genetics

Question 1

Your patient is 46XX but their genetic councilor informed them that they have an SRY translocation which is why they look male. What does this SRY region code for and what happens when its missing in a 46XY male?

Answer 1

The SRY region is the sex determining region of the Y chromosome that codes for a transcription factor responsible for activating male development and repressing female development. This includes testes determining factor (TDF) which promotes development of the primitive sex cords to testis, testosterone production from leydig cells, and the secretion of MIS in sertoli cells which degrades the female mullerin ducts.

In a 46XY male they would look phenotypically female and have sawyer syndrome a pure gonadal dysgenesis with streak gonads and delayed puberty.

Question 2

During spermatogenesis when there is XY pairing what region is being paired and which genes are involved in recombination in this region?

Answer 2

pseudoautosomal region contains the PAR1 and PAR2 genes. The other portions of the X chromosome form heterochromatin so that only certain regions are free to “line up” with the Y chromosome so their is more equality in this match up; allowing for division in meiosis.

PAR1 is required for pairing

Question 3

Describe what happens during the fertilization of gametes that leads to diploidy; explain each general step.

Answer 3

Ootid (N) receives the spermatozoan (N) to become the ovum which then contains a pronuclei, upon fusion of the nuclei the ovum becomes a zygote; which is diploid.

Question 4

Why are X-linked dominant disorders less severe in women?

Answer 4

They have a back up copy of the X chromosome that can be used for proper function whereas men do not. Certain genes can escape inactivation and promote functionality.

Question 5

Whats the only known survivable monosomy?

Answer 5

turners syndrome

Question 6

Screens serve what purpose in prenatal decision making? Why not just test these kids?

Answer 6

Screens help avoid invasive and expensive tests that are usually unnecessary. This helps physicians and patients to decide who’s high risk and needs testing to confirm a diagnosis; such as a chorionic villus sample or amniocentesis.

Question 7

Trisomy 13, 18, 21?

Answer 7

Patau, edwards, downs

Question 8

What first trimester serum markers are used for screening and what do they indicate?

Answer 8

HCG, and PAPP-A in conjunction sometimes with maternal age. (Pregnancy associated plasma protein A)

High HCG low PAPP-A= Trisomy 21 risk with advanced maternal age.

Low HCG and PAPP-A = Trisomy 13, 18 risk

Each should be combined with US to increase detection rates.

Question 9

What US findings would support a trisomy diagnosis in the first trimester?

Answer 9

Increased nuclei translucency (fluid at back of neck)
Increased impedance through ductus venous
Tricuspid regurg
Hypoplasia of nasal bone

Question 10

What is a cell free fetal DNA test and how is it administered

Answer 10

It’s a prenatal screen used to detect trophoblasts in maternal blood. Genomic sequencing allows for ID of aneuploidy; 13,18,21

Question 11

What are the second trimester screening serum markers used to ID trisomy 21? how is this different for trisomy 18?

Answer 11

triple screen- decreased AFP or MSAFP, increased HCG, decreased uE3 (unconjugated estriol; from placenta) 60%

Quad screen-increased dimeric inhibin A, inhibits FSH
75%

Trisomy 18 decrease in all three metrics of the triple screen 80%

Question 12

What US findings would support a trisomy diagnosis in the second trimester?

Answer 12

increased nuclei fold, decreased humerus length, kindney enlargement, heart problems, choroid plexus cyst (though alone this cyst doesn’t confirm a trisomy)

Question 13

What do you use to detect anencephaly and spina bifida and which trimester do you screen; secondary detection?

Answer 13

2nd trimester MSAFP, secondary detection via US and amniocentesis. High incidence in trisomy 13,18

Question 14

You have a positive screen for trisomy 21 serum markers and US nuchal translucency in the first trimester and are looking to confirm with a chorionic villus sample. The patient has active vaginal pathology and some spotting. What method would you use to obtain the sample, and when is it appropriate (wks); explain your rational. Where is the chorionic villi?

Answer 14

I would use a transabdominal approach because of vaginal pathology r/o transcervical. I would do the procedure during weeks 10-12.

Chorionic villi- is at the placental material blood interface

Question 15

Which test can be used at week 23 to confirm a suspicious trisomy?

Answer 15

amniocentesis 15+ wks

Question 16

You detect a mosaicism during chorionic villus sampling (CVS) and want clarification. What test could you perform that would also allow you to check for hemoglobinopathies.

Answer 16

Fetal blood sample

Question 17

Metabolic deficiencies like AKU rely on an increase in what?

Answer 17

metabolite. If minor repeat, major follow up

Question 18

What do you have to consider when weighing ethical considerations of the screening process?

Answer 18

False positives abound due to transient increases in serum markers. Also whether the test will impact or influence the pregnancy. Complication vs risk of disorder.

Question 19

The genetic defect affecting migration of olfactory neurons and regulation of GnRH is due to what neural cell adhesion molecule?

Answer 19

Extracellular matrix glycoprotein in Kallman syndrome

Question 20

Mutations in FGFR1 can lead to kallman syndrome via what pathway? What more common mutation leads to kallman syndrome with more phenotypic defects?

Answer 20

FGFR1 can activate smell via binding with FGF2 with the addition of KAL1/heparin complex completing proper signal transduction into the cell.

KAL1 mutation is more common

Question 21

If someone with kallman syndrome had both a KAL1 and FGFR1 mutation leading to anosmia what would you call that?

Answer 21

synergistic heterozygosity which a partial defect in 2 or more genes in the same pathway leads to disease

Question 22

How can mutations of the GnRH receptor lead to nIHH?

Answer 22

They can disrupt ligand binding or signal transduction

Question 23

What is an acrocentric chromosome? What is a robertsonian translocation?

Answer 23

Very short q arm and most genetic info on the p arm

Robertsonian translocation occur in the acrocentric chromosomes; i.e. chromosomes 13,14,15,21,22 (patau, downs) . The chromosomes break at the centromeres and the two long and two short arms fuse. The short arms (with most the info) are lost after a few cell divisions.

Question 24

How does maternal age affect chromosomes?

Answer 24

Decline in cohesion leading to destabilized chiasmata and decreased association between sister centromeres.