Developmental Genetics

Question 1

Single Abnormalities:

Answer 1

1. Malformations: errors occurring in the initial formation of structures, primary structural defect of an organ. (congenital heart abnl, cleft lip/palate, polydactyly). Multifactorial.
2. Disruptions: disturbances after an organ has been formed; result of external force not genetics. (Phocomelia “shortened arms/legs”
3. Deformations: mechanical distortions (clubfoot by lack of amniotic fluid or intra-uterine crowding). Resolves after birth.
4. Dysplasias: abnormalities in tissue org (thanatophoric dysplasia “FGF3R mutation”). Monogenic.

Question 2

Multiple abnormalities

Answer 2

1. Sequences: cascades of effects (Potter seq due to decr. amniotic fluid)
2. Syndromes: grp of anomalies that consistently occur together due to a single underlying cause “Down synd”
3. Associations: traits coincide more often than expected

Question 3

SHH

Answer 3

• induces cell prolif and tissue patterning
• expressed in: neural ectoderm like notochord and ventral floor plate of NT = dorsal -> ventral patterning
• hair follicle, tooth, lung and pancreas devlp.
• Zone of polarizing activity ZPA=> limb patterning

Question 4

SHH-Ptch-Gli pathway

Answer 4

1. Shh is cleaved to an N-terminal form (N-SHH) -> modified by addition of cholest.
2. nl action of Ptch is to inhibit Smo. But when Ptch bound by SHH = inhibition removed.
3. Gli protein and CREBBP interact and activate gene exp by binding to regulatory seq. on DNA

(overexpression of SHH in limb bud or mutation in Gli3 lead to polydactyly)

Question 5

SHH mutations

Answer 5

• heterozygous mutation of SHH = autosomal dom. Holoprosencephaly (HPE3) = wide clinical variability such as: cyclopia, premaxillary agenesis, mild hypotelorism or single central maxillary incisor to microcephaly.
• polydactyl could result from ectopic exp of Shh in ant. limb bud.
• Rare in humans but incr. SHH in frontal nasal prominence promotes mediolateral expansion “hypertelomerism”

Question 6

Holoprosencephaly

Answer 6

• mutation in SHH or Six3 gene(regulator of Shh)
• modifier effects: a spectrum of defects and disorders.
• mild effects: single incisor
• moderate: cleft lip/palate
• severe: cyclopia

Question 7

Smilth-Lemi-Opitz syndrome

Answer 7

• mutation in 7-dehydrocholesterol reductase

- microcephaly, mental retardation, malformation of mesodermal origin, syndactly and polydactly

Question 8

Gorlin syndrome (Nevoid basal cell carcinoma)

Answer 8

• mutation in Patched “Ptch”

- early age basal cell carcinoma

Question 9

Pallister-Hall syndrome

Answer 9

• rare
• mutation in Gli genes
• brain tumors, polydactyl

Question 10

Rubinstein-Taybi syndrome

Answer 10

• mutation in the CREBBP gene

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

Question 11

Hox genes

Answer 11

• TFs that confer identity to indiv body segments.
• patterning of ant/post or body axis
• mutations in mammalian Hox genes = no dramatic phenotype b/c there are many copies of Hox genes. Must have a complete knockout to see phenotype.
• loss of single Hox gene in humans = incr. susceptibility to childhood leukemia w/ extra cervical ribs.
• Disruption of Hoxd13 = polydactyly

Question 12

Achondroplasia

Answer 12

• AD, full penetrance
• mutation in transmemb domain of FGFR3 = stimulation of chondrocyte growth and prevents diff to bone and formation of osteoblast.
• GoF mutation, G-C transversion “substitution of Arg for Glyc”
• 80% of cases as a result of spont mutation during spermatogenesis “sperm w/ selective adv”
• 20% of cases result of inheriting.
• abnl body proportions (upper arms/thighs more shortened than forearms and lower legs.
• large head, flat nasal bridge, trident hand

Question 13

Severity of Achond:

-severe to less severe?

Answer 13

-Thanatophoric dysplasia > SADDAN dysp > Achondroplasia > Hypochondroplasia

Question 14

Thanatophoric dysplasia (TD)

Answer 14

• mutation in EC domain and distal tk domain.
• severe: similar to homoz achond “lethal”
• short limbs, narrow chest, small ribs, undevlp lungs, enlarged head.
• usually still born or die after birth.

Question 15

ACH

Answer 15

• mutation in transmemb domain
• intermediate severity
• nl lifespan
• enlarged skull, short and flattened vertebral disks.

Question 16

HYP

Answer 16

• mut in proximal and distal tk domain
• mild severity
• child appear nl at birth
• as child grows, arms and legs don’t dvlp properly.
• nl life span

Question 17

Y-chrom

Answer 17

• SRY gene: directs male/female differentiation during embryonic dvlp. Produces Testis determining factor TDF.
• AZO spermia regions facilitate spermatogenesis in males.

Question 18

Gonadal differentiation

Answer 18

• Y-chrom absent: gonadal primordia dvlp into ovaries. If present, testes form.
• ovaries produce Est and enable dvlp of Mullerian duct into uterus.
• Testis produce anti-Mullerian duct hormone and Testo

Question 19

46, XX Male Syndrome (de la Chapelle syndrome)

Answer 19

• caused by translocation of SRY gene on Y chrom due to unequal crossing over.
• typical boys and men
• slightly shorter stature
• nl male genitalia
• 10% show hypospadias
• Mullerian tissue absent
• infertile b/c only SRY gene were translocated and AZO wasn’t.

Question 20

46, XY Swyer sydrome

Answer 20

• pure gonadal gysgenesis
• caused by loss of function mutation of SRY gene
• nl female genatalia w/ well dvlp mullerian structures
• bilat streak gonads instead of ovaries or testes.
• delay puberty
• incr. LH causes clitoromegaly
• treatment: incr. chance of germ line tumors; streak gonads removed
• HRT w/ Est or Prog
• don’t confuse w/ Androgen insensitivity syndrome (mutation in Androgen rcp but can produce T )