Genetics - Diseases

Question 1

Neurofibromatosis

Answer 1

Mutation: deletion in the NF-1 gene

Usually has GTPase activity, which will normally inactivate the RAS oncogene (mutation causes increased RAS activity = increase cell proliferation)

Symptoms: neurofibromas (cafe au lait spots), freckling of axillary or inguinal region, optic tumors, Lisch nodules, osseous lesions, 1st degree relatives with NF-1;

Question 2

Marfan’s

Answer 2

Fibrillin 1 gene (FBN1) - 95% penetrant

If genetic testing has been performed, only ONE of the following must be present:
Aortic root enlargement
Ectopia lenti
If not: score 7 on symptom scale

• Caused by a mutation of the fibrillin 1 gene (FBN1)
    ◦ Located on chromosome 15
    ◦ Causes dysfunctional or less abundant FBN1
    ◦ Autosomal dominant disorder
• Results in abnormalities of connective tissue
    ◦ Leads to fewer functional microfibrils

* Tend to have long arms, legs, fingers, toes
* Common complications: mitral valve prolapse, aortic aneurysm, retinal detachment, lens detachment, bulla of the lung → pneumothorax

Question 3

Split Hand Deformity

Answer 3

95% penetrance

Question 4

Achondroplasia

Answer 4

80% born to parents of normal height
Mutation in fibroblast growth factor receptor (FGFR3)
FGFs normally limit proliferation of bone - activate it too early = achondroplasia
Mutation rate increases with PATERNAL age
Gain-of-function mutation (overactive gene)
Homozygotes very severely affected, often lethal

Question 5

Crouzon syndrome

Answer 5

Affects FGFR2

Causes craniosynostosis

Question 6

Thanatophoric dysplasia

Answer 6

Affects FGFR3

Lethal most of the time; causes the lungs to be unable to inflate

Question 7

4 most common recessive diseases

Answer 7

Cystic fibrosis
Sickle cell anemia
PKU
Tay Sachs disease

Question 8

Hemophilia A (“Classic”)

Answer 8

Affects Factor VIII C
Diagnosed by 2 YO and characterized by prolonged bleeding after minor injury; spontaneous bleeding into joints, muscles
Most common severe bleeding disorder
Severity depends on how much Factor VIIIC is present in blood: <1% = severe; 1-5% = moderate; 6-40% = surgical risk

Question 9

Color Blindness

Answer 9

X-linked

Question 10

XLD-Rett Syndrome

Answer 10

Affects females
Mutation in MECP - methyl CpG Binding Protein 2 – methylation turns the gene off
Children have normal development for 6-18 months, then experience regression with impaired language, loss of hand skills, seizure, and unsteady gait

Question 11

Polyploidy

Answer 11

3+ complete sets of chromosomes (69 pairs); responsible for 8-10% spontaneous abortions

Question 12

Aneuploidy

Answer 12

Extra or missing individual chromosomes (ex: trisomy 21)

Question 13

Results of nondisjunction in meiosis 1

Answer 13

2 trisomic; 2 monosomic (once fertilized)

Before fertilization: 2 with two sister chromatids; 2 with no chromatids

Question 14

Results of nondisjunction in meisos 2

Answer 14

2 normal, one trisomic; one monosomic (once fertilized)

Before fertilization: two with one chromatid (normal); one with two chromatids, one with no chromatids

Question 15

Which chromosomes are acrocentric?

Answer 15

13, 14, 15, 21, 22

Question 16

Down Syndrome

Answer 16

trisomy 21

***INCREASED INHIBIN-A during maternal serum testing in second trimester!!!

Common findings: hypotonia, flat nasal bridge, epicanthal folds, *single palmar crease, dots in iris

Additional risk factors: Congenital heart defects, 10-20 fold increase for leukemias (but very responsive to treatment); premature aging; increased risk of alzheimer’s; hearing and vision problems (due to structural differences of head)

Question 17

Patau syndrome

Answer 17

trisomy 13

Common findings: abnormal brain development; wide-set eyes (hypertelorism); cyclopia; cleft lip/palate; polydactyly; malformed ears; undescended testes

Additional risk factors: tetralogy of Falot; truncus arteriosus

80% du to maternal nondisjunction; 20% due to translocation

98% die in utero

Question 18

Edwards syndrome

Answer 18

trisomy 18

Common findings: micrognathia, small eyes, hands in fist with two middle fingers tucked under, rocker bottom feet

Additional risk factors: omphalocele at birth; diaphragm defects; cardiac valve problems; GU problems, hypotonia; learning disabilities

Life expectancy: 3 YO

Question 19

Cri du Chat

Answer 19

Characteristic cry

Deletion in p arm of chromosome 5
12% due to parent with balanced translocation
80% due to deletion within dad’s sperm

Question 20

Wolf-Hirschhorn syndrome

Answer 20

Deletion in p arm of chromosome 4
Characteristic symptom: “Greek helmet nose”
Short philtrum

Question 21

Williams-Beuren Syndrome

Answer 21

Autosomal dominant
Deletion in the q arm of chromosome 7
“Elfin facies” ear to ear smile; long philtrum; overfriendly as children, withdrawn as adult

Question 22

Klinefelter

Answer 22

XXY (47, XXY)

Male; swelling of breasts; small testicles; no/poor sperm production; most common chromosome disorder; androgen-deficiency = poor muscle tone, poor libido, poor bone mineralization

Question 23

Turner

Answer 23

X0 female (45, X0)

Short stature; “webbed neck”; edema in the newborn feet and hands; coartication of the aorta

Can be mosaic
80% due to paternal meiotic error
Possible to be mosaic with some Y in some cells

Question 24

XXX

Answer 24

Tall, thin females with menstrual irregularities; reproductive loss OR, if not, does NOT pass extra chromosome to offspring

Question 25

Huntington’s

Answer 25

Autosomal dominant

36+ CAG repeats in HTT gene
Chorea, mood/personality changes (especially with aggression); cognitive decline

Question 26

Cystic Fibrosis

Answer 26

Autosomal recessive

CFTR gene is altered; multi-system disease; respiratory insufficiency; intermittent production of sputum; congenital absence of vas deferens in males; high chloride levels in sweat

Question 27

BRCA-1/BRCA-2

Answer 27

Increased risk for breast/ovarian cancers due to mutation in tumor suppressor gene (normally repairs double-stranded DNA breaks)

Autosomal dominant with incomplete penetrance (87% for females; 20% for males)

Question 28

When is triple test performed and what does it do?

Answer 28

11-13 weeks; non-invasive

Checks hCG and PPAP-A hormones plus nuchal translucency (indicative of neural tube defect or trisomy); gives accurate date

Elevated PPAP-A suggests possibility of trisomy
Elevated hCG suggests possibility of down’s
Depressed hCG suggests possibility of tri 18/13

Screens for aneuploidy, heart/diaphragmatic defects

Question 29

What is maternal serum testing and what does it do?

Answer 29

Second trimester; noninvasive

Checks uE3; AFP; hCG; and Inhibin A

Inhibin A elevated in Down
AFP elevated with neural tube defects
All others - depressed levels indicate potential for trisomy or neural tube defect

Question 30

Maternal Serum Alpha Fetoprotein

Answer 30

16-18 weeks;

Measures protein made by fetus in mom’s blood
Elevated = neural tube defect risk
Depressed = Down Syndrome risk

Question 31

Chorionic Villus Sampling

Answer 31

Invasive, diagnostic test

Transcervical: 10-12 weeks
Transabdominal: Any time but becomes more difficult later in pregnancy
Take sample from fetal-derived chorion

Question 32

Amniocentesis

Answer 32

Invasive diagnostic test
15 weeks from last period (16-18 weeks)
Usually not performed after 22 weeks
Measures AFP and karyotype 
(AFP elevated in neural tube defects; depressed in down syndrome)

Question 33

NIPS

Answer 33

Non-invasive prenatal screening - detects trisomy 13, 18, 21
Occasional false positives; compares quantities of DNA to suggest existence of trisomies

Might be consideration if patient’s pregnancy is at-risk for trisomy and/or they initially declined CVS/amniocentesis

Question 34

Karyotyping

Answer 34

Requires live DNA - “method of first resort” to diagnose child after birth

Question 35

FISH

Answer 35

Fluorescent in situ hybridization
Tag chromosomes, see if legs are too long (translocation) or don’t have even numbers (mono/aneuploidy), or if there is uncontrolled growth/reproduction (cancer)

Question 36

Karyotype vs FISH

Answer 36

FISH is faster, simpler, no live tissue needed, and higher resolution. Must know where to look (already have suspicion); cannot acquire whole chromosome picture.

Karyotyping can scan for abnormalities of all chromosomes, arms, regions, and bands of cell. Takes several days, requires live samples, and provides low resolution results.

Question 37

Array-based comparative genomic hybridization (CGH)

Answer 37

scan entire genome, detect dna imbalances, cannot see balanced translocations or rearrangements
Shifts LEFT = deletion
Shifts RIGHT = duplication
Detects deletions/duplications >1000 bp; so won’t catch something like Marfan’s which is tiny deletion

Question 38

Mom passes disease to all of her children and father passes to none

Answer 38

Mitochondrial inheritance

Question 39

Affected offspring have affected parent

Answer 39

Autosomal dominal

Question 40

Male-to-male transmission

Answer 40

NOT X-linked dominant

Question 41

Males only transmit trait to daughters

Answer 41

X-Dominant

Question 42

Affected males related through an unaffected mother

Answer 42

X-recessive