genetics final review 1

Question 1

Newfoundland Recombinant:

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Answer 1

Newfoundland Recombinant:

1. Pericentric Inversion

Chromosome 3

Question 2

Huntington’s Disease

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Answer 2

Huntington’s Disease:

• Chromosome 4
• AD, Polyglutamine repeat of CAG on 4p,Huntington gene in the coding region
• Mutated gene causes abnormal interactions with TFs, they are stuck to the abnormal gene
• Under 40 repeats is pre-mutation→ paternal anticipation
• Chorea, athetosis (slow, involuntary, convoluted, writhing movements of the fingers, hands, toes, and feet), dystonia (sustained muscle contractions cause twisting and repetitive movements or abnormal postures), loss of cognition, psychiatric abnormalities (depression, dementia).

Question 3

Cri Du Chat

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Answer 3

Cri Du Chat:

• Chromosome 5
• 1. micro Deletion (interstitial or something deletion) on chromosome 5 ! 10-15% people with cri-du-chat syndrome inherit the chromosome abnormality from an unaffected parent. In these cases, the parent carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. Balanced translocations usually do not cause any health problems; however, they can become unbalanced as they are passed to the next generation.
     * a. Mostly spontaneous inheritance
• Child has a mewing cry, low birth weight, failure to thrive, hypotonia, psychomotor retardation, microcephaly, hypertelorism (excessive width between body parts), round face, anti-mongoloid slant of eyes, epicanthus fold of skin of upper eyelid over inner angle of the eye, mental retardation, low-set ear
• Survival into adulthood is not common

Question 4

Cystic Fibrosis

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Answer 4

Cystic Fibrosis

• Chromosome 7
• Autosomal recessive, common in northern European populations
• 60% of the time is from a mutation in CFTR on 7q, delta F508
• NBD-1 domain is usually affected.
• Modifier genes:
  
  • MBL-2 loss of function, results in a worse phenotype
  • TGFbeta1 gain of function results in a worse phenotype increasing the scar tissue in the lungs
• Diagnosed with sweat test being overly salty, pancreatic insufficiencies result in greasy stools and deficiencies in fat soluble vitamins
• Thick mucus in the lungs results in pulmonary infections and eventually failure
• Vas deferens are absent in 95% of males→infertility

using ASO (specific aligonucleotide) (DNA) you find 3 base inframe deletion at codon 508 (phynyl alanine)

ASO also used for sickle cell (locating single base pair change.

Question 5

William’s Syndrome: Elfin

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Answer 5

William’s Syndrome: Elfin

• Chromosome 7
• Deletion of 26 genes from 7q, includes the elastin gene
• Elfin facial appearance, cheerful demeanor, ease with strangers, loves music
• Aortic stenosis
• Transient (lasting only for a short time) hypercalcemia

Question 6

Recombinant 8

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Answer 6

Recombinant 8:

• Pericentric inversion on chromosome 8
• Common with Hispanics in the Southwest US
• Lethal condition caused by severe cardiac abnormalities and mental retardation.

Recombinate 8 patient has 6% chance of producing a child that has recombinant 8 disease.

Question 7

ABO Blood Group System

Answer 7

ABO Blood Group System:

chromosome 9

1. Frameshift Mutations between A and B (4 nucleotides)
2. 3 alleles for one gene
3. A and B are co-dominant
4. O is recessive→ just the H antigen and no transferases, null mutation
5. Transfusion incompatibility→hemolysis

Question 8

Friedrich Ataxia

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Answer 8

Friedrich Ataxia

Chromosome 9

AR defect in the FRDA gene: repeats of GAA in the first intron impairing transcriptional elongation, inhibits polymerase

a. Expansion of 100-1200 copies (7-34 is normal)

Mutation is in mRNA (GAA repeats in first intron)→ non-coding repeats→ causes gene silencing through induction of heterochromatin structure.

Symptoms include spinocerebellar ataxia that manifests before adolescence (puberty) with incoordination of limb movements, difficulty with speech, cardiomyopathy, scoliosis, diminished or absent tendon reflexion and impaired position and vibratory senses.

Question 9

Acute Intermittent Porphyria:

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Answer 9

Acute Intermittent Porphyria:

• chromosome 11
• AD mutation in PGPD
• Uroporphyrinogen I synthase/PBG deaminase/HMB synthase
• More females than males are observed
• Porphobilinogen (PBG) and delta ALA accumulate in blood→ urine (uroporphyrin)
• Presents with acute intermittent abdominal pain, hallucinations, depression, anxiety, seizures, arrhythmias (problem with the rate or rhythm of the heartbeat), NO photosensivity
• Triggered by: barbituates, steroids, catabolic diet, surgery
• Heme level is decreasing because more cytochrome p450 enzymes are being produced

Note: catabolic diet are foods that actually have a negative calorie effect. These are foods that supposedly take a person more calories to digest them than the food itself actually contains.

Question 10

Hemoglobin C Disease (HbC)

Answer 10

Hemoglobin C Disease (HbC)

Chromosome 11

1. AR mutation @ position 6: Glu→Lys
2. Tends to crystalize, less soluble than HbA, mild anemia,
   note: it is a beta thalassemia disease (there are 2 beta genes, unlike alpha that has 4)

Question 11

Hemoglobin Hammersmith:

Answer 11

Hemoglobin Hammersmith:

Chromosome 11

1. AD mutation in beta chain @ 42 Phe→ Ser
2. Unstable hemoglobin to be unstable causes heme to drop out of its pocket
3. Low oxygen affinity causes cyanosis

note: it is a beta thalassemia disease (there are 2 beta genes, unlike alpha that has 4)

Question 12

Hemoglobin Hyde Park (HbM)

Answer 12

Hemoglobin Hyde Park (HbM)

Chromosome 11

AD mutation in the beta chain @ 92 His→ Tyr

Methemoglobin: oxidized heme iron is incapable of reversible oxygenation

Cyanosis in **heterozygotes **

note: it is a beta thalassemia disease (there are 2 beta genes, unlike alpha that has 4)

Note Trick: Call it METhemoglobin hyde park disease.

meet me at the park across the street from P.S 92 during lunch between history class and theater (his→tyr beta chain mutation) arts under behind the swings for some heterosexual action that will take your breath away (cyanosis) PERMANENTLY ( oxidized heme (Fe 3+) iron irreversible (NOT reversible) !.

Question 13

Hemoglobin Kempsey:

Answer 13

Hemoglobin Kempsey:

Chromosome 11

1. AD missense mutation @ 99 Asp→ Asn (Asparagin)
2. Gain of Function mutation
3. Locks Hb in its high affinity oxygen state—relaxed structure
4. Causes polycythemia: abnormal increase in the number of circulating RBCs

Question 14

Sickle Cell Disease:

Answer 14

Sickle Cell Disease:

Chromosome 11

1. Autosome Recessive!!! i know i know all blood disease are autosomal dominate…except this one!!!
2. Transversion missense mutation in the 6th codon of beta globin Glu→ Val
3. Mutation causes HbS where the two mutant chains replace 2 normal alpha chains
4. Hemoglobin polymerizes during deoxygenated conditions (T state) sticking, causing an inflexible RBC
5. The RBCs are also destroyed prematurely causing inflexible RBC
6. Microvascular occlusion→ ischemia, pain, organ damage in the spleen, CNS, bones, liver, kidneys and lungs
7. Patient will have jaundice (because of the high RBC turn over rate due to shortened RBC lifespan), splenomegaly, sausage digits, repeated infection (cause of death) and an Tb level of 6-10 g/dL

note: it is a beta thalassemia disease (there are 2 beta genes, unlike alpha that has 4). in this case, changes in beta chain effects alpha chains.

Question 15

Pallister-Killian

Answer 15

Pallister-Killian:

Chromosome 12

1. Isochromosome mosaic Duplication of all or part of chromosome 12p
2. Results in a partial trisomy (notes say “This leads to the development of tetrasomy 12p”)→ mosaicism
3. Severe mental retardation, poor muscle tone, coarse facial features, prominent forehead, thin upper lip with a thicker lower lip and a short nose, sparce hair (mo hawk)
4. Patients presents with seizures, poor feeding, stiff joints, cataracts in adulthood, hearing loss and heart defects

Question 16

Phenylketonuria (PKU)

Answer 16

Phenylketonuria (PKU)

Chromosome 12

1. AR, patients are usually compound heterozygotes
   
   1. a. Milder mutation predominates for phenotype
2. Classic: mutations @ both alleles of PAH gene: Phenylalanine hydroxylase
3. Non-Classic: Tetrahydrobiopterin (BH4) problems with recycling BH4, which is a co factor for phenyalaline hydroxylase
4. Phenylalanine can’t be made into tyrosine and it builds up to toxic levels
5. Presents with mental retardation via developmental delay in infancy, microcephaly, heart malformation, seizures, hyperactivity, and behavioral disturbances, musky smell to urine (phenylpyruvate acid)
6. Is tested for @ birth in industrialized nations with a heel-prick of the newborn
7. Child can be affected if the mother has uncontrolled PKU
   
   1. a. CNS abnormailities: mental retardation
8. Treated with diet modification( low phenylalanine and supplement tyrosine. avoid sweetners that contain aspartam…which has phenylalanine in them too).

Question 17

Trisomy 13: Patau’s Syndrome

Answer 17

Trisomy 13: Patau’s Syndrome

Chromosome 13

1. Most severe of the three trisomies
2. Micropthalmia (abnormally small eyes)
3. Microcephaly (mental retardation)
4. Polydactyl (bunch of fingers)
5. bilateral cleft lip
6. Prenatal Testing: decreased PAPPA, Decreased hBCG, decreased U3e concentration, decreased inhibin A

mother age is a factor as for all trisomies

Question 18

Retinoblastoma

Answer 18

Retinoblastoma

Chromosome 13

1. Retinoblastoma
   
   • Mutation of Rb on Chr. 13
   • Normal function of Rb is to regulate G1→S phase; its normally not

phosphorylated so it binds E2F and PREVENTS transcription

* Retinoblastoma: Rb get HYPER phosphorylated; can’t bind E2F, so

transcription and growth happens (cell gets into S phase)

* Inherited/Mendelian vs Non-inherited/Sporadic  o In inherited retinoblastoma (dominant trait), there are multiple

bilateral tumors, having an early age of onset—one Rb1 mutation is

inherited, and any mutation in the second allele would lead to cancer. o In sporadic retinoblastoma, there are single unilateral tumors, having a late age of onset—two “hits” of the Rb1 mutation need to take place.

side note:

P53:

• Transcription factor that regulates cell cycle/ DNA repair
• Causes cell death
• Phosphorylated P53 = active→ binds to P21 to induce apoptosis
• Active ARF also binds and inhibits Mdm2 to cause P53 to enter nucleus and

continue its normal function

• Mdm2 (is a E3 ubiquitin Kinase) – normally inhibits P53 by keeping it in the

cytoplasm so it doesn’t activate P21

• I= 1/20,000, autosomal dominant
• Found in infants, rapid rate of proliferation creates tumors in the eyes, **white **reflex, removal of eye for treatment, 2nd incidence is a matter of chance

Question 19

Alpha-1-Antitrypsin Deficiency:

Answer 19

Alpha-1-Antitrypsin Deficiency:

Chromosome 14

1. AR mutation in alpha 1 antitrypsin which inhibits elastase production from neutrophils
2. Z allele: homozygotes will have aggregates of alpha-1-antitrypsin in the hepatocytes, trapped in the rough endoplasmic reticulum, (15% of normal)
   
   1. Little alpha-1-antitrypsin is secreted→ conformational disease
   2. Smoking makes this worse by oxidizing methionine in the active site causing a reduced affinity of the alpha-1-antitrypsin for elastase
      
      1. i. Elastase can now travel to the lungs and breakdown alveoli walls
3. This mostly affects the lungs and liver resulting in emphysema and cirrhosis

Question 20

Angelman Syndrome:

Answer 20

Angelman Syndrome:

Chromosome 15

•15q (3-4 Mb deletion inherited from mother (46)
on chromosome 15)

• Inherited from the mother
• SO ONLY HAVE COPIES FROM DAD
• Protein affected is Ube3A
• The function of Ube3A is to ubiquitinate ARC and target ARC for destruction. Arc’s normal job is to decrease neuronal signaling levels
• Because Arc is now NOT being degraded as often, ARC causes an abnormal lowering of neuronal signaling leading to impaired neuronal communication and synaptic development.
• Signs and Symptoms
• Inappropriate laughter, Unusual facial features, severe mental retardation, ataxic gait, seizurses, flapping hands, sleep disturbances, spasity (Spasticity is stiff or rigid muscles)

caused by uniparental disomy

Question 21

Prader-Willi Syndrome:

Answer 21

Prader-Willi Syndrome:

1. 3-4Mb deletion inherited from the father (46), proximal portion
2. Mutation from the father
3. 1/3 of cases have uniparental disomy—no copies from the father and 2 from mom
4. Obesity (love to eat!), hypogonadism, small hands and feet, short stature

Question 22

Tay-Sachs Disease

Answer 22

Tay-Sachs Disease: Gm2 Gangliosidosis

Chromosome 15

1. Autosomal Recessive lysosomal storage disorder common in the Ashkenazi Jewish population
2. Frameshift mutation in HEXOAMINIDASE A alpha subunit
   
   1. a. Addition of TATC in the HEX A gene for the alpha subunit (80% of AJ pop)​
3. Accumulation of sphingolipid GM2 gangliosides
4. Newborns will appear normal until 3-6 months of age until rapid mental/motor deterioration, skeletal, cherry red macula, cardiac, respiratory dysfunction followed by dementia, difficulty swallowing, paralysis, blindness and death by **ages 2-4 **

Question 23

Sandhoff Disease

Answer 23

Sandhoff Disease

Chromosome 15

1. Mutation of the HexB gene and production of a defective beta subunit leads to the inactivation of both hexosaminidase A and B activity
2. Both hexosaminidase A and B activity require a functional beta subunit.
3. The clinical course of this disease is similar to Tay-Sachs but with an accelerated course because of the **accumulation of both GM2 and **globoside in the lysosomes

Question 24

Alpha Thalassemia:

Answer 24

Alpha Thalassemia:

Chromosome 16

Alpha globin is found in both

• Adults: αβ/αβ
• Fetuses: αγ/αγ
• And is therefore presented at birth!!

Result of deletions

• Misal​ignment, homologous pairing and recombination between the α1 and α2 genes on separate chromosomes

Alpha-2: one loci is deleted→ silent

Alpha-1 trait: two loci are deleted→ mild microcytic anemia

Hbh: three loci are deleted, moderately severe anemia and splenomegaly

• Body tries to use 4 beta subunits to compensate

Barts/Hydrops Fetalis: γγ/γγ

• Gamma tetramer results from compensation
• Ineffective oxygen transport, common in southeast Asians
• Death occurs in utero or shortly after birth with massive generalized edema.

Question 25

Charcot Marie Tooth

Answer 25

Charcot Marie Tooth

Chromosome 17

1. Duplication of PMP22 (peripheral myelation protein) on short arm
2. Due to increased production of myelin, there is an inability to maintain compact myelin
3. Distal leg muscle wasting, demyelinating neuropathy, progressive weakness
4. high arched feet with hammer toes.

Question 26

Li-Fraumeni Syndrome

Answer 26

Li-Fraumeni Syndrome

Chromosome 17

1. AD transcription factor defect creating a mutant TP53 gene for p53 which is usually a tumor suppressor
2. Affected members in 70% of families with LFS carry a mutant form of TP53 as a germline mutation.
3. Mutations in both alleles are necessary to inactivate the p53 gene
4. Rare cancer families with a history of different forms of cancer (affected at a relatively early age) including bone and soft tissue sarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma

Usually p53 senses cell stress such as DNA damage and causes arrest in G1

• ​​​a. Negatively regulated by binding of MDM2
• b. P53 usually binds p21 transcription factor.

Question 27

Smith-Magentis:

Answer 27

Smith-Magentis:

Chromosome 17

1. Deletion of RAI1 (retinoic acid induced 1 which encodes protein active in nerve cells in the brain) gene on 17p
2. Multiple congenital abnormalities
3. Nervous system development flaws (because Rai1 defect.
4. Delayed speech and language
5. Distinct facies, sleep problems, Behavioral Problems

Question 28

Trisomy 18: Edward’s Syndrome

Answer 28

Trisomy 18: Edward’s Syndrome

Chromosome 18

1. Severe malformation of the heart
2. Failure to thrive, low postnatal survival
3. Rocker-bottom feet, large occiput, clenching/overlapping pattern of fingers, prominent calcanei (large bone in back of foot).
4. Prenatal Testing: decreased PAPPA, Decreased hBCG, decreased U3e concentration, decreased inhibin A

Question 29

Myotonic Dystrophy 2:

Answer 29

Myotonic Dystrophy 2:

Chromosome 19

1. Expansion of CCTG tetranucleotide in the first intron of the gene endocing zinc finger protein 9
2. Identical phenotype of MD-1

Question 30

X Chromosome:

Answer 30

X Chromosome:

_*color blindness is X link RECESSIVE so femails don’t get it._

**X-linked recessive: daughters of affected males will be obligate carriers

**X-linked dominant: daughters of affected males WILL HAVE the disease

Inactivation: epigenetic silencing via methylation of one of the 2X chromosomes in a female shortly after fertilization

1. Xist: gene that functions as an RNA (not translated into protein)
   a. **Expressed on the inactive X chromosome** **
   b. Macro H2A is the histone involved with the Barr bodies

2) Barr bodies= number of X chromosomes – 1 (activated X chromosome)

3) Inactivation is what accounts for the mosaicism seen in X-linked dominant disorders in females.

Non-random inactivation:

a. Abnormal X Chromosome and normal
i. Abnormal X is inactivated
b. Balanced Translocation: part of the autosome is on the X chromosome and part of the x is on the autosome
i. Normal X is inactivated so there is no loss of expression of the part of the translocated autosome

c. Unbalanced Translocation: the defective X has part of an autosome on it and on top of that there is already two normal copies of that same autosome (Partial trisomy for that section)

i. The defective X is inactivated to prevent the trisomy genes from being expressed

D. If the translocation is balanced, normal X chromosome is inactive

E. Unbalanced offspring of a balanced carrier: only the translocation product carrying the X-inactivated chromosome is present and this chromosome is invariably inactivated→ normal X is always active

Question 31

Beckers Muscular Dystrophy

Answer 31

Beckers Muscular Dystrophy

1. X-linked recessive

2. Truncated dystrophin (shorter)

3. 46% of deletion mutations are reported to be in the ‘spectrin-like’ repeats present between the NH2 and COOH termini, they are “in-frame” substantiated by Western blot and histological immunofluorescent staining, using anti-dystrophin antibodies
4. CK level is only slightly elevated at time of onset
5. IQ problems, less aggressive than Duchenne’s, onset is at 11 (if still walking at age 16—BMD diagnosis) patients remain ambulatory well into adult life, slightly reduced life expectancy

Question 32

Duchenne Muscular Dystrophy:

Answer 32

Duchenne Muscular Dystrophy:

1. X-linked but not recessive!!!! it’s X-linked DOMINATE.

2. Caused 60% of the time by a deletion in the dystrophin gene

a. Analyzed by Multiplex CDR

3. Most female carriers will at least develop cardiomyopathy
4. Frameshift mutations, duplications
5. Dystrophin normally links laminin to actin cytoskeleton in the ECM between muscle cells
6. Pseudohypertrophy of calves, Gower maneuver, elevated serum creatine kinase, progressive muscle weakness,
7. Onset 3-5 and death before teen years from cardiorespiratory failure.

Question 33

Fragile X:

Answer 33

Fragile X:

1. X-linked dominant mutation in the FMR1 gene, abundance of CGG repeats in the 5’ UTR of the first exon (greater than 200 repeats results in hypermethylation of the promoter)→ Gene Silencing
   a. Occurs almost exclusively during gametogenesis in the female
   b. Severity of phenotype depends on the number of repeats
2. Penetrance in females is at 50-60%
3. Most likely from mom
4. Coarse facial features, macro-orchidism, very low IQ, behavioral problems, long face, prominent jaw, protruding ears, high arched palate
5. Second most common form of mild mental retardation in boys

Question 34

Fragile X associated tremor/ataxia syndrome FXTAS

Answer 34

Fragile X associated tremor/ataxia syndrome FXTAS

1) Late-onset, progressive cerebellar ataxia and intention tremor due to the formation of intranuclear neuronal inclusions. Evidence suggests that FXTAS results from the 2 to 5 fold increased levels of the FMR1 mRNA present in these patients, representing a gain-of-function mutation.
2) FMRP: RNA binding protein that associates with polyribosomes to suppress the translation of proteins from its RNA targets. These targets are involved in cytoskeletal structure, synaptic transmission and neuronal maturation. The disruption of these processes is likely to underlie the mental retardation and learning abnormalities seen in fragile X patients.
3) FMRP appears to regulate the translation of proteins required for the regulation of synaptic plasticity, a process critical to learning and memory.

Question 35

Glucose-6-Phosphate Dehydrogenase Deficiency(G6PDD):

Answer 35

Glucose-6-Phosphate Dehydrogenase Deficiency(G6PDD):

1) X-linked recessive that affects 10% of African-American males
2) G6PD is deficient and usually is asymptomatic unless triggered by certain drugs that increase ROS (reactive oxygen species)
a. Anti-malarial, sulfonamides (like “naphthalene”) , analgesics, non-sulfa antibiotics
b. Primoquine
c. Favabeans→ Favism
3. RBCs of these patients are more susceptible to oxidative damage and overproduce NADPH which usually protects the cell from oxidative damage by regenerating reduced glutathione in its oxidized form, hemoglobin will precipitate as Heinz bodies, and membrane lipids may undergo peroxidation weakening the RBC membrane causing hemolysis
4. Symptoms include hemolytic anemia, fever, jaundice, reddish brown urine, acute renal failure
5. **Accumulation of ROS in RBCs gives a person a protection against malaria→ heterozygote advantage.

Question 36

Alzheimer’s Disease

Answer 36

Alzheimer’s Disease

Multifactorial Disorder Alzheimer’s disease and the Secretases.

Alzheimer’s Disease: and the Secretases

1) PSEN1: Presenillin, Chromosome 14
a. Early Onset Alzheimer’s: 35-60
b. 10% of all Alzhemier’s patients
c. Gain of Function mutation (1 and 2) in gamma secretase cofactor
2) 1-2% of patients, 40-85 years of age @ onset

a. BAPP: Beta amyloid precursor protein,Chromosome 21–DS

b. PSEN2: Presenillin, Chromosome 1

3) ApoE: Chromosome 19 late onset—most common
a. Complex inheritance Alzheimer’s
b. Susceptibility allele
c. Many genes but e4 allele is most commonly associated and found in the plaque accumulations
d. E4/E4 homozygotes have highest probability of getting Alzheimer’s
4) Extracellular Accumulations: ApoE and B42
5) Intracellular Accumulations (intraneuronal): hyperphosphorylated Tau
a. Neurofibrillary Tangles→ Tau is not mutated in Alzheimer’s

6) Alpha Secretase: good→ Claves BAPP→ AB40 fragments→ nontoxic

7) Beta and Gamma Secretases: Bad→ AB40 and AB42 fragments

a. AB42 is fibrillinogenic

Question 37

Diabetes Type I IDDM

Answer 37

Diabetes Type I IDDM

1) Genetic susceptibility and subsequent environmental insult
2) Chromosome 6: MHC Class II HLA-DR3 and DR4 susceptibility loci
a. 95% of patients express a DR3 or DR4 allele or both compared to 50% of controls
b. DQB1*0201 allele segregates with DR3
c. DQB1*0302 allele segregates with DR4
3) CTLA4, PTPN22, insulin genes can also be mutated

Question 38

Idiopathic Cerebral Vein Thrombosis

Answer 38

Idiopathic Cerebral Vein Thrombosis

1. Environmental Factor
   a. Oral contraceptives increase the expression of:

i. Factor X
ii. Prothrombin

2. Genetic Factor
   a. Factor V (Lieden)
   b. Prothrombin

Question 39

Hereditary Nonpolyposis Colon Cancer (HNPCC)

Answer 39

Hereditary Nonpolyposis Colon Cancer (HNPCC)

1) Mutations in genes MLH1, MSH2, MSH6 DNA mismatch repair proteins are mutated MutL or MutS
2) Predisposition resulting in 2-5% of all colorectal cancer cases, most common autosomal dominant inherited form of colorectal cancer—80% risk of developing an early onset internal cancer.
3) Caused by inherited defects in DNA MMR (mismatchrepair) with 5 different MMR genes linked to HNPCC→ MLH1, MSH2, MSH6 being the most common (prototypical caretaker TSGs)
4) Secondary mutations: other TSGs including APC and TGFBR2
5) RER+ (replication error positive) phenotype seen in cells lacking both copies of MSH2 includes enormous increase in point mutations and instability of DNA segments contain simple sequence repeats→ Microsatellite polymorphisms
6) Polyps will be in the dozens not thousands

Question 40

Hirschsprung Disease

Answer 40

Hirschsprung Disease

1. Can be inherited AD, AR and multifactorial
2. RET ligand AD form, long segment form resulting from a loss of function

a. RET is also an oncogene

3. GDNF, EDNRB, EDN3 Short segment form, complex/multifactorial
   a. Most common pattern: three loci are located at 10q, 3p and 19q
   b. I = 1/5000; males have a 2x higher risk
   c. Complete absence of some or all of the intrinsic ganglion cells in the colon resulting in **severe constipation, symptoms of intestinal **obstruction, and megacolon
   d. Parasympathetic nervous system is impaired, incapable of peristalsis
   e. Very high relative risk ratio for sibs (~200), but MZ twins do not show perfect concordance

Question 41

Polycystic Kidney Disease

Answer 41

Polycystic Kidney Disease – Chromosome 16 and 4

autosomal dominate

1. PKD1 (Chromosome 16 ) is 80% of patients - polycystin 1, a transmembrane receptor-like protein of unknown function
2. PKD2(Chromosome 4) encodes polycystin 2, an integral membrane protein homologous to voltage-activated sodium and calcium a1 channels
3. Locus (2 Genes) and Allelic Heterogeneity
4. PKD1 and PKD2 are two protein components of primary cilia, the filamentous structure on the cell surface of each renal tubular cell
5. Age at onset: childhood through adulthood
6. Pleiotropic Disease
7. ADPKD is one of the most common genetic disorders with a prevalence of 1 in 300 to 1 in 1,000. In the United States, it

accounts for 8% to 10% of end-stage renal disease.

8. Features:
   
   1. -Progressive renal failure
   2. -Renal and hepatic cysts
   3. -Intracranial saccular aneurysms
   4. -Mitral valve prolapse
   5. -Colonic diverticula
   6. Progressive Renal Failure
9. Cyst formation follows a “two-hit” mechanism as observed with tumor-suppressor genes and neoplasia; both alleles of either PDK1 or PDK2 must lose function for cysts to form
10. The mechanism of how loss of PDK1 or PDK2 causes cyst formation involves mislocalization of cell surface proteins that are normally restricted either to basolateral or epithelial surfaces of developing renal tubule cells.
11. Adult polycystic kidney disease is caused by structural and functional abnormalities of primary cilia in kidney epithelia as the cells fail to sense fluid flow.
12. The primary cilium is designed to sense fluid flow in the developing kidney tubule and signal the cell to stop proliferating and to polarize.
13. The continued cell division leads to the formation of cysts, fluid filled spaces lined by renal tubular cells.

Question 42

Rett Syndrome:

Answer 42

Rett Syndrome:

1. Rett syndrome - MECP2 gene - methyl-CPG binding protein 2 - LOF

Hypothesized to mediated transcription processing

Cpg isalnds are highly mutable

c. Sx:

• Normal pre/neonatal growth
• Rapid onset of neurological systems
• Loss of milestone b/w 6-18 months
• Toe walking after 12 months
• Pseudostabalization – no more decline for a while then =
• SEVERLY RET

After pseudostabilation:

• Spacitic
• Ataxic
• Irritable
• Autstisic
• Purposely wringing or flapping high
• Rigidity
• Scoliosis
• Live until adulthood
• Death is unexplained
• **INSIDIOUS = CHILD HAS NO ABNORMAL SIGNS BUT 6- 18 RAPID ONSET OF NEUROLOGICAL SYMPTOMS **
• CAN BE PRESENT IN XXY MALES (Kleinfelter)
• Somatic Mosaicism
• Lethal in males at birth (lethal in males due to hemizygotosity. no male to male transmission)

Question 43

Familial Hypercholesterolemia

Answer 43

Familial Hypercholesterolemia:

1. Mutations are: Small nucleotide subs, dels, ins
   a. 2-10% of the time is structural rearrangement
2. LDL receptor
   a. Loss of function, Chromosome 19
3. ApoB100 Binding domain
   a. Loss of function, Chromosome 2
4. PCSK9 protease
   a. Gain of function, Chromosome 1
   b. Some variants can be beneficial and lower LDL levels
5. ARH
   a. Loss of function, Chromosome 1

Question 44

Homocysteinuria

Answer 44

Homocysteinuria

1. Autosomal Recessive
2. Increase in substrate derivatives
3. Classic: defective cystathionine beta synthase Homocysteine can’t be converted to cystathionine, methionine and homocysteine accumulate
4. Deficiency in its cofactor Vitamin B6 (pyridoxal phosphate)
5. Deficiency in methionine synthase or its cofactors Folate and vitamin B12
6. Clinical Presentation: excessive blood clotting in the arteries and veins Thromboembolism in vein/arteries, accelerated atherogenesis, similar to except that joints are tight (loose in Marfan’s), retinal damage, damage to the neuronal network of the eye, and even loss of vision, lens dislocation (inferomedial direction (down and in), mental retardation, osteoporosis, long-bone fractures
7. Treatment: special diet restricted in protein and methionine and sypplemented with cysteine. Oral pyridoxine produces a decrease in plasma methionine and homocysteine concentration in body fluids (50% of all patients experience reduction), Folate and Vitamin B12 (cobalamin) should be supplemented. Betaine can also lower homocysteine levels.

Question 45

Osteogenesis Imperfecta:

Answer 45

Osteogenesis Imperfecta:

1. COL1A1 on Chromosome 17, COL1A2 on Chromosome 7
   a. 90% of patients have mutations in both of these
   i. 2 pro alpha1 chains, 1 proalpha2 chain
   b. Missense Mutation in pro-alpha-1 chain: 1 normal: 3 abnormal chains
   c. Missense Mutation in Pro-alpha-2 chain: 1 normal: 1 abnormal chain
2. Type 1: null mutations→collagen made is normal but in reduced amounts
   a. AD, Mutations in mRNA stability
   b. Mildest form, blue sclera, bones are predisposed to fracture,

triangular face, brittle teeth, hearing loss, spinal curvature

3. Type 2: Missense mutation
   a. New mutation, glycine is substituted with a bulkier and more positive amino acid in the carboxy 2/3 of the chain→ Lethal
   b. Baby dies in utero or shortly after birth
4. Type 3: Missense Mutation
   a. AD, progressive deforming, fractures are present at birth, dentinogenesis imperfect, hearing loss, **blue sclera **
5. Type 4: Missense Mutation
   a. AD, normal sclera, 2nd mildest after type 1, spinal curvature, short stature, hearing loss, dentinogenesis imperfect

Question 46

Congenital Adrenal Hyperplasia

Female Pseudohermaphroditism

Answer 46

Congenital Adrenal Hyperplasia-

Female Pseudohermaphroditism

Chromosome 6 Recessive

Congenital adrenal hyperplasia is defects in enzymes of adrenal cortex for cortisol biosynthesis that would regulate androgen levels.

mutation in CYP21 gene on chromosome 6p encoding for **21-hydroxylase **causing abnormally high androgen levels

1. AR, 46XX have normal ovarian tissue but with ambiguous or male external genitalia Most common defect is a deficiency of 21-hydroxylase which leads to abnormally high androgen levels in both XX (baby hulk) and XY patients
2. Can affect both male and female patients, males will have **precocious (early) **puberty very early at about age 2-3.
3. Results in virilization (developement of male physical characteristics of female infants. ovarian development is normal but excess production of androgens causes clitoris enlargement and labial fusion.
4. Older patients will undergo masculinization during puberty, deepening of the voice and appearance of facial hair, failure to menstruate

Question 47

Severe Combined Immunodeficiency Disease SCID

Answer 47

Severe Combined Immunodeficiency Disease SCID

1. Autosomal: ADA and PNP deficiencies causing neurodevelopmental delay indicative of mental retardation, due to different causes than X-linked SCID
2. X-linked SCID “Bubble Boy”
   a. mutations in the gamma chain of the subunit for IL-2, IL-4 , IL-7, IL-9 and IL-15 cytokine receptors.
3. Child lacks almost all immune defenses and develops life-threatening infections caused by bacteria typical of a B cell deficiency and also by viruses, opportunistic germs in the case of a T cell deficiency. There will be no thymus on X-ray. Major treatment is needed to survive beyond infancy





Question 48

Leber’s hereditary optic neuropathy

Answer 48

Leber’s hereditary optic neuropathy

_Mitochondrial Disease _

1. Expressed phenotypically as the, painless bilateral vision loss due to optic nerve atrophy in young adults
2. Mutations in the oxidative phosphorylation in complex 1
3. Depending on the mutation, there is often some recovery of vision but the pathogenic mechanisms of the optic nerve are unclear.
4. Affected individuals may be male or female but penetrance is much higher in males, about **50% of male carriers but only about 10% of female carriers **develop the symptoms (5:1 ratio)
5. The variance in penetrance and male bias of the phenotype have been shown to be determined by a haplotype on the short arm of X chromosome
   a. Alcohol and tobacco use increases probability of blindness in carriers and act as optic nerve toxins.

Question 49

MELAS

Answer 49

MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

**Mitochondrial Disease **

1. Point mutation in tRNA for Leucine @ 3243 A→G

2. Heteroplasmic: variable expressitivity due to proportion of mutant to normal mitochondrial DNA in cells
3. Symptoms appear in childhood following a period of normal development with muscle weakness and pain, loss of appetite, vomiting, seizures, recurrent headaches this progresses to stroke like episodes begging before age 40, which can progressively damage the brain leading to vision loss, problems with movement and dementia
4. Lactic acid can buildup leading to vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing, myoclonus, ataxia, hearing loss, heart and kidney problems, diabetes and hormonal imbalances

Question 50

MERRF:

Answer 50

MERRF (Myoclonic epilepsy with ragged-red fibers):

Mitochondrial Diseases

1. mtDNA gene encoding the tRNA Lys is the gene most commonly associated. A→G transition at nucleotide 8344. Mutations are usually present in all tissues and detected via blood leukocyte mtDNA.
2. Four main symptoms are : myoclonus, generalized epilepsy, ataxia and ragged red fibers in the muscle biopsy.
3. Multisystem disorder characterized by myoclonus, epilepsy, ataxia, weakness and dementia. Onset is usually in childhood, occurring after normal early development. Presents with hearing loss, short stature, optic atrophy and cardiomyopathy, occasionally pigmentary retinopathy and lipomatosis are observed.

Question 51

Chromosome 22

Answer 51

Chromosome 22:
22q11.2 Deletion Syndrome:
Variation in the symptoms of the disease is related to the amount of genetic material lost in addition to DeGeorge Syndrome
C- cardiac, especially tetralogy of fallot
A- abnormal facies
T-thymic aplasia

• the failure of an organ or tissue to develop or to function normally.

C- cleft palate
H- hypocalcemia
22

DeGeorge Syndrome:

• *DOMINATE.**
  1. Deletion
  2. Structural or Functional defects of the thymus
  3. T-cell immunodeficiency
  4. Hypoparathyroidism → hypocalcemia
  5. Conutruncal heart defects

VCFS: Velocardiofacial Syndrome

1. Deletion
2. Palate abnormalities such as cleft palate, high arched palate, bifid uvula
3. Cardiac diseases, and characteristic facial appearance
4. hypernasal speech
5. poor learning + social disabilities
6. early onset of mental illness
7. bland effect

Cat-Eye Syndrome:

1. Duplication: Tetrasomy for 22q
2. Duplicated region is in an inverted orientation!
3. Ocular coloboma

• a congenital malformation of the eye causing defects in the lens, iris, or retina.

4. Congenital Heart Defects
5. Craniofacial anomalies
6. Moderate Mental Retardation

Question 52

Beckwith-wiedman

Answer 52

Beckwith-Wiedman:

Imprinting defect (excess paternal or loss of maternal contribution) on chromosome 11p

1. Uniparental disomy for imprinted portion of chromosome 11p
2. Includes IGF-2→ Creates big babies (macrozomia)
3. Macroglossia
4. Severe hypoglycemia
5. Malignant neoplasms of the kidney, adrenal glands, and liver
6. abdominal wall defect such as ambilical hernias, Omphalocele: Intestines or abdominal organs are present outside of the body at birth.
7. wilms tumors (Wilms tumor is a type of kidney cancer that occurs in children).

other genes imprinted is igf2 (as seen above), cdkn1c (a cyclin dependent kinase inhibitor to nefatively effect grown), KCNQOT1 and H19.

Question 53

Beta Thalassemia

Answer 53

Beta Thalassemia:

Chromosome 11

1. 2 copies of the beta globin gene, mutations are due to single-base-pair substitutions→ point mutations
2. Presents 2 to 6 months after birth when fetal gamma globin is converted to adult beta globin
3. B0 Allele: no HbA present
   a. Complex: large deletions that can result in an absence of beta globin
4. B+ Allele: 10-30% of HbA is detectable
   a. You need 2 beta chains to form HbA2→less is produced
   b. Simple: decrease in the abundance of beta globin
   i. Mutations in the mRNA such as splicing, promoter mutants, capping, frameshift mutations, nonsense mutations (truncated beta globin)
5. Thalassemia Minor: Carriers with one mutated allele
   a. Genotype of B+/B or B0/B→ Microcytic anemia
   b. Lower than normal MCV value, increase in the fraction of HbA2 and a decrease in the fraction of HbA
6. Thalassemia Major /Cooley’s Disease when both copies have no function or are missing
   a. Genotype of B+/B0 or B0/B0 or B+/B+
   b. Toxic inclusions reduce RBC lifespan, severe hemolytic anemia, chipmunk faces, fractures, teardrop cells, hypochromia and microcytosis
   c. Upregulation of HbF and HbA2 occur because there isn’t enough HbA
   d. Death will occur in childhood if not treated with transfusions, iron chelation and splenectomy, bone marrow transplant can cure.

Question 54

Denys-Drash Syndrome (DDS)

Answer 54

Denys-Drash (drag queen) Syndrome (DDS)

Chromosome 11

Dominate mutation

chromosome 11

1. AD mutation in the WT1 gene, which is a Wilm’s tumor suppressor gene on 11p
2. Causes XY males to have ambiguous external genitalia
3. Disrupts normal testicular development, loss of playfulness, decreased appetite, weight loss, growth delay, abnormal skeletal development, insomnia, abdominal pain, constipation, anuria (failure of the kidneys to produce urine).
4. Early nephrotic syndrome and culminates in renal failure in the first 3 years of life.

Traid of pseudo-hermaphroditism, mesangial renal sclerosis, wilms tumor

Question 55

Frasier Syndrome

Answer 55

Frasier Syndrome

Chromosome 11

Dominate mutation

1. Severe AD disease due to mutations in the Wt1 gene on 11p
2. Characterized by nephropathy, complete gonadal dysgenesis (XY female) and risk of gonadal blastoma in early childhood

Question 56

Camptomelic Dysplasia:

Answer 56

Camptomelic Dysplasia (sox= sucks):

Chromosome 17

Dominate disorder

1. AD mutation of SOX9 gene on 17q
   
   1. Duplication (increase) of SOX9: XX male
   2. Mutation (inactivation) in SOX9: XY female even if you have SRY.
2. SOX9 normally expressed early in development and usually initiates testis formation even in the absence of SRY
3. 75% of XY patients with this are sex reversed and phenotypicaly females
4. Results in lethal skeletal malformations so don’t even try solving SRY mutations with SOX9

Question 57

Trisomy 21: Down’s Syndrome

Answer 57

Trisomy 21: Down’s Syndrome

1. Deep simian groove, white brush-field spot in iris of eye, sandal gap toes, small hands and feet, 15 fold increase risk of leukemia (GATA1 gene mutation), susceptibility to Alzheimer’s because of overexpression of Tau.

2. Single most-common genetic cause for moderate mental retardation
3. Much higher incidence rate for a child with down’s syndrome if the mother is over 35
4. 95% of patients: maternal non-disjunction
5. 4% have 46 chromosomes but have the disease because of Robertsonian Translocation
   a. Between 21q and the long arm of another acrocentric chromosome (14 or 22), translocation chromosome replaces one of the normal acrocentric chromosomes
   b. NO RELATION TO MATERNAL AGE
6. Testing: increased hBCG, decreased Ue3, increased inhibin A, decreased AFP concentration, increase in NT (nuchal transiency ) in the cervical spine→ edema (seen on ultrasound)

10-15% recurrency rate if you got it from mom

Note on Trisomies:

These chromosomes have the least number of genes, which is why they don’t result in a spontaneous abortion. Chromosome 21 has the smallest number of genes, besides the Y chromosome, and thus you see the most successful development in this trisomy.

Question 58

male pseudohermaphroditism

Answer 58

•One cause: Deficiency of the steroid 5a-reductase (this enzyme converts testosterone to its active form dihydrotestoserone)

-Ambiguous genitalia (normal testicular development, small penis and blind vaginal pouch)

•Another cause: **Androgen insensitivity syndrome (AIS) due to the **lack of androgen receptors in target cells

• Chromosomal males have normal female external genitalia with a blind vagina, and no uterus or uterine tubes
• Testes are present either within the abdomen or in the inguinal canal, and are sometimes mistaken for hernias in infants who otherwise appear to be normal females
• AIS is inherited in an X-linked recessive manner
• Mutation can be a complete deletion or point mutations in the

androgen-binding or DNA-binding domains of the androgen receptor

Question 59

Klinefelter’s Syndrome

Answer 59

Klinefelter’s Syndrome

X-linked

1. Duplication of X chromosome
2. Tall, thin males with relatively long legs
3. hypogonadism
4. gynecomastia
5. infertility
6. learning problems
7. poor psychosocial adjustment, narrow shoulders and chest
8. **Decreased testicular hormone/endocrine function in individuals
   often results in a low /

decrease serum testosterone but increased LH and FSH**

9. Low sperm count
10. may go undiagnosed until teen years when the male develops breasts

Question 60

Turner’s Syndrome

Answer 60

Turner’s Syndrome:

X-linked

1. Deletion
2. 45X genotype or 46 Xi (Xq)
3. 25% of patients are mosaic, while 99% are miscarried
4. Webbed neck, coarcation of the aorta, short stature and infertility presenting as amenorrhea (an abnormal absence of menstruation) during puberty.
5. 99% cases end in miscarriage
   i. fetal hydrops (hydrosfetalis), lymphedema
   ii. soft tissues filled with fluid, red color, cystic hygroma
6. NOT associated with advanced maternal or paternal age
7. Elevated frequency of renal and Cardio Vascular animalies.

Question 61

Y Chromosome

Answer 61

Y Chromosome:

Psuedoautosomal region: segments on the X and Y that pair and undergo recombination during male meiosis, important in normal male development

DAX gene: suppresses activity of SRY

SRY gene: Sex-determining-Gene

1. NOT LOCATED in the pseudoautosomal region
2. Lost to the X chromosome during recombination results in a 46XXmales
3. If the SRY gene is deleted, 46 XY females

AZFc gene: (part of the family of AZF regions on the Y chromosome)

1. Contains spermatogenesis genes
2. Mutations can result in infertility

Notes:

3 NON-overlapping regions on the Y chromosome that were identified as being deleted in males who could not produce sperm.

• AZFa- azospermia factor region A: USP99Y. it was identified as either being deleted or having de novo point mutations, which cause male infertility.
• Gene in AZFc region? DAZ gene. it means deleted in azospermia.

Question 62

Ehler’s Danlos Syndrome (EDS):

Answer 62

Ehler’s Danlos Syndrome (EDS):

1. Mutations are on 15 of the 24 chromosomes, 10 different inherited connective tissue disorders→ Clinically heterogeneous
   a. Quantitative/Qualitative abnormalities in collagen synthesis
   b. Some are AD some are AR
   c. Lysine hydroxylase is mutated→ no hydroxylysine
2. Characterized by joint hypermobility, cutaneous fragility, cigarette paper skin, hyperextensibility, sutures fall out after surgery

Question 63

Chorionic Villus Sampling

Answer 63

Chorionic Villus Sampling: 10-11 weeks (1st trimester)

Invasive Prenatal Diagnosis:

1. CPM (Confined placental mosaicism) occurs in 2% of all samples. represents a discrepancy between the chromosomal makeup of the cells in the placenta and the cells in the baby.
   a. There can be a trisomy confined to the placenta. CPM is when the trisomic cells are found only in the placenta.
   i. Fetus needs to be checked for trisomy rescue.
2. 1% abortion risk

Question 64

Amniocentesis

Answer 64

Amniocentesis 15-16 weeks (2nd trimester)

Invasive Prenatal Diagnosis:

1. Karyotyping and DNA testing
2. Done to measure alpha fetoprotein (AFP) which can also be tested for with maternal blood serum to look for neural tube defect
   a. NTD testing for neural tube defects
3. 1% abortion risk

Question 65

First Trimester serum levels

Diagnosis

Answer 65

Non-invasive Prenatal Diagnosis:

First Trimester @ 11 and 13 weeks:

1. Pappa: decreased in all trisomies
2. hBCG: decreased in 13/18 trisomies, increased in 21 trisomy

Question 66

Second Trimester serum levels

Diagnosis

Answer 66

Non-invasive Prenatal Diagnosis:

Second Trimester @ 15 & 20 weeks:

1. MSAFP (Maternal Serum Alpha-Fetoprotein)
   a. Increased concentration if child has neural tube defect
   i. **Folic Acid prevents**
   b. Decreased concentration if child has trisomy 21
2. hBCG: decreased in 13/18 trisomies, increased in 21 trisomy
3. UE3: decreased in all trisomies
4. Inhibin A: decreased in 13/18 trisomies, increased in 21 trisomy

5. Ultrasound:

a. Increase in NT: indicates edema in 21 trisomy
b. Determines sex from week 15 on

Question 67

sex reversed female

Answer 67

sex reversed female

46-xy, SRY not affected

duplicaion of DAX1 gene on Xp 21.3

1. encodes a TF that plays a role in dosage sentive role in determining gonadal sex, tight regulation with SRY
2. suppresses normal male-determining function of SRY and ovarian development results.

Question 68

Neurofibromatosis:

Answer 68

Neurofibromatosis:

DOMINATE

chromosome 17

1. AD, loss of function mutation of NF1 causing cell proliferation
2. NF1 normall acts as a tumor suppressor that activates RAS GTPase to

regulate cell proliferation

3. Café au lait spots hyperpigmentation, benign and malignant tumors of the

nervous system, lisch nodules (iris), pleiotropic!!

Question 69

Retinitis Pigmentosa:

Answer 69

Retinitis Pigmentosa:

1. Digenic Inheritance (2 rare mutations in ROT1 and peripherin)
2. Common cause of visual impairment due to photoreceptor degeneration

3. Can be AR, AD, X-linked or complex

4. shoes locus heterogeneity (Mutations in 43 different loci)

Question 70

Marfan’s Syndrome:

Answer 70

Marfan’s Syndrome:

DOMINATE

1. AD mutation in Fibrillin gene FBN1 which encodes for the glycoprotein fibrillin-1 which maintains elastic fibers and forms them in the ECF
2. Usually binds latent TGFbeta, sequestering it
   a. Mutation allows TGFbeta levels to increase resulting in faulty
   scaffolding
3. Skeletal: thin elongated fingers, limbs, hypermobile joints, scoliosis, pectus excavatum
4. Heart: dilation of ascending aortic root, mitral or aortic regurgitation
5. Eye: dislocated lens