Genetics of Development

Question 1

What is Pierre Robin Sequence?

Answer 1

Patient presents with cleft lip, cleft palate, and small/receding lower jaw.

History of oligohydramnios (low amniotic fluid)

Physical exam will show airway obstruction. Recurrence risk is low and prognosis is pt may need more surgery

Question 2

What is Treacher-Collins Syndrome?

Answer 2

Mutation in treacle protein

Recurrence risk is high

Family history of similar anomalies and imaging shows multiple craniofacial abnormalities and airway obstruction

Question 3

What are the genetics in early development?

Answer 3

Regulative phase occurs until end of week 2

Loss of a cell is either compensated or embryo or aborted - all or nothing

Genome is maximally unmethylated at implantation - epigenetic programming starts

Question 4

How is the primitive streak formed in a developing embryo?

Answer 4

Emergence of primitive streak ends the regulative phase (day 15) - formation of mesoderm

Primitive streak will become notochord and mark anterior/posterior axis

At anterior end of primitive streak is the node

Nodal gene is required for formation of the primitive streak - nodal protein is secreted protein of the TGF-beta family and nodal protein inds to serine kinase receptors in plasma membrane

Question 5

What is the nodal protein considered?

Answer 5

A morphogen which is a diffusable substance that exerts control over morphogenesis by forming a concentration gradient

Question 6

How is the dorsal/ventral and left/right axis formed?

Answer 6

Dorsal development is induced by two morphogens secreted from the node: noggin and chrodin

Left/Right asymmetry is supported by cilia that generate a unidirectional current and Asymmetric expression of sonic hedgehog (Shh)

Left/Right asymmetry defects occur rarely

Question 7

How are patterns formed after axis are developed?

Answer 7

Determined by the Hox genes.

Hox genes encode homeobox binding transcription factors

Each tissue expresses a different combination of Hox genes

Tissue development depends on which set of Hox genes is expressed

Hox code provides positional information - ex. distance from the anterior pole of the anterior/posterior axis

Question 8

What is epigenetic regulation during development and differentiation?

Answer 8

Developmental methylation

Environmentally induced methylation

Parent of origin specific imprinting

Question 9

What is developmental methylation in relation to epigenetic regulation?

Answer 9

At time of implantation of embryo, genome is maximally unmethylated. As cell lineages differentiate, even more genomic regions are inactivated

Question 10

What is environmentally induced methylation in relation to epigenetic regulation?

Answer 10

DNA methylation in response to starvation or stress in first trimester

Question 11

What is parent of origin specific imprinting in relation to epigenetic regulation?

Answer 11

occurs ar about 200 loci during gametogenesis, chromosomes in egg/sperm have different imprints, some genes turned off in sperm, others turned off in egg, zygote has just one active copy of these genes (parent of origin specific monoallelic expression)

Question 12

What is parent of origin methylation?

Answer 12

De novo DNA methylation occurs all through development to permanently change gene expression pattern. In first trimester to adapt to environmental influences. During gametogenesis to mark the parental origin of a chromosome (imprinting)

DNA methylation patterns are erased before implantation (erase old developmental pattern) and early in gametogenesis (erase old parent of origin imprint)

Question 13

What is X chromosome inactivation?

Answer 13

Occurs inindividuals with two or more X chromosomes - 46, XX or 47,XXX or 47, XXY

All but one of the X chromosomes are inactivated

Mediateed by transcript of the XIST gene

DNA is methylated and histones deacetylated

Not complete - some regions escape inactivation

Question 14

What is the process of X chromosome inactivation?

Answer 14

1. In X chromosome inactivating center (gene in XIC on X chromosome designated XIST)
2. On the X chromosome to be inactivated, the XIST gene is transcribed
3. XIST RNA associates closely with the X chromosome and mediates the inactivation of the most of the chromosome by histone and DNA methylation (some regions escape inactivation and remain active)

Question 15

What are the cycle of methylation/demethylation of events that occur during development?

Answer 15

1. At fertilization, zygote obtains one set of chromosomes with a paternal and maternal imprint. Both chromosomes have their DNA methylation pattern
2. Developmental DNA methylation is erased after fertilization and at time of implantation, erasure of developmental DNA methylation is complete but parent of origin imprint remains
3. After implantation, new developmental DNA methylation is established
4. During gametogenesis, parent of origin specific imprint is erased
5. Following sex determination, a new parent of origin imprint is established and depending on the sex of the individual, both chromosome sets have either a male or female imprint. Meiosis produces gametes that have developmental and parent of origin DNA methylation patterns

Question 16

How is the cause of a defect described?

Answer 16

Described by terms malformation, deformation, dysplasia, and disruption

Question 17

How is the mechanism by which one defect causes multiple abnormalities?

Answer 17

Described by terms sequence and syndrome

Question 18

What are malformations and examples?

Answer 18

Malformations result from intrinsic abnormality in the developmental process

Example: Polydactyly often results from errors in HOX signaling during patterning - intrinsic abnormality

Question 19

What are deformations and examples?

Answer 19

Deformations result from an extrinsic influence on development

Example: Lack of amniotic fluid prevents extension of limbs and impairs development

Question 20

What is dysplasia and examples?

Answer 20

Dysplasia results from an abnormal organization of cells within a tissue

Example: Hypochondroplasia results from premature ossification of cartilage (similar to achondroplasia)

Question 21

What are disruptions and examples?

Answer 21

Disruptions result from the destruction of developing tissue

Example: Strings of amniotic tissue can form amniotic bands. Amniotic bands can wrap around limbs, amputate by cutting blood supply

Question 22

What are syndromes and examples?

Answer 22

Syndromes are caused by a single defect that simultaneously affects the development of different systems

Example: Down Syndrome

Question 23

What are sequences and examples?

Answer 23

Sequences are caused by a single defect that starts a cascade of events

Example: Pierre Robin Sequence

Question 24

What are the extents of damage during different developmental stages?

Answer 24

During the first 1-4 weeks (blastogenesis): Multiple major abnormalities in entire embryonic regions

From week 5 - 8: Organogenesis. Abnormalities in specific organs, single major anomalies

After week 9: After organ formation. Mild effects

Question 25

What is an association?

Answer 25

Group of birth defects that for unknown reasons often occur together

Question 26

What does VACTERL stand for?

Answer 26

Vertebral defects

Anal atresia

Cardiac abnormalities

Tracheo-Esophageal fistula

Renal abnormalities

Limb abnormalities

Question 27

What is VACTERL?

Answer 27

An association

very few patients present with all the defects in VACTERL and diagnosis is made when 3 of the abnormalities are found

Defects are thought to occur in the blastogenesis phase of development

Known risk factor: Maternal Diabetes

Question 28

What are the most common birth defects?

Answer 28

Heart defects

Pyloric stenosis

Neural tube defects

Orofacial clefts

Clubfoot

Question 29

How is growth regulated?

Answer 29

Development is very tightly regulated

One extra round of cell division early in development is likely fatal

An extra cell division late in developmental can lead to segmental overgrowth

Question 30

Describe the robustness of development.

Answer 30

Development is a robust process.

Disturbances to the normal developmental process occur regularly and these disturbances can be countered by regulatory mechanisms

Examples: Genetically identical mice with formin mutation, raised under identical conditions. 20% develop bilateral renal aplasia, 80% do not. Renal development depends to a certain extent but not entirely on formin. Formin mutation has reduced penetrance (20%) - not explained by environment and can only be understood if one assumes formin mutation does not cause renal aplaisa, but increases the probability and things like chance are tied into it