Routine karyotyping of the amniotic fluid cells B Routine karyotyping of the unaffected father C Southern blot analysis of DNA from the amniotic fluid cells D PCR analysis of the mother's FMR1 gene E No further testing

34) C Failure to find amplified product by PCR analysis in such a case could mean that the fetus is not affected, or that there is a full mutation that is too large to be detected by PCR. The next logical step is a Southern blot analysis of genomic DNA from fetal cells. Routine karyotyping of the amniotic fluid cells is much less sensitive than a Southern blot analysis. Karyotyping of the unaffected father cannot provide information about the status of the FMR1 gene in the fetus because amplification of the trinucleotide occurs during oogenesis. For the same reason, PCR analysis of the mother's FMR1 gene is of no value. PBD9 169-171, 175-178 BP9 241-242 PBD8 176-178 BP8 277

35) A 19-year-old man has experienced failing eyesight and progressive muscle weakness for the past 7 years. Family history reveals that several of the patient's male and female relatives have similar symptoms. His mother, her brother and sister, and two of the aunt's children are affected, but the uncle's children are not. Which of the following types of genetic disorders is most likely to be present in this patient? A Trinucleotide repeat expansion B Genetic imprinting C X-linked inheritance pattern D Mitochondrial mutation E Uniparental disomy

35) D This is a classic pattern of maternal inheritance resulting from a mutation in mitochondrial DNA. Males and females are affected, but affected males cannot transmit the disease to their offspring. Because mitochondrial DNA encodes many enzymes involved in oxidative phosphorylation, mutations in mitochondrial genes exert their most deleterious effects on organs most dependent on oxidative phosphorylation, including the central nervous system and muscles. The other listed options do not exhibit strict maternal inheritance. PBD9 171-172 BP9 243 PBD8 171 BP8 250

36) A 3-year-old boy has had progressive developmental delay, ataxia, seizures, and inappropriate laughter since infancy. The child has a normal karyotype of 46,XY, but DNA analysis shows that he has inherited both of his number 15 chromosomes from his father. These findings are most likely to be indicative of which of the following genetic mechanisms? A Genomic imprinting B Maternal inheritance pattern C Mutation of mitochondrial DNA D Trinucleotide repeat expansion E X-linked inheritance pattern

36) A This child has features of Angelman syndrome, and the DNA analysis shows uniparental disomy. The Angelman gene encoded on chromosome 15 is subject to genomic imprinting. It is silenced on the paternal chromosome 15, but is active on the maternal chromosome 15. If the child lacks maternal chromosome 15, there is no active Angelman gene in the somatic cells. This gives rise to the abnormalities typical of this disorder. The same effect occurs when there is a deletion of the Angelman gene from the maternal chromosome 15. The other listed options do not occur in uniparental disomy. PBD9 172-173 BP9 243-244 PBD8 172-173 BP8 251-252

38) A study of families with fragile X syndrome reveals that 20% of affected men are carriers, but do not develop mental retardation. Genomic sequencing shows that these men have premutations having 55 to 200 trinucleotide repeats in the FMR1 gene. Half of these men exhibit a progressive neurodegenerative disease with cerebellar signs after age 50. Through which of the following mechanisms is their disease mediated? A Loss of mRNA transcription B Methylation with gene silencing C Random inactivation of the X chromosome D Reduced translation of the FMR1 protein E Toxicity from gain of function

38) E FMR1 protein (FRMP) normally acts as a translation regulator to reduce protein synthesis at synaptic junctions. Thus a reduction in FMRP (loss of function) in the classic fragile X syndrome results in increased protein translation from mRNAs to alter synaptic activity and cause mental retardation. In the fragile X tremor/ataxia syndrome, the FMR1 gene is not methylated and silenced but continues to be transcribed, and CGG-containing FMR1 mRNAs accumulate in the neuronal nucleus and form intranuclear inclusions of aggregated mRNA that sequester RNA-binding proteins, leading to events that are toxic to the cell. Inactivation of the X chromosome occurs when more than one X chromosome is present, such as in a normal female or Klinefelter male. PBD9 168-171 BP9 241-242

39) A clinical study is performed involving complex genetic traits such as hypertension, heart disease, and diabetes. The study makes use of naturally occurring variations in DNA sequences that are found in exons and introns and are frequent and stable. Which of the following genetic markers is being used in this study? A Proto-oncogenes B Robertsonian translocations C Single-nucleotide polymorphisms D Three-base pair frameshift deletions E Trinucleotide repeat mutations

39) C

4) An 8-year-old girl experiences sudden severe dyspnea. On examination, she has upper airway obstruction from soft tissue swelling in her neck. A radiograph shows a hematoma compressing the trachea. Laboratory studies show her prothrombin time (PT) is normal, but her partial thromboplastin time (PTT) is increased. Further testing reveals less than 1% of normal factor VIII activity. Both parents and two female siblings are unaffected by this problem, but a male sibling has experienced a similar episode. Which of the following genetic abnormalities is most likely to account for the findings in this girl? A Autosomal dominant mutation B Genomic imprinting C Germline mosaicism D Random X inactivation E Spontaneous new mutation

4) D This girl has features of hemophilia A. This X-linked recessive condition is expected to occur in males who inherit the one maternal X chromosome with the genetic mutation, and they do not have another X chromosome with a normal functional allele, as is the case in her brother. Hemophilia in a female can be explained by the Lyon hypothesis, which states that only one X chromosome in a female is active (the "turned off" X chromosome is the Barr body) for most genes, but this inactivation is a random event. Some unlucky females are out on the tail end of the Poisson distribution of random events and have few active X chromosomes with the normal allele, leading to markedly diminished factor VIII activity. The other choices do not explain this phenomenon. PBD9 142 BP9 220 PBD8 142-143 BP8 246

40) In a study of inheritance of the cystic fibrosis gene (CFTR), the genetic mutations in carriers and affected individuals are documented. Based on these findings, investigators determine that there is no simple screening test to detect all carriers of mutations of the CFTR gene. Which of the following is most likely to be the greatest limitation to development of a screening test for CFTR mutations? A Both copies of the gene must be abnormal for detection B Fluorescence in situ hybridization is labor-intensive and expensive C Frequency of mutations among ethnic groups limits sensitivity D Less than 1 individual in 10,000 is a heterozygote E Most mutations cannot be detected by PCR

40) C

41) A 32-year-old woman has had three pregnancies, all ending in stillbirths in the first trimester. On physical examination, she and her only spouse for all pregnancies have no abnormalities. Which of the following laboratory tests is most appropriate to perform on this woman for elucidating potential causes for recurrent fetal loss? A Genome-wide association study B Fluorescence in situ hybridization C Karyotyping D PCR analysis E Tandem mass spectroscopy

41) C

42) A case-control study is performed involving persons diagnosed with essential hypertension. Genetic analysis reveals linkage disequilibrium. Haplotypes of affected persons differ from the controls in the chromosome containing the angiotensinogen gene. Which of the following types of genetic analysis is most likely to yield this information? A Fluorescence in situ hybridization B Giemsa banded karyotyping C RNA expression D Single nucleotide polymorphisms E Southern blotting

42) D

43) A pedigree reveals that multiple family members over four generations have been affected by the onset of congestive heart failure within the first four decades of life. A cardiomyopathy is suspected, but specific features of the disease are not known, and no prior genetic testing has been performed. Which of the following techniques involving DNA sequencing is most likely to identify a specific mutation in a cost-effective manner? A Pyrosequencing B Sanger sequencing C Targeted sequencing D Whole exome sequencing E Whole genome sequencing

43) D

5) A 66-year-old man has been prescribed clopidogrel to help prevent future acute coronary events. He states that his father, aunt, and brother took this drug and had adverse side e ffects, including excessive bleeding, when prescribed the recommended dose. Which of the following genetic tests will help determine the most appropriate dose of clopidogrel for this man? A Enumeration of tandem repeat sequences B Expression profiling of mRNA C FISH analysis for the karyotype D Measurement of an enzyme level E Probing for a cyp450 polymorphism

5) E Pharmacogenomic testing may reveal polymorphisms that affect drug metabolism. The cytochrome P-450 system in hepatocytes is involved in metabolism of many substances, including drugs. Detection of polymorphisms can provide information about modification of drug dosing, or the need for a different drug. Trinucleotide repeat mutations may affect gene expression, such as the huntingtin gene, but unlikely those involved in drug metabolism. Changes in DNA lead to alterations in mRNA expression, but detecting the DNA alterations directly tends to be a more effective testing strategy. FISH analysis is useful in identifying altered regions of chromosomes, not single genes abnormalities. Autosomal recessive conditions may affect enzyme levels, such G6PD, but polymorphisms may not affect enzyme or substrate levels that can be reliably detected. PBD9 144 BP9 216-217

6) A 22-year-old man has a sudden loss of vision in the right eye. On physical examination, there is a subluxation of the right crystalline lens. On auscultation of the chest, a midsystolic click is audible. An echocardiogram shows a floppy mitral valve and dilated aortic arch. The patient's brother and his cousin are similarly affected. He is prescribed a beta-blocker. A genetic defect involving which of the following substances is most likely to be present in this patient? A Collagen B Dystrophin C Fibrillin-1 D NF1 protein E Spectrin

6) C Marfan syndrome is an autosomal dominant condition that is most often caused by qualitative defects in fibrillin from missense mutations in the fibrillin (FBN1) gene. An abnormal collagen gene can cause osteogenesis imperfecta and Ehlers-Danlos syndrome. Genetic mutations in the dystrophin gene are involved in Duchenne and Becker muscular dystrophies. The NF1 protein is abnormal in neurofibromatosis type 1. Disordered spectrin causes hereditary spherocytosis. PBD9 144-145 BP9 220-221 PBD8 144-145 BP8 230-231

7) An 11-year-old child has exhibited poor wound healing, even with minor trauma, since infancy. On examination she has hyperextensible joints and fragile, extremely stretchable skin. A diaphragmatic hernia was repaired soon after birth. One parent and one of three siblings are also affected. A mutation in a gene encoding for which of the following type of proteins is most likely causing this child's disease? A Enzyme B Growth regulation C Ion channel D Receptor E Structural support

7) E This classical form of Ehlers-Danlos syndrome (EDS) results from an abnormality in collagen synthesis, and lack of normal collagen affects connective tissues in skin, bone, eye, and vasculature. There are multiple forms of EDS from different mutations affecting different aspects of collagen synthesis. The inheritance pattern described here is autosomal dominant, typical for inherited defects in structural proteins. Inborn errors of metabolism involving enzymes typically have an autosomal recessive pattern of inheritance, because half of gene function is sufficient to prevent disease. Genes involved in growth regulation are typically protooncogenes and tumor suppressor genes, and mutations may underlie development of malignancies. Cystic fibrosis results from mutations in the CFTR gene that encodes chloride ion channels. Familial hypercholesterolemia is an example of a disease resulting from an abnormal LDL receptor. PBD9 145-146 BP9 221-222 PBD8 150-152 BP8 235-237

8) A 4-year-old girl has sudden onset of right hip pain. On examination, the child's right hip is dislocated. The child can bend her thumb backward to touch the forearm. Her skin is noted to be extraordinarily stretchable. Radiographs of her spine show marked lateral and anterior curvature. She develops retinal detachments later in childhood. A sibling is similarly affected. A mutation in tenascin-X is identified. Which of the following is the most likely cause for this child's findings? A Congenital syphilis B Deficient collagen synthesis C Diet lacking in vitamin D D Multiple congenital anomalies E Trauma from battering

8) B The joints are frequently involved in most variants of Ehlers-Danlos syndrome (EDS), and tensile strength is reduced so that skin is hyperextensible, and joints are hypermobile. Deficiency of the enzyme lysyl hydroxylase can lead to defects in types I and III collagen and is inherited as an autosomal recessive disorder. Kyphoscoliosis and ocular problems also are present in this type of EDS. When EDS-like features are present, but no collagen gene mutations identified, then abnormal tenascin-X, a large multimeric protein of extracellular matrix that affects synthesis and fibril formation of type VI and type I collagens may be present. Congenital syphilis can produce abnormalities of bone, such as saber shin from periosteitis and perichondritis, but does not affect the skin. Vitamin D deficiency in childhood producing rickets is accompanied by bowing deformities of long bones, but not skin abnormalities. The pattern of findings here suggests a structural gene defect leading to development of abnormalities, and not congenital anomalies without a specific cause. Battered children typically have multiple contusions and fractures, but the skin and bone structure are normal. PBD9 145-146 BP9 221 PBD8 145-146 BP8 231-232

9) A clinical study is undertaken with subjects from families in which complications of atherosclerotic cardiovascular disease and tendinous xanthomas occurred before age 30 years. Some of the children in these families are observed to have early atheroma formation. These affected individuals benefit from treatment with pharmacologic agents that inhibit HMG-CoA reductase. Affected individuals in these families are most likely to have a mutation in a gene encoding a cell surface receptor for which of the following? A Cortisol B Insulin C LDL cholesterol D Leptin E TGF-α

9) C Familial hypercholesterolemia results from mutations in the LDL receptor gene, causing plasma LDL cholesterol to increase because it is not catabolized or taken up by the liver. It is an autosomal dominant disorder with a carrier rate of 1 in 500, so the frequency of homozygosity is 1 in 1 million. Heterozygotes have total serum cholesterol levels twice normal; homozygotes have levels even higher, with death from myocardial infarction by the second decade. The statin drugs inhibit the HMG-CoA reductase and reduce cholesterol levels in heterozygotes. Steroid hormone receptors, such as those for cortisol, are located in the cell nucleus. Insulin receptors play a role in glucose metabolism and glycemic control that may be part of diabetes mellitus with risk for atherosclerosis; statin drugs have no effect on diabetes mellitus. Abnormal leptin receptors may play a role in some forms of obesity. TGF-α is a growth factor with a role in inflammation, cell proliferation, and repair. PBD9 147-149 BP9 222-223 PBD8 147-148 BP8 232-233