Genetics of Development

Question 1

Robin sequence

Answer 1

A case of cleft palate in which an extrinsic constraint on fetus interferes with growth of jaw; also causes sleep apnea due to airway constriction

Question 2

Treacher-Collins syndrome

Answer 2

A cause of cleft palate; autosomal dominant disorder that causes small jaw, down-slanting palpebral fissures, and malar hypoplasia; recurrent risk is 50%

Question 3

Embryonal period of development

Answer 3

Weeks 1-8: 4 cell divisions without cell growth –> morula –> blastocyst –> epiblast and hypoblast differentiation –> gastrulation and three germ layers (endoderm, ectoderm, and mesoderm) –> primitive streak –> first axis

Question 4

Morula

Answer 4

16 cell embryo that transforms into blastocyst

Question 5

Blastocyst

Answer 5

Comes from morula; hollow sphere containing a group of cells called inner cell mass

Question 6

Time of implantation

Answer 6

Day 7-12

Question 7

Inner cell mass

Answer 7

Group of cells inside blastocyst; forms epiblast during time of implantation

Question 8

Epiblast

Answer 8

Formed from inner cell mass; forms embryo

Question 9

Gastrulation

Answer 9

Formation of three germ layers (endoderm, ectoderm, and mesoderm); produces primitive streak

Question 10

Endoderm

Answer 10

Forms cells of gut and lung epithelium

Question 11

Mesoderm

Answer 11

Forms bone, muscle, and most internal organs

Question 12

Ectoderm

Answer 12

Forms skin and nervous system

Question 13

Regulative vs. mosaic development

Answer 13

1. Regulative phase is the first phase, where cells are functionally equivalent and loss can be compensated for – phase where identical twins start and where chromosomal aberrations need to be looked for
2. Mosaic phase is the second phase, where it is important for cells NOT to be lost because they cannot be compensated for – leads to loss of tissue

Question 14

Pre-implantation diagnosis

Answer 14

Removing cell from embryo in morula phase (of regulative phase) to check for chromosomal aberrations

Question 15

Primitive streak

Answer 15

Formed from ectodermal cells invading to form mesoderm; takes place after about 14 days of gestation; marks groove at which ectodermal cells invade space between epiblast and hypoblast to form separate germ layer

Question 16

What are the three axes in the developing embryo?

Answer 16

1. Anterior/posterior
2. Dorsal/ventral
3. Left-right

Question 17

Which is the first visible axis in developing embryo?

Answer 17

Anterior/posterior axis

Question 18

Anterior/posterior axis

Answer 18

First visible structure in embryo; defined by primitive streak which is defined by position of sperm entry into egg; node exists at anterior end of primitive streak

Question 19

Function of the node

Answer 19

Forms anterior end of primitive streak and gives off noggin and chordin

Question 20

Nodal

Answer 20

Gene that is required for formation of primitive streak (also for formation of left/right axis); diffuses through tissues and goes wherever needed

Question 21

Noggin and chordin

Answer 21

Secreted protein used to specify dorsal/ventral axis; induces dorsal development in concentration-dependent manner; secreted from the node

Question 22

Sonic hedgehog (Shh)

Answer 22

Important morphogen secreted from the notochord that causes left/right asymmetry due to its asymmetric expression; causes nodal to be expressed more on left side to initiate left-looping of heart tube

Question 23

Situs solitus

Answer 23

Normal left/right axis formation (asymmetry of thoracic cavity)

Question 24

Situs inversus

Answer 24

Defect in left/right axis formation in which all organs are complete mirror image of normal

Question 25

Situs ambiguus

Answer 25

Defect in left/right axis formation in which all organs have randomized orientation; usually accompanied by heart defects

Question 26

3 axes of the developing limb

Answer 26

1. Proximal-distal = shoulder to fingertip 2. Anterior-posterior = thumb to fifth finger 3. Dorsal-ventral = dorsum to palm

Question 27

Homeobox (HOX) genes

Answer 27

Family of transcription factors containing the homeodomain; 4 clusters on 4 genes with 13 members

Question 28

Homeodomain

Answer 28

Special DNA binding domain used by HOX genes

Question 29

Patterning and the role of HOX

Answer 29

Determined by HOX genes; expression of each gene correlates with position of respective cell in embryo and timing (earliest HOX genes expressed near head, latest near caudal end)

Question 30

5 processes in which cells participate in development

Answer 30

1. Gene regulation 2. Cell-cell signaling 3. Development of cell shape/polarity 4. Movement and migration of cells 5. Programmed cell death

Question 31

Clinical dysmorphology

Answer 31

Field of study describing etiology of birth defects that gives valuable clues to underlying abnormalities

Question 32

Terms to describe defects

Answer 32

Cause of abnormality = malformation, deformation, and disruption How phenotypes are seen = syndrome and sequence

Question 33

Malformation

Answer 33

Results from intrinsic abnormality in developmental process (ex. polydactyly due to interference with limb development)

Question 34

Polydactyly

Answer 34

Too many fingers on one hand

Question 35

Deformation

Answer 35

Results from extrinsic (outside of developing embryo, normally from environment in womb) influence on development (ex. lack of amniotic fluid, or oligohydramnios)

Question 36

Disruption

Answer 36

Results from destruction of developing tissue (ex. amputations by strings of amniotic tissue)

Question 37

Isolated anomalies

Answer 37

Defects affecting a single body region (ex. cleft palate) that are sporadic or multifactorial in origin; account for about 60% of major birth defects

Question 38

Sequences

Answer 38

Caused by single defect starting a cascade of events (ex. Robin sequence); usually sporadic or multifactorial; requires more preventative management and has higher risk for complications

Question 39

Syndromes

Answer 39

Caused by single defect that simultaneously affects development of different tissues (ex. Down syndrome); requires more preventative management and has higher risk for complications

Question 40

Impact of problems during first 4 weeks

Answer 40

Occur during blastogenesis; produce multiple major abnormalities in entire embryonic regions (ex. VACTERL association)

Question 41

VACTERL association

Answer 41

Vertebral defects, Anal atresia, Cardiac abnormalities, Tracheo-Esophageal fistula, Renal and Limb abnormalities; originate from damage to developing mesoderm at 20-25 days from conception (maternal diabetes is risk factor)

Question 42

Impact of problems during weeks 5-8

Answer 42

Occur during organogenesis; produce abnormalities in specific organs and single major anomalies (ex. congenital heart defects)

Question 43

Impact of problems later in development (after week 9)

Answer 43

Occur after organ formation; mild effect such as palmar crease

Question 44

Major anomalies

Answer 44

Anomalies with surgical or cosmetic consequences (ex. cleft lip or amputated limb)

Question 45

Minor anomalies

Answer 45

Anomalies with little impact on well-being on the patient that give diagnostic clues about presence of a syndrome

Question 46

Percentage of total mortality of birth defects

Answer 46

20% (most common cause of death in infants)

Question 47

Percentage of infant deaths due to prematurity

Answer 47

20%

Question 48

Percentage of children born with recognizable birth defects

Answer 48

2-3%

Question 49

5 most frequent birth defects

Answer 49

1. Heart defects (1/100-200) 2. Pyloric stenosis (1/300) 3. Neural tube defects (1/1,000) 4. Orofacial clefts (1/700-1,000) 5. Clubfoot (1/1,000)

Question 50

Percentage of birth defects with complex inheritance

Answer 50

50%

Question 51

Percentage of birth defects caused by chromosomal defects

Answer 51

25%

Question 52

Percentage of birth defects caused by single-gene mutations

Answer 52

20%

Question 53

Percentage of cases that can be traced to non-genetic factors (maternal medication/infections)

Answer 53

5%

Question 54

Segmental overgrowth

Answer 54

Can be caused by one additional cell division per affected cell late in development; typically fatal in early development

Question 55

Robustness of development

Answer 55

Many factors that are capable to disturb orderly development are recognized by developing embryo and countered through regulatory mechanisms

Question 56

Role of chance in expression of developmental defects

Answer 56

Formin mutation does not cause but instead increases the probability for developing renal aplasia