Genetic Disorders CoH APTER 5 BP6 Chapter 7 - Genetic and Pediatric Diseases PBD6 Chapter 6 - Genetic Disorders 1. An absence of low-density lipoprotein (LDL) receptors on liver cells, inherited as an autosomal dominant cond tion, is best characterized by which of the following Iubo- ratory test findings in a 22-year-old male who has had myocardial infarction OA) Abetalipoproteinemia OG) Hypertiglyceridemia (©) Ketonuria O(D) Hypoglycemia © © Hypercholesterotemia 2. A 25-year-old male has a work-up for infertility and is found to have oligospermia. Physical examination findings include bilateral gynecomastia, reduced testicular size, and reduced body hair. Karyotypie analysis will most likely reveal whieh of the following abnormalities? 1A) 46.1%) OW) 47XYY OO 47,XxY OD) 46XX/47XX, +21 OF) 46XY.del22q11) For the descriptions of a patient with a genetic disease in questions 3, 4, and 5, select the most closely associated letered gene product that is likely to be abnormal or ab- sent with that disease: (A) Adenosine deaminase ®) Alphay-antitypsin (©) Alpha -iduronidase (©) Dystroptin (6) Factor VItt (EF) Fibrtin (G) Giebin chains (H) Glucocerebrosidase (1) Ghucose-6-phosphatase GQ) Hexosaminidase (K) Homogentsic oxidase (L) Lysosomal acid maltase (M) Muscle phosphorylase (N) Speetrin (©) Sphingomyel 3. Male children over several generations ina family have been affected by a progressive disorder involving multiple organ systems. These children have had coarse facial features, comeal clouding, joint stiffness, hepato- splenomegaly, and mental retardation. Laboratory testing reveals increased urinary excretion of mucopolysaccharides. The accumulated mucopolysaccharides are found in macro phages (“balloon cells filled with minute vacuoles) on bone marrow biopsy. Some of the children at autopsy have had subendothelial coronary arterial deposits that produced myocardial infarction. () 4, An appacently healthy 25-year-old female drops out of her aerobic exercise class because of severe muscle cramps during every session for the past 2 months. Several hours after each of these sessions, she has noticed that her urine hhas a brown color. ( of Tver and loge Gri int-drg30 mM Port! GENERAL PATHOLOGY radiograph reveals marked cardiomegaly. ‘The child dies with congestive heart failure at 19 months of age. At autopsy, the myocardial fibers and fiver cells are seen microscopically to have the appearance shown in the fig- ure. () 6. Moltifactorial inheritance is most likely to play a signif icant role in the appearance of OFA) Marfan syndrome O1B) Tay-Sachs disease O(©) Enythroblastosis fetalis OLD) Cleft ip ©) Polycystic kidneys For each of the patients with genetic disorders in ques- tions 7 and 8, match the most characteristic cause of death from the Tis: (A) Acute leukemia (B) Aortic dissect (© Bronchicetasis (D) Chronic renal failure (E) Heart failure caused by thickness of coronary artery endothelium and valve leaflets Heart failure caused by myocardial glycogen accu mulation Intracerebral hemorrhage (H) Malignant transformation of subcutaneous tumor (D) Myocardial infarction () Pneumocystis cavinii pneumonia (K) Severe diarrhea and liver failure (L) Severe congenital heart malformation ® @ 7. An infant bom to a 36-year-old mother was observed at birth to have microcephaly, @ cleft lip and palate, and six fingers on cach hand. (— 8. An otherwise normal 12-year-old female with fatty de- posits under the skin (ie., xanthomas) of her elbows col- lapsed suddenly while playing volleyball. ( 9. A 10-year-old male, although mentally retarded, is able to carry out activities of daily living, ineluding feeding and dressing. himself, On physical examination, he has brachy ccephialy and oblique palpebral fissures with prominent epi- ccantbal folds. On the palm of each hand is seen a trans- verse erease. On auscultation of the chest, there is a grade IIVVI systolic murmur. Which of the following diseases will he most likely have by the age of 20? (A) Acute leukemia OG) Hepatic cirthosis OC) Chronic renal failure O(D) Acute myocardial infarction ©) Aonic dissection 10. The left hand of a baby bom at 38 weeks" gestation has the appearance shown in the figure. Which of the following chromosomal abnormalities is most likely 10 be present? OWA) 45. OB) 47.Xx,421 O© A7XY,418 OLD) XX O) 47.XX¥ IL. A young man’s ophthalmologist refers him to a neu- rologist because, in addition to failing eyesight, he com- plains of progressive muscle weakness, The neurologist lakes a careful history and finds that several of this young ‘man's male and female relatives are similarly affected. His mother, her brother and sister, and two of his aunt's chil- dren are affected, but his uncle's children seem to be fine. His genetic disorder is an example of (A) Trinucleotide repeat expansion OG) Genetic imprinting OC) X-linked inheritance pattern O(D) A mitochondrial mutation ‘© ©) Uniparental disomy 12. Which of the following karyotypic abnormalities in & liveborn baby is most likely to be found in a parent? ‘O(A) Robertsonian translocation ©) Ring chromesome © © Isochromosome ©(D) Paracentrie inversion O1B) A qarm deletion For cach of the clinical histories in questions 13 and 14, ‘atch the most closely associged leygged karyotype: (A) 46,XX, (B) 47.XX,+4y REGISTERED 9) sang SLON de?" ADDS NO b WA TERMAR, tnd ur P gst! canon to have14. A 25-year-old male, a professional hockey player who has never won the Lady Byng trophy, is 195 cr tal. ‘There are no abnormal findings on a physical examination, fother than some prominent facial acne scars and some missing teeth, He is married and has wo children who show normal development for a CCourtay of Dr. Mathew Fries, Deparment of Pathology. University of “Teazs Southwestern Mies! Center, Dall, TX 15, A 10-yeur-old neurologically normal child has hepato splenomegaly slong with anemia and leukopenia. A bone marrow biopsy is performed and shows at high magnifica tion the findings depicted in the figure. Therapy for this condition can be accomplished by infusion of OLA) Glucocerebrosidase OG) Acid maluse ©) Glucose-6 phosphatase ©) Sphingom ©) Hexosami 16, Mental retardation has affected several generations of fa family. Only male family members manifest this condi tion, In general, it appears that the severity of mental retardation has increased with each passing generation. By which of the following mechanisms is this genetic condi tion most likely to be produced!? (A) Trinvcleotide repeat mutation O(B) Frameshift motation O(© Missense mutation ‘O(D) Point mutation ‘© .€) Mitochondrial DNA mutation 17. About a dozen pale brown macules averaging 2 to Sem in diameter and having irregular borders are ob- served on the trunk and extremities of a 15-year-old fe- male. Examination of her eyes with a slit lamp reveals pigmented nodules in the iris. Other family members are similacly affected, Which of the following neoplasms is she most likely to develop? (A) Dermatofibroma ©1B) Leiomyoma OC) Neurohbroma OD) Lipoma © (E) Hemangioma Chopter§ GENEIIC DisoRDERS mi 31 I8. A fetus is most likely to be carried (0 term with which of the following chromosomal abnormalities? OVA) Triploigy 1B) Monosomy ©) Ancuploidy OW) Tevaploidy O© Mosaicism 19. A baby born at term has ambiguous extemal genita- lia. The parents want to know the baby’s sex, but the physician is hesitant to assign @ sex without further infor- mation. A chromosome analysis is performed, and the karyotype is 46,XX. An abdominal computed tomography (CT) scan reveals bilaterally enlarged adrenal glands, and the internal genitalia appear to consist of uterus, tubes, and ‘ovaries. This is most likely to be an example of ©(A) Female pseudohermaphroditism OG) Testicular femininization (©) A nondisjunetional event with loss of a Y chromo: OW) Excessive trinucleotide repeats © (E) Mitochondrial DNA mutation 20. A L-year-old female is brought to attention because of failure to thrive, mental retardation, and poor motor function, Examination of the retina reveals a cherry red spot in the macula. Both parents and a brother and sister are normal. However, one brother died, with a similar condition, at the age of 18 months. This genetic disorder most likely resulted from which of the following underly. ing abnormalit (A) Mutation in @ mitochondrial gene ‘O1B) Mutation in 2 gene encoding a lysosomal enzyme ©(C) Mutation in a gene encoding a receptor protein ‘O(D) Mutation in a gene encoding a structural protein OE) Genomic imprinting 21. A 10-year-old male presents with recurrent infections Physical examination reveals a cleft palate and murmur suggestive of congenital heart disease. A thoracic CT scan reveals a smaller than normal thymus. Results of laboratory investigations suggest mild hypoparathyroidism. Which of the following tests is most likely to beshelpful in arriving al the diagnosis? level ? S ‘ Of) Feegy Gh? ivoniiraion 0G ae , with eiemiane 2qlt ro) 010 yg a a ee a OW Ss REGIST La VERSION © .(E) LMM node biopsy chita Genronstrates “faillre 10 thrive,32 8 Port 1 GENERAL PATHOLOGY positively for glycogen. Which of the following conditions best explains these findings? O(A) McArdle OW) von Gi OC) Tay-Sachs disease OCD) Hurler syndrome OE) Pompe disease 23. An S-year-old female can bend ber thumb back to touch her forearm. She can pull her skin out from her abdomen about 8 em, and a cut to her skin gapes open and is difficult to repair. Her underlying disease process results from an inherited defect in 1A) Alphay-antirypsin OB) Retinoblastoma (Rb) protein OO LDL receptor ‘O(D) Collagen O(E) Factor VIIL Coutssy of Dr. Vijay Tonk, Depainent of Pathology, University of Texas Southwestern Medical Cone, Dall, TX. 24. An ultrasound examination performed at 18 weeks re ‘eas that this male fetus is mildly growth retarded. Multiple congenital anomalies are observed, including a ventricular septal defect, atrial septal defect, horseshoe kidney, and om phalocele. An amniocentesis is performed, and the fetal cells ae examined with FISH. Based on the findings shown in the figure, the most likely karyotypic abnormality is OA) 46XY.der( 14:21(q10:q10),+21 OW) a7xY+18 ©) 47 XXV OW) 46XY.del2g11) © ©) 45X/46XX 25. A 4-year-old child demonstrates severe neurologic de- terioration, Examination reveals marked bepatosplenomeg- aly, and a bone marrow biopsy shows numerous foamy vacuolated macrophages. Which of the following tests is likely to reveal the diagnosis of this condition’? OFA) The number of LDL receptors on hepatocytes ©(B) The level of sphingomyelinase in splenic macro- phages O(C) The rate of synthesis of collagen OLD) The level of glucose-6-phosphatase in liver cells OE) The level of ey-antitrypsin in the liver 26, A fetus is delivered stllbom ut 19 weeks’ gestation. ‘The macerated fetus shows marked hydrops fetalis. There is a large posterior cystic hygroma of the neck. Autopsy reveals internal anomalies, including aortic coarctation and a horseshoe kidney. Which of the following karyotypes is most likely to be found on chromosome analysis of fetal cells? OVA) AT.XX418 O(B) 48.XxX OO A7XX,+21 OD) 47 XV O® 45x 27. A (3-year-old male has been drinking large quantities Of fluids and has an insatiable appetite, even for a teenager However. he is losing weight and has become more tired and listless over the past month. A complete blood count is normal, but he is found to have a fasting serum glucose of 17S mpldL.. A diagnosis of type 1 diabetes is made, What is the probable inheritance pattern of his underlying dis- (A) Avtosomal dominant O(B) Multifactoriat O(O) Xlinked recessive O(D) Mitochondrial DNA OLE) Autosomal recessive 28. A pregnant woman with a family history of fragile X syndrome Wants prenatal diagnosis of her fetus. Amplifica tion of the appropriate region of the FMR/ gene by PCR is attempted on DNA from amniotic fluid cells, but no ampli fied products are obtained. What is the best next step? 1A) Routine karyotype of the amniotic fluid cells O(B) Routine karyotype of the unaffected father ©(C) Southern blot of the DNA from the amniotic fluid cells OLD) PCR analysis of the mother's FMRI gene OE) No further tests necessary 29. A 3year-old child with developmental delay, ataxia, Ber 1g seizures, and inappropriate la GXY), but DNA a both of his numbgy aryolype His prear-old male has Joss of vision from a sublux ation QQ crysaline ly nee IQR mid-systli cet es ae a = wd ara(A) Dystrophin O(B) Collagen © Fibritlin ©) NFI prowin OLE) Spectrin t ANSWERS 1. (B) Fanillial bypercholesterolemia results from: muta- tions in the LDL receptor gene such that LDL cholesterol is inereased in the blood because it is not catabolized or taken up by the liver, Triglycerides are not primarily. af fected. Ketonuria can occur with starvation or insulin defi- ciency. The LDL receptors do not play a direct role in ¢luconeogenesis. BP6 182-183 PBD6 150-153 2. (C) He has Klinefelter syndrome. one of the more common chromosomal abnormalities, which occurs in about 1 of 850 liveborn males. The findings can be subtle. ‘The 46,X,i(Xq) is a variant of Tumer syndrome (seen only in females), caused by a defective second X chromosome. ‘The 47,XYY karyotype is not uncommon—about 1 in 1000 liveborn 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 persons with the more typical 47,XX,+21 karyotype. The 22ql deletion syndrome is associated with congenital de- fects affecting the palate, face, and heart, and in some cases, T-cell immunodeficiency. BP6 196 PBD6 174 3. (C) This is Hunter syndrome, one of the mucopolysac- charidoses (MPS) that result from deficiencies of lysosomal enzymes, such as a-t-iduronidase. 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 an X-linked recessive. BP6 187-188 PBD6 159-160 4. (M) She has McArdle syndrome, a form of glycogen storage disease with an onset in young adulthood and in hich there is a deficiency of muscle phosphorylase en- zyme. As 4 consequence, glycogen accumulates in skeletal muscle, Because strenuous exercise requires glycogenolysis, and use of anaerobic metabolism, muscle cramps ensue and the blood lactate level does not rise. Myoglobinuria is seen in about one half of cases, BP6 188-189 PBD6 160,163 5. (L) This is Pompe disease, a form of glycogen storage iscase that results from a deficiency in lysosomal glucosi- dase (acid maltase). The glycogen stored in the myocar- dium results in massive cardiomegaly and heart failure within 2 years BP6 188-189 PBD6 160,163 Chapter GENETIC DISORDERS ml 33 6 (D) Cleft lip and most congenital malformations are not determined by a single gene, and they may be condi- tioned by environmental influences (multifactorial inheri- tance), Marfan syndrome is an autosomal dominant disor- der affecting fibrillin. Tay-Sachs disease, a lysosomal storage disorder, is inherited as an autosomal recessive trait, Erythroblastosis fetalis results from maternal sensitiza tion to fetal red blood cells and formation of antibody that ccan cross the placenta in future pregnancies to produce hemolysis. Polycystic kidneys may be caused by dominant, recessive, oF sporadic mutations. BP6 190 PBD6 165 7. (L) Cleft lip and palate, along with microcephaly and polydactyly, are features of trisomy 13. These patients also have severe heart defects. BP6 194 PBD6 172 8. (D This patient has homozygous familial bypercholes- terolemia, characterized by severe hypercholesterolemia that gives rise to xanthomas and premature coronary artery disease leading to myocardial infarction, BP6 182-183 PBD6 151-152 9. (A) He has Down syndrome, or trisomy 21, Thi fone of the trisomies that can result in a liveborn baby However, there are often many associated congenital anom- alies, particularly congenital heart disease, including ven- tricular septal defect. These are happy children who can function fairly well. However, there is a 10- to 20-fold increased risk for acute leukemia. If persons with Down syndrome live to the age of 40, virwally all of them will have evidence for Alzheimer disease. Hepatic cirrhosis is a feature of galactosemia. Chronic renal failure may be seen with genetic disorders that produce polycystic kidneys. Myocardial infarction at a young age suggests familial hy- percholesterolemia. Aortic dissection is seen in persons ‘with Marfan syndrome, BP6 193-195 PBD6 170-172 10, (B) There is a single palmar flexion crease and a single flexion erease on the fifth digit. These are features of trisomy 21, Monosomy X may be marked by & short fourth metacarpal, With trisomy 18, the fingers are often clenched, with digits 2 and 5 overlapping 3 and 4, Trip loidy may be marked by syndactyly of digits 3 and 4, There are no characteristic featu hand of a male with Klinefelter syndrome, BP6 193-194 PBQS 1 5 fent on oxi- ichdding the-cental Hervous. sys eas NO present 4 eS only « small alfytdyp arm from each chromoege Test Staines i Tcuses in « mothe vint-aris34 mM Pat} GENERAL PATHOLOGY ries @ robertsonian translocation will also be a carrier, In balanced reciprocal wanslocation, the same possibility of inheriting the defect exists. However, other structural ab- normalities are likely to result in loss of significant genetic material, reducing survivability, or t© interfere with me BP6 192-193 PBD6 168-170 13. (©) The features are those of classic Tumer syn- drome. Patients who grow to adulthood are usually mosa- ics, karyotype of 45,X/46,XX, BP6 196-197 PBD6 174-176 14. (D) The extra ¥ chromosome is seen in about 1 of 1000 liveborn males. There is a tendency for such persons, to be tall and prone to severe acne. The missing teeth are specific to hockey, not to an extra Y chromosome. There is 2 controversy about whether such individuals exbibit more aggressive behavior. However, the behavior of virtually all 46,XYY males is indistinguishable from that of otber males. BP6 196 PBD6 174 15. (A) Gaucher disease has three forms. Type 1 ac- ‘counts for 99% of cases and does not involve the CNS, as in this child. It is caused by a deficiency of glucocerebrosi- dase, and infusion with this enzyme reduces severity and progression. Type 2 involves the CNS and is lethal in nfaney. Type 3 also involves the CNS, although not as severely as type 2. A deficiency of acid’ maltase is a fea ture of Pompe disease. Von Gierke disease results. from deficiency of glucose-6-phosphatase. Sphingomyelinese de- ficiency leads (0 Niemann-Pick disease types A and B, Type A, the more common form, is associated with severe neurologic deterioration. ‘Type B, the less common form, may resemble this case, but the appearance of macrophages is different: they contain many small vacuoles. In Tay- Sachs disease, there is a deficiency of hexosaminidase A. It Iso associated with severe mental retardation and death efore 10 years of age. BP6 187 PBD6 158-159 16. (A) This is fragile X syndrome, a condition in which there are 250 to 4000 tandem repeats of the trinucleotide sequence CGG. In general, the more repeats, the worse is the disease or the earlier the onset in conditions caused by trinucleotide repeats. The trinucleotides are dynamic; be- cause their size increases during oogenesis, the male off- spring have more severe disease compared with, for exam- ple, their grandfathers, With a frameshift’ mutation, one, two, or three nucleotide base pairs are inserted or deleted. ‘The protein transcribed is abnormal, A missense mutation results from a single nucleotide base substitution, resulting in an abnormal protein being elaborated. Abnormalities of mitochondrial DNA are transmitted on the maternal side. BP6 176-178 PBD6 143, 177-178 17. (©) She hes neurofibromatosis type 1. Neurofibromas fare most numerous in the dermis but may occur in visceral organs as well. Dermatofibromas are also subcutaneous masses, but they are typically small and solitary and not seen with neurofibromtosis, Leiomyomas are most fre quent in disorder. sporadic cally on type I BP6 189-190 PBD6 162-164 the uterus and are not typically part of a genetic Lipomas can occur just about anywhere but are in occurrence. Hemangiomas may occur sporadi- the skin. They are not part of neurofibromatosis 18. (B) There are a greater number of potentially normal cells having the proper chromosomal complement with mo- saicism, and this may allow babies with abnormalities of chromosome number to make it to term and beyond. Trip: oid fetuses rarely go past the second trimester and are virally never liveborn. Likewise, tetraploidy accounts for many firstrimester fetal losses and is not survivable. Loss of a chromosome is devastating; the only monosomy in which there is possible survival 16 term is Turner syndrome (monosomy X). Most aneuploid conditions (trisomies and monosomies) lead to fetal demise, Trisomy 21 is the most likely to go to term, BP6 191 PBD6 168 19, (A) It is important to be careful in assigning sex; changing your opinion of the sex is about as popular as an umpire changing the call, True hermaphoditism, with ovat- jan and testicular tissue present, is rare. This patient has female pseudohermaphroditism, resulting from exposure of the fetus to excessive androgenic stimulation, as can occur ‘with congenital adrenal hyperplasia. Both the gonadal and karyotypic sex is female. Male pseudohermaphroditism has 2 variety of forms, but the most common is testicular Feminization that results from androgen insensitivity, and the affected persons are phenotypically females but have testes and a 46,XY karyotype. Nondisjunetional events lead to monosomies or trisomies. Trinucleotide repeats are seen with fragile X syndrome in males. Abnormalities of mito- chondrial DNA have @ maternal transmission pattern and do not involve sex chromosomes or sexual characteristics, PBD6 176 20. (B) This patient seems to have a severe inberited neurologic disease that gives rise to a cherry red spot in the retina. The pattern of inheritance (e.g., normal parents, an affected sib) is consistent with autosomal recessive in- heritance. This is most likely Tay-Sachs disease, caused by ‘mutations in the gene that encodes a lysomal enzyme hexo- 155-156, 179, and 18 BP6 186 PERE 2, So eeeoW ciency’ associated]ciency, but it is not associated with congenital malforma- tions. A lymph node biopsy may show a reduction in T or B cells associated with various forms of immunodeficiency, but this is not a specific test 10 help confirm a specific diagnosis. PBD6 173 22. (B) This patient has von Gierke disease. Because of the deficiency of glucose-6-phosphatase, glycogen is not metabolized readily to glucose; and the patients have se- vere hypoglycemia, leading to convulsions. Intracyto: plasmic accumulations of glycogen occur mainly in liver and kidney. Another form of glycogen storage disease, McArdle syndrome, results from a deficiency of muscle phosphorylase and leads to muscle cramping. Tay-Sachs discase is characterized by a deficiency in hexosaminidase A and results in severe neurologic deterioration. In Hurler syndrome, the enzyme a-L-iduronidase is deficient, Af fected children have skeletal deformities and buildup of ‘mucopolysaccharides in endocardium and coronary arteries, leading 10 heart failure. Cardiomegaly and heart failu mark Pompe disease, another form of glycogen storage disease. BP6 188-189 PBD6 160-163 23. (D) She has Fhlers-Danlos syndrome, which results, from a collagen defect that makes connective tissues weak and fragile. A deficiency of ay-antitrypsin leads to liver and lung disease. A mutated Rb protcin is associated with development of retinoblastoma and esteosarcoma. Inherited defects in the number of LDL receptors result in early and advanced atherosclerosis. A deficiency of factor VIII oc- curs in hemophilia A. BP6 182 PBD6 149-150 24. (B) The baby has findings associated with trisomy 18. In the FISH analysis, the chromosomes in each cell hhave been painted with a marker 10 chromosome 18, and there are three markers per cell, consistent with a trisomy. In reality, many cells would have to be counted to allow for artifacts in preparation. Trisomy 18 results from nondis junctional events in most cases. Most trisomy 18 cases are stillborn, and survival beyond 4 months is rare. BP6 194 PBD6 172 25. (B) The clinical features of this child—neurologic involvement, hepatosplenomegaly, and accumulation of foamy macrophages—suggest @ lysosomal storage diso der. One such disorder, with which the clinical history is quite compatible, is NiemanmPick disease type A. It is characterized by lysosomal accumulation of sphingomyelin due to a severe deficiency of sphingomyelinase. Reduced numbers of LDL receptors on hepatocytes can be seen with familial hypercholesterolemia. Collagen synthesis is. im- paired with Ehlers-Danlos syndrome. The glycogen storage disease known as von Gierke disease results from glucose G-phosphatase deficiency. Globules of ay-antitrypsin are seen in liver cells with inherited deficiency of ay-anti- trypsin, BPO 186-187 PBD6 156-158 Chapter GENETIC DISORDERS mM 35, 26. (E) These are findings of Turner syndrome. The hy- ‘groma is quite suggestive. Such affected babies are rarely liveborn. Turner syndrome accounts for a considerable por- tion of first trimester losses. Trisomy 18 can be marked by multiple anomalies as well, but overlapping fingers and & short neck are more typical features. Additional X chromo- somes may not have a serious effect, because all but one X chromosome is inactive. Down syndrome (47,.XX,+21) may be accompanied by a hygroma and hydrops, but ven- tricular septal defect is more frequent than coarctation, and horseshoe kidney is uncommon, 47,XXY does not result in siilbirth. These males have no congenital defects. BP6 196-197 PBD6 174-176 27. (B) He has type 1 diabetes mellitus, which has an increased frequency in some families, but the exact mecha- nism for inheritance is unknown. The risk is about 6% for offspring when firstorder relatives are affected. HLA- linked genes and other genetic loci along with environ tal factors are considered important. This pattern of inheri- tance is multifactorial BP6 190, 564-565 PBD6 165, 915-916 28. (C) Failure to find amplified product by PCR 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 picked up by PCR. The next logical step is a Southern blot analysis of genomic DNA from fetal cells. Routine karyotype of the amniotic fluid cells is much less sensitive than a Southern blot. Karyotype of the unaffected father cannot provide information on the status of the FMRI gene in the fetus, because amplification of the trinucleotide occurs during oo” ‘genesis. For the same reason, PCR of mother’s FMRI gene is of no value. PBD6 183-184, Fig. 6-36 29, (D) These are features of Angelman syndrome. The DNA analysis shows uniparental disomy. The Angelman ‘gene encoded on chromosome 15 is subject to genom 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 Angel- rman gene in the somatic cells. This gives rise to the abnor- malities. typical of this disorder Duchenne’ ‘abnormal perfect and Brormal in pe T, Disordered spectrin Teads 0 & WATERMARK < o Crint-aning