Developmental Genetics

Question 1

Sonic hedgehog (Shh)-Patched (Ptch)-Gli pathway

Answer 1

Shh cleaved then modified with cholesterol –>ssh binds to PTCH receptor –> removed inhibition of SMO –> SMO activation of Gli and CREBB –> active gene expression

Question 2

Holoproencephaly

Answer 2

Heterozygous mutations, Autosomal dominant

Mutation in Shh or Six3 (regulator of shh)

-a spectrum of defects and disorders-mild effects such as single incisor, moderate effects such as cleft lip and palate, to severe effects such as cyclopia

Question 3

Gorlin Syndrome (Nevoid basal cell carcinoma)

Answer 3

Mutation in PTCH of the Shh pathway

• early age basal cell carcinoma (<20 years)
• rib defects

Question 4

Pallister-Hall Syndrome

Answer 4

Extreamly Rare

• mutation in Gli genes of Shh pathway
• brain tumors, polydactyl

Question 5

Rubinstein-Taybi Syndrome

Answer 5

• mutation in the CREBBP gene in Shh pathway

- broad thumbs and toes, mental disability, short stature, small head, facial features

Question 6

Preaxial polydactyly

Answer 6

Could result from ectopic expression of Shh in the anterior limb bud as well as mutations in Gli3 or Hoxd13 gene

Affects Homeotic (HOX) gene patterns

Question 7

Smith-Lemi-Opitz Syndrome

Answer 7

cholestrol reductase mutation in shh pathway

Question 8

Achondroplasia

Answer 8

• short arms and legs with a normal torso size
• typically upper arms/thighs are more shortened than forearms and lower legs
• flattened facial fetures

Mutation in FGFR3 (G-C transversion at nucleotide 1138 Arg - Gly)

80% new mutation, 20% AD inheritance

Question 9

Hypochondroplasia

Answer 9

Mutation of the proximal and distal tyrosine kinase domains of FGFR3

-mild severity, arms and legs do not grow proportionately.

Question 10

Thanatophoric Dysplasia (TD)

Answer 10

mutation in the extracellular domain and distal tyrosine kinase domain or FGFR3

Similar to homozygous achondroplasia (lethal)

-short limbs, narrow chest, small ribs, undeveloped lungs, enlarged head

Question 11

Male differentiation

Answer 11

Determined by Sry gene on short arm of Y chromosome which produces Testis Determining Factor (TDF) that form the testis which produce anti-mullerian factor

Question 12

De La Chapelle syndrome

Answer 12

46 XX, Male Syndrome

TRANSLOCATION OF THE SRY GENE ON THE Y CHROMOSOME TO THE X AS A RESULT OF UNEQUAL CROSSING OVER DURING MEIOSIS

• Are typical boys and men
• Slightly shorter than normal stature
• Normal male external genitalia
• 10% show hypospadias
• Mullerian tissue absent
• Infertility

Question 13

Swyer Syndrome

Answer 13

46, XY Pure Gonadal Dysgenesis

LOSS OF FUNCTION MUTATION OF THE SRY GENE

• Normal female genitalia
• Well-developed mullerian structures
• Bilateral streak gonads instead of ovaries or testes
• Teens show delay in the onset of puberty
• Elevated luteinizing hormone (LH) causes clitoromegaly

increased risk of germline tumors

Question 14

First Trimester Screening

Answer 14

11-14 Weeks
Pregnancy Related Plasma Protein A (PAPP-A)
Human Chorionic Gonadotrophin (beta-hCG)

Question 15

Second Trimester Screening

Answer 15

Triple Test: looks for 3 markers

• AFP (alpha fetal protein)
• Estriol (unconjugated estriol, or uE3)
• Human chorionic gonadotrophin (beta-hCG)

Quad test: Includes another marker
Inhibin A

Question 16

AFP Serum Screening

Answer 16

AFP synthesized in yolk sac, liver, and fetal GI

Peak @ 12-14 weeks

Normal ~1, > = spina bidfida,&raquo_space; Anencephaly, < 1 = T21

Question 17

T21 Screening

Answer 17

Low serum AFP, estriol and PAPPA with high β-hCG and Inhibin A indicate a risk for Down Syndrome

1st trimester
Increased Nuchal trans., Increased beta-hCG

2nd trimester
Increased beta-hCG, Increased Inhibin A

*PAPP-A, uE3 & AFP depressed in both

Question 18

T18, T13 screening

Answer 18

Low serum AFP, estriol, PAPPA and β-hCG and indicate a risk for trisomy 18 (Edward syndrome) or trisomy 13 (Patau syndrome,
much more rare)

Both will show increased nuchal translucency