Chromosomal disorders

Question 1

Symptoms: Premature aging, atherosclerosis, osteoporosis, diabetes, multiple cancers
Problem: mutation in the WRN gene which codes for RecQ helicase, which unwinds DNA for homologous recombination and replication
Little old people

Answer 1

Werner syndrome

Question 2

colorectal endometrial, gastric or urothelial carcinomas, glioblastomas: Onset<50 yo
autosomal dominant familial cancer syndrome
Defective mismatch repair pathway due to inherited mutations in one or more of the following genes (MSH 2,3,6 MLH1, PMS1,2)
1/200-1/500- 5% of all colon cancers, 7500 cases/yr

Answer 2

Lynch Syndrome/ (Hereditary non-polyposis colorectal cancer (HNPCC)

Question 3

Infant: incoordination, nystagmus
Childhood: immune deficiencies, frequent infections, capillary expansions,-easiest to see in bulbar conjunctivae, extremely sensitive to radiation, multiple cancers
Problem: Defective translation DNA replication and signaling to p53 due to mutation in the ATM gene that begins in infancy-homologous repair

Answer 3

Ataxia telangiectasia

Question 4

Symptoms: short stature, narrow face w/ prominent nose, skin sensitivity to sun, butterfly shaped facial rash, immunodeficiency, cancer, possible mental retardation
Problem: defective DNA replication and recombinational repair due to mutation in BLM gene that encodes a RecQ like DNA helicase which unwinds the DNA in homologous recombination.

Answer 4

Bloom syndrome

Question 5

Symptoms: premenopausal breast and ovarian carcinomas- 3% of breast cancers
Problem: defective homologous recombinational repair pathway due to mutations in BRCA 1/2
Autosomal dominant. BRCA 2 protein is twice the size of BRCA 1 protein
BRCA 1 mutations are associated w/ onset @ a younger age

Answer 5

BRCA 1/2- familial breast/ovarian cancer

Question 6

4% of what translocation occurs between the chromosome 21 and another acrocentric chromosome

Answer 6

Robertsonian Translocation (14,22)

Question 7

Defective nucleotide excision repair (NER) pathway due to mutations in one or more of the following genes (8total): XP defective translation DNA replication.
1/1,000,000. 1000 fold increased risk of skin cancers
Children of the night

Answer 7

Xeroderma pigmentosum

Question 8

Symptoms: short stature, myeloid cancers, digit abnormalities, café au lait spots
Problem: defective recombinational DNA repair due to mutation in one or more of the following genes which regulate interstrand DNA crosslink repair; FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG

Answer 8

Fanconia Anemia

Question 9

Symptoms: severe mental retardation starting @ 3-4 months old, epilepsy, microcephaly, musty odor, eczema, hypopigmentation
Problem: Phe hydroxylase deficiency; inability to process Phe into tyrosine, Phe buildup is toxic
Autosomal recessive, caucasian 1/10,000 Turkey 1/2,600

Answer 9

Phenylketonuria (PKU)

Question 10

Symptoms: Ptosis, dysphagia, dysphonia, facial weakness, weakness in proximal limbs, limited mobility, cant see very well- autosomal dominant-fully penetrant. Does not shorten life span
Problem: triplet repeat of GCG in PABPN1 gene on c14=hyperaggregation= toxic. Protein required for termination of Poly(A) tail synthesis @ 250-300 nucleotides
Autosomal dominant
Treatment: supportive, surgical correction of ptosis, diet adjustments

Answer 10

Oculopharyngeal muscular dystrophy

Question 11

Symptoms: long narrow face, prominent ears, jaw, forehead, enlarged testicles, mental impairment, ADHD, motor delays
Problem: triplet repeat expansion of CGG, mutation in the FMR-1 gene on the 5’UTR of the promoter of the gene for fragile X mental retardation protein (FMRP)
- X linked dominant, male can be a carrier, female heterozygotes for triplet nucleotide expansions often develop problems such as ovarian failure and ataxia
*5-50 repeats=normal, 50-200=pre-mutation, >200= full mutation

Answer 11

Fragile X

Question 12

Symptoms: corea, ataxia, dysarthria
Problems: CAG repeats located in exon 1 of the HD gene. HD gene is IT15 located at 4p16.3 and encodes the Huntington protein; regulates intracellular transport, fxns in transcription by shuttling transcription factors in and out of the nucleus required for normal embryonic development and neurognesis.
<26 normal, 27-35 does not cause, 36-39 variable penetrance >39 full penetrance
Autosomal dominant

Answer 12

Huntington’s disease

Question 13

Symptoms: muscle weakness in arms/legs, loss of coordination, vision/hearing impairment, slurred speech, scoliosis, diabetes, heart disorders
Problem: triple repeat GAA in the intron @ FXN gene on c9 which encodes frataxin to remove iron from the cytoplasm around the mitochondria. Iron build up causes free radical damage to the mitochondrial membrane which effects nerve and muscle cells
Autosomal recessive- 1/50,000 in USA- 25% recurrence risk

Answer 13

Friedrich ataxia

Question 14

Symptoms: cafe au lait spots, freckling, neurofibromas, lisch nodules, bony lesions, increased risk of cancers
Problem: deletion of NF1 gene @ 17q11.2 causing RAS-GTP lock in “on” position
100% penetrance, highly variable expressivity, new mutations acct for 50% of all cases- 1/3500
Autosomal dominant

Answer 14

Neurofibromatosis Type 1 (NF1)

Question 15

Symptom: abnormal cleft, flexed fingers, rocker bottom feet, normal birth weight, clenched fists, risks when mom >40 yo
Problem: trisomy

Answer 15

Patau syndrome- trisomy 13

Question 16

Symptoms: chronic upper respiratory infections, delayed puberty, non viable sperm in males
Problem: CFTR gene deletion @ 7q31
Fully penetrant, chloride channels are non functional b/c protein formation error. Heterozygotes (carriers) have protection agains diarrheal disease such as cholera and typhoid
1/2500 caucasians, 1/31,000 Asians

Answer 16

Cystic fibrosis

Question 18

Symptoms: cleft palate, velopharyngeal incompetence, growth and learning defieciency. Face: long narrow, tubular nose, round tip. Heart: ventricular septal defect
Problem: deletion in gene @22q11.2
Autosomal dominant

Answer 18

22q11.2 deletion syndrome

Question 19

Symptoms: short stature, shortening of arms and legs, macrocephaly, facial features w/ frontal bossing, normal IQ, CNS complications b/c small foramen magnum
Problem: FGFR3 activation of fxn mutation= inhibition of bone growth
Autosomal dominant- Complete penetrance, most common form of short limbed dwarfism, 80% de novo, 100% from fathers germ-line, homozygosity= lethal

Answer 19

Achondroplasia

Question 20

Symptom: tumor of the eye
Problem: Rb gene inactivation: loss of TSG (tumor suppressant gene) results in uncontrolled cell proliferation- Need a 2nd hit b/c technically it is autosomal recessive- dont need both alleles to show phenotype b/c 2nd hit comes as a somatic cell mutation that triggers the tumor growth

Answer 20

Retinoblastoma (Rb)

Question 21

Symptoms: cat like cry due to hypotonia and laryngeal abnormality, growth restriction, microcephaly, round face w/ widely spaced eyes, single palmar crease, moderate to severe mental retardation
Problem: Large 5p (short arm) deletion
non recurrent

Answer 21

Cri du chat

Question 22

Symptoms: at least 4 of the following skeletal changes: pectus carinatum, pectus excavatum, wrist and thumb signs, scoliosis, reduced extension @ the elbows, very tall and lanky
Problem: Mutation of FBN1 gene which affects fibrillin protein- which affects microfibrils
Autosomal dominant- Highly penetrant, rare germline mosaicism, 25% de novo

Answer 22

Marfan’s Syndrome

Question 23

Symptoms: Wilms tumor of kidney, Aniridia- lack of an iris, Genital anomalies, Retardation of growth and development
Problem: microdeletion of PAX6 gene(aniridia)/WT1 gene(WGR) @ 11p13

Answer 23

WAGR syndrome

Question 24

Symptoms: depressed nasal bridge, eye puffiness, blue eyes, long philtrum, wide mouth, delayed development, cocktail personality, hypercalcemia
Problem: microdeletion of ELN gene @ chromosome 7; contiguous gene syndrome

Answer 24

Williams syndrome

Question 25

Symptoms:
Upslanting palpebral fissures, over folded helical, single palmar transverse crease, short-bent 5th fingers
Problem: extra arm on 14 or 21, or 3 copies of 21, can occur in material meiosis 1
Robertsonian translocation (can be inherited)

Answer 25

Trisomy 21. Down syndrome

Question 26

Symptom: small firm testicles, tall, long legs, gynecomastia ( same breast cancer risk as women), hypogonadism, azospermia, increase in Xs= increase in mental retardation
Problem: maternal nondisjunction @ meiosis 1, phenotype cannot be detected @ birth
1/1,00 males, infertile

Answer 26

Klinefelter syndrome- 47, XXY

Question 27

Symptoms: normal unless high stress environment, slight learning disability, may be conduct disorder
Problem: paternal nondisjunction @ meiosis 2 or maternal nondisjunction @ meiosis 1

Answer 27

47, XYY/XXX

Question 28

Symptoms: short stature, streak gonads/ infertility
Problem: Pseudoautosomal recombination resulting in gain/loss of SRY on cX/cY

Answer 28

46, XY(female) or 46, XX (male)

Question 29

Symptoms: Female: missing teeth, patches of anhidrosis, thin hair. Male: no teeth, anhidrosis, sparse to no hair
Problem: random inactivation of one X chromosome
reduces expression to one allele
always apparent in males that have it b/c they cannon silence the x chromosome

Answer 29

Hypohidrotic ectodermal dyspasia

Question 30

Symptoms: skin redness/blisters, thickened skin, hyperpigmentation, majority are neurologically normal
Problem: defect in NEMO gene
seen only in females

Answer 30

Incontinentia pigmenti

Question 31

Symptoms: normal @ birth, progressive muscle weakness, wheelchair by 10, pseudo-hypertrophy, respiratory insufficiency due to diaphragm weakness, progresses to death
Problem: deletion on Xp21: inability to encode a protein called dystrophin
1/3 of cases are new mutations, rest have a female carrier mother

Answer 31

Duchenne muscular dystrophy

Question 32

Symptoms: exessive bleeding into the joints as well as bruising
Problem: reduced factor VIII: important in the clotting cascade
treated by protein replacement therapy
x linked recessive disorder

Answer 32

Hemophilia A

Question 33

Symptoms: problems in every day life; cant see red or green
Problem: due to missing opsins gene in the cones of the eye. in females, wehn the X chromosomes pair up, there can be a misalignment and the chromosome may lose the ability to identify red, green or both after crossing over takes place
8% of men
0.5% of women

Answer 33

Red green color blindness

Question 33

Symptoms: short sternum, overlapping fingers w/ clenched fists, missing digits, severe intellectual deficiency, heart defect, low frontal hairline, blunt nasal tip
Problem: trisomy

Answer 33

Edwards syndrome- Trisomy 18

Question 34

Symptoms: aortic coartication, edema of hands/feet, web neck, lack of puberty and short stature
Problem: absence fo paternal X or Y, or mosaic, haploinsuffiency of SHOX gene (Xpter-p22.32)
1/5000 births, 80% due to paternal error
no increase in recurrence for the parents

Answer 34

Turner syndrome- 45, X