Genetics

Question 1

BRCA

Answer 1

Breast/ovarian cancer tumor suppressor gene
* AD inheritance maternal or paternal.
* If male, increased risk prostate, pancreas, stomach skin, gallbladder, breast
* Carrier frequency: 0.04-0.2% BRCA1 carriers, lower for BRCA 2. If Ashkenazi, 2% for BRCA1/2

Question 2

BRCA screening guidelines

Answer 2

25-29 yo:
 Annual Br MRI w/ contrast and exams q6-12mo.
>30 yo:
 alternating breast MRI w/ contrast and MMG q6 months + exams q6-12 months

Question 3

Risk reducing BSO in BRCA patients

Answer 3

• Most effective method for reducing ovarian cancer risk in high risk women (70-85% risk reduction)
• Reduces risk of ovarian cancer by 90% and breast cancer 50%
• Also reduction in breast cancer mortality and all-cause mortality in this population
• Recommended 35-40 for BRCA1 and 40-45 for BRCA2
• Distal FT site of origin for early malignancies in pts having RRSO
• Should be counseled on surgical menopause: libido, VM sx, osteoporosis, vaginal atrophy, CVD
  o HRT can prevent and alleviate many of these

Question 4

Endometrial CA risk in BRCA patients?

Answer 4

May be a/w higher risk uterine papillary serous CA w/ BRCA1 carriers

Question 5

HRT after BSO in BRCA

Answer 5

• 60% of women w/ BRCA1 or 2 mutation undergo RRSO ages 35-40 and enter menopause
• Lack of guidelines about follow up after surgery: yearly pelvic exam, CA125 monitoring, weight bearing exercise, Ca/Vit D, DEXA 1-2 years after RRSO, consideration of HRT in eligible pts
• Increased risk: sexual dysfunction, vaginal atrophy, VM sx, cognitive changes, CHD, osteoporosis
• Use of HT after oophorectomy in pts at increased risk for GYN cancer controversial
• Few studies done on BRCA carriers using HRT and no data on Lynch
• Prospective cohort of BRCA1/2 carriers after RRSO: HRt after RRSO not a/w increased risk brCa but cumulative incidence of BrCa in E2/P4 group higher than E2 alone (22% vs 12%)
• Given risk of CVD a/w RRSO before age 50, benefits of HRT may outweigh risks w/o increased risk brCa
• Reasonable to consider HRT for women without personal h/o breast ca
• Non hormonal options: SSRIs, alpha 2 adrenergic agents, dietary/lifestyle modification

Question 6

Hemoglobinopathies

Answer 6

o CBC w/ RBC indices in all TTC
o HbE if suspicion of hemoglobinopathy based on ethnicity or based on CBC result (low MCV, MCH)
o 1:10 AA carriers for SCD
 If affected, Hb SS, small amount A2 and F
 Carriers Hb AS
o Remember alpha thal will not be detected on HbE. Must do molecular genetic analysis
 Deletion of 2+ alpha globin genes (everyone has 4)
 Typically have low MCV
o Beta thal: mutation in B-globin gene

Question 7

Cystic fibrosis

Answer 7

Carrier frequency 1:24-94 (Ashkenazi = Caucasian >Hispanic > AA > Asian). Disease incidence 1:2500 in Caucasian
o Screening sensitivity <50% in Asian vs 94% Ashkenazi
o >2100 CF mutations identified, can’t screen for all
 A negative test reduces but does not eliminate possibility that individual is CFTR carrier
o Can do full genomic sequencing: still will not identify 10% of mutations
o ACOG: Complete CFTR sequencing not appropriate for routine carrier screening
 More useful if: family hx and family test results not available or patient negative CF carrier screening, patient has CF, males w/ CBAVD, newborns w/ +newborn screen when mutation testing negative
o 23 mutation panel will detect 90% of detectable mutations in NH white, DeltaF508 accounts for 75% of all CF cases in this population
o If R117H variant detected, muct do 5T/7T/9T testing helps predict phenotype for certain variants (CBAVD)
 5T/7T/9T not a/w disease on their own

Question 8

Chromosomal Inversion

Answer 8

• 2 breaks on same chromosome, rotation of intervening segment 180 deg, and reintegration into chromosome
• Paracentric: Breaks on one side of centromere/one chromosomal arm. More likely to be detected based on infertility or RPL rather than phenotypic abnl in offspring
  o Either transmitted chromosome interverted/compatible w/ life (parent)
  o Normal transmitted chromosome
  o Recombination in inverted region transmitted chromosome acentric (no centromere )or dicentric NOT viable
   Case reports of affected offspring
• Pericentric: Breaks on both sides of centromere, position of centromere may change
  o Telomeric/toward end of chromosome, partial duplication or deletion
  o Larger inversions have increased risk phenotypic abnormalities duplicated and deleted segments

Question 9

Histone

Answer 9

Nuclear protein that DNA is wrapped around in somatic cell nuclei

Question 10

Protamine

Answer 10

Protein to package DNA more tightly in spermatazoa (40x tighter)

Question 11

Describe metabolic changes requires for fertilization and embryo development

Answer 11

Sperm need glucose
cleavage stage embryo needs ATP from Krebs cycle (pyruvate/lactate)
later stage embryo needs glycolysis (glucose)
Does convert some glucose to lactate via aerobic glycolysis

Question 12

Early blastocyst

Answer 12

Blastocoel is less than half volume of embryo

Question 13

Blastocyst

Answer 13

blastocoel is more than half the volume of embryo

Question 14

Full blastocyst

Answer 14

blastocoel completely fills embryo

Question 15

how does RRBSO affect ovary and breast cancer risk

Answer 15

decreases breast cancer risk by 50%
decreases ovarian cancer risk by 70-85%

Question 16

Maternal chromosome 15

Answer 16

Prader willi
uniparental disomy when embryo tries to correct for trisomy