Diseases (Mutations, Phenotypes, etc.)

Question 1

Down Syndrome Mutation

Answer 1

Trisomy 21. 3-4% unbalanced 21 translocation. 1% mosaic trisomy. Associated with maternal age, Caused by abnormal non-disjunction (chiasmata too close or too far from centromere)

Question 2

Down Syndrome Phenotype

Answer 2

Rate: 1/800 live births
Normal Size, Midface Hypoplasia, Upslanting Palpebral Features, Epicanthal folds, Small Ears, Large Tongue, Low Muscle Tone, Short Fingers, Increased Joint Mobility, Transverse Palmar Crease,

Question 3

Down Syndrome Complications

Answer 3

Cardiac: 50%, atrioventricular canal common
GI: 10-15%, structural abnormalities (dudenal artresia) and feeding problems, GERD, constipation
Ophthalmic: blocked tear ducts, myopia, lazy eye, nystagmus, cataracts

Question 4

Duchenne Muscular Dystrophy Clinical

Answer 4

Progressive Myopathy. Large calves, Gowers maneuver, abnormal gait, high creatine kinase levels (muscular damage)

Question 5

Duchenne MD Inheritance/Prominence

Answer 5

X-linked recessive, 1 in 3,000 males

Onset at 2 years, Wheelchair bound at 13, death at 18

Question 6

Duchenne MD Mechanism

Answer 6

Loss of function: deletion or frame shift mutation in Dystrophin gene (Xp21.2).
High new mutation rate. In-frame deletion or missense mutations lead to milder Becker’s MD

Question 7

Duchenne MD Testing

Answer 7

Genetic Sequencing: can determine deletion and frame shift mutation.

Question 8

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Clinical

Answer 8

Temporary neuropathy following pressure to nerves. Typically full recovery. Onset 20s-30s

Question 9

HNPP: Inheritance/Prominence

Answer 9

Autosomal Dominant

Question 10

HNPP Mechanism

Answer 10

Loss of function, Deletion of PMP22 gene (17p11.2) (glycoprotein in nerves).

Question 11

HNPP Testing

Answer 11

Deletion: FISH, Microarray

Question 12

Osteoenesis Imperfecta Type 1 Clinical

Answer 12

Brittle bones, increased fractures, blue sclerae, normal stature, adult progressive hearing loss

Question 13

Osteogenesis Imperfecta 1 Inheritance/Prominence

Answer 13

Autsomal Dominant

Question 14

Osteogenesis Imperfecta 1 Mechanism

Answer 14

Loss of function nonsense frame mutation in COL1A1 gene (early termination). Unstable mRNA that gets degraded, loss of collagen 1, decreases collagen strength

Question 15

Osteogenesis Imperfecta 1 Testing

Answer 15

DNA sequencing for mutation in gene

Question 16

Charcot-Marie-Tooth Type 1A Clinical

Answer 16

Demyelinating motor and sensory neuropathy, lower extremity weakness, muscle atrophy, and sensory loss.

Question 17

CMT 1A Inheritance/Prominence

Answer 17

Autosomal Dominant

Question 18

CMT 1A Mechanism

Answer 18

Gain of function duplication of PMP22 gene (17p11.2)

Question 19

CMT 1A Testing

Answer 19

Duplication tested by FISH, Microarray, DNA sequencing

Question 20

Osteogenesis Imperfecta II-IV Clinical

Answer 20

Brittle bones, increased fractures, blue sclerae

Question 21

Ost Imperfecta II-IV Inheritance

Answer 21

Autosomal Dominant

Question 22

Ost Imperfecta II-IV Mechanism

Answer 22

Novel Property Mutation: Collagen 1A2 has different folding due to mutation. Still forms trimers with Collagen 1.

Question 23

Ost Imperfecta II-IV Testing

Answer 23

DNA sequencing?

Question 24

Huntington Disease Clinical

Answer 24

Progressive neurodegeneration as adult, corea, death within 15 years of onset

Question 25

Huntington Disease Inheritance

Answer 25

Autosomal Dominant, 1/10,000: presence with # of repeats Genetic Anticipation: # of repeats likely to increase in subsequent generations 2' to slippage. Maternal expansions more likely.

Question 26

Huntington Disease Mechanism

Answer 26

Increase in # of CAG (glutamate) repeats in Huntington gene (4p16.3). Ranges: 39 full penetrance; >60 juvenile onset

Question 27

Huntington Disease Testing

Answer 27

Trinucleotide Repeat: Fish? DNA Sequencing gives specific number

Question 28

Myotonic Dystrophy Clinical

Answer 28

Droopy eyes, intellectual difficulty, hypotonia

Question 29

Myotonia Dystrophy Inheritance

Answer 29

Autosomal Dominant

Question 30

Myotonia Dystrophy Mechanism

Answer 30

Increase of CTG repeats within 3' UTR of DMPK gene

Question 31

Myotonia Dystrophy Testing

Answer 31

Trinucleotide repeats: DNA sequencing

Question 32

Phenylketouria Clinical

Answer 32

Early onset epilepsy, hyperactivity, intellectual delay

Question 33

PKU Inheritance

Answer 33

Autosomal Recessive, High allelic heterogeneity w/ 400 mutant alleles

Question 34

PKU Mechanism

Answer 34

Loss of function: Defect in phenylalanine hydroxylase enzyme which converts phenylalanine to tyrosine most common. Also possible to have BH4 deficiency (cofactor also used in dopamine and seratonin synthesis)

Question 35

PKU Testing / Screening

Answer 35

Newborn screening post partum when mother's enzymes gone, can change diet to prevent effects Mass Spectrometry: fast detection of amount of enzyme in blood. Guthrie test: too much PA let bacteria grow

Question 36

PKU Treatment

Answer 36

Low phenylalanine diet. Maintained during pregnancy to prevent complications BH3 replacement PO

Question 37

Alpha 1 Trypsin Deficiency Clinical

Answer 37

Adult onset, increased risk of emphysema and liver cirrhosis/cancer

Question 38

ATD Inheritance

Answer 38

Autosomal Recessive. 1/2500. 1/25 carriers.

Question 39

ATD Mechanism

Answer 39

Loss of SERPINA1 protein is inhibitor of elastase. Elastase released in lungs by neutrophils, if not degraded it destroys lung elastin. Process accelerated by smoking b/c more neutrophils recruited to lungs.

Question 40

ATD Allelic Heterogeneity

Answer 40

``` M allele normal, most common Z allele (Glu342Lys) misfolded protein that accumulates in ER of liver cells. S allele (Glu264Val) unstable, less effective protein Z/S intermediate between Z/Z and S/S ```

Question 41

ATD Testing

Answer 41

Sequencing for point mutations, FISH probes for each allele, Enzyme function tests

Question 42

ATD Treatment

Answer 42

Enzyme infusion and aerosol treatment

Question 43

Tay-Sachs Disease Clinical

Answer 43

Progressive CNS neurodegeneration, onset 3-6 months. Muscle weakness, decreased attentiveness, startling at sound. Then seizures, vision/hearing loss, reduced mental function, paralysis. "Cherry red spot in eye". Death at 3-4 years

Question 44

Tay-Sachs Inheritance

Answer 44

Autsomal Recessive. 1/360,000 general; 1/3,600 Aschkenazi Jewish

Question 45

T-S Mechanism

Answer 45

LSD, defect in HexA subunit of GM2 degrading complex. GM2 cannot be degraded, aggregates in lysosomes of CNS neurons. Allelic heterogeneity: 4 bp insertion frame shift mutation most common

Question 46

T-S Screening/Testing

Answer 46

Screen potential carriers for enzyme function, test for 3 main mutant alleles in parents and child

Question 47

Sandhoff Disease

Answer 47

Similar to T-S but mutation in HexB subunit

Question 48

AB-Variant of T-S

Answer 48

Severe form of T-S where HexA and HexB are fine but mutation in GM2AP prevent normal funciton.

Question 49

Cystic Fibrosis Clinical

Answer 49

Salty skin, poor growth and weight gain, mucus accumulation, chest infections, coughing and SOB

Question 50

Cystic Fibrosis Inheritance

Answer 50

Autosomal Recessive

Question 51

Cystic Fibrosis Mechanism

Answer 51

Loss of function mutation of CFTR gene

Question 52

Achondroplasia Clinical

Answer 52

Short Stature, Rhizomelic limb shortening, large head, megalencephaly, trident hand, spinal cord compression 2' to small foramina. Brain stem compression = 3-7% early death

Question 53

Achondroplasia Inheritance

Answer 53

Autosomal Dominant. 1/40,000. Homozygous is lethal!

Question 54

Achondroplaisa Mechanism

Answer 54

Gain of function mutation Gly380Arg in FGFR3 gene. Tyrosine kinase constitutively on, inhibits bone growth. Mutations in father's germline.

Question 55

Neurofibromatosis Clinical

Answer 55

Cafe au lait spots, axillary and inguinal freckling, multiple neurofibromas, Lish nodules on eyes. 100% penetrant.

Question 56

Neurofibromatosis Inheritance

Answer 56

Autosomal Dominant

Question 57

Neurofibromatosis Mechanism

Answer 57

Mutation of NF1 gene on chromosome 17

Question 58

Marfan Syndrome Clinical

Answer 58

Connective tissue disorder with ocular, skeletal, and cardiac manifestation. Tall and skinny. Hypermobile joint, pectus excatum. Risk of Aortic Aneurysm

Question 59

Marfan Syndrome Inheritance

Answer 59

Autosomal Dominant 1/5,000

Question 60

Marfan Syndrome Mechanism

Answer 60

Mutation in FBN1 gene (fibrillin)

Question 61

Familial Hypercholesteremia

Answer 61

High cholesterol levels from mutations in LDL receptor so it can't clear LDL from bloodstream

Question 62

Fragile X Clinical

Answer 62

Childhood onset mental deficiency, dysmorphic facies, enlarged testicles, speech delay, autism-like, large ears and prominent jaws

Question 63

Fragile X Inheritance

Answer 63

X-linked dominant

Question 64

Fragile X Mechanism

Answer 64

Trinucleotide expansion in 5' UTR of fragile X region leading to hypermethylation. Haplotype effect. Ranges: Grey zone 6-45; Premutation 59-200; penetrance 200+ Maternal genetic anticipation.

Question 65

Fragile X Premutations

Answer 65

FTAXS (59-200 repeats): adult onset tremor, ataxia, Parkinsonian features, memory loss. Women also premature ovarian failure. From increased RNA production, sites not hypermethylated yet

Question 66

Hemophilia A Clinical

Answer 66

Reduced clotting

Question 67

Hemophilia A Inheritance

Answer 67

X-linked Recessive

Question 68

Hemophilia A Mechanism and Treatment

Answer 68

Factor VIII deficiency, fixed with Factor VIII supplementation

Question 69

Turner Syndrome Clinical

Answer 69

Gonadal Dysgenesis, short stature, heart defects, fused kidneys, webbed neck, brown nevi, wide nipple placement, infertility, social difficulties, difficulty with math

Question 70

Turner Syndrome Inheritance and Mechanism

Answer 70

45 X0; 1/2,000-5,000 live births; Meiotic non-disjunction

Question 71

Klinefelter Syndrome Clinical

Answer 71

Gonadal dysgenesis/hypogonadism, infertility, tall stature, gynecomastia, likely sterile, language trouble

Question 72

Klinefelter Inheritance and Mechanism

Answer 72

47, XXY; Meiotic Nondisjuction