3. Developmental Genetics

Question 1

Define and discuss the basic classifications used in dysmorphology (objective)

Answer 1

Answer later

Question 2

Discuss the basic principles of morphogenesisdevelopment (objective)

Answer 2

Answer later

Question 3

Discuss broadly some of the clinical syndromes seen in human developmental biology, including the associated genes (objective)

Answer 3

Answer later

Question 7

Congenital Anomalies (frequency)

Answer 7

Undescended testicles and heart defect most common

Cleft palate, craniosynostosis, syndactyly

Question 8

Deformation

Answer 8

Unusual forces on normal tissue

Usually no inherent problem in the embryo/fetus/neonate

Mechanical forces result in altered morphogenesis, usually molding

Examples: uterine constraint, oligohydramnios, breech position, positional plagiocephaly

Recurrence risk is generally low

Question 9

Disruption

Answer 9

Breakdown of normal tissue

Normal fetus subjected to destructive problem causing breakdown or loss of normal tissue

Causes: vascular, infection and mechanical problems

Example: amniotic band sequence (don’t need to karyotype)

Usually sporadic; but in large series there are more associated anomalies

Question 10

Dysplasia

Answer 10

Abnormal organization of cells into tissue (seen microscopically)

Abnormal migration of cells

Not in use as widely currently

Question 11

Malformation

Answer 11

Poor formation of tissue

A single localized abnormality in formation of tissue that initiates a chain of subsequent defects

Can be nearly normal or more severe

Can suggest a syndromic diagnosis

Many examples in JCB

Question 12

Syndrome

Answer 12

A pattern of anomalies, at least one of which is morphologic, known or thought to be causally related

-A mutation in a key developmental gene may be associated with multiple malformations (called malformation syndrome)

Question 13

Sequence

Answer 13

One or more secondary morphologic anomalies known or presumed to cascade from a single malformation, disruption, dysplasia, or deformation

Question 14

Anomaly

Answer 14

An anatomic (microscopic and macroscopic) phenotype that represents a substantial departure from the appropriate reference population

Question 15

Phenotypic Heterogeneity

Answer 15

Different mutations in a gene

Hypochondroplasia (H)
Thanatophoric dysplasia (T)
Achondroplasia (A)

Question 16

Non-specificity of cleft lip/palate

Answer 16

Isolated cleft lip/palate

Vs.

Syndromic cleft lift/palate (EEC syn.)

Syndromic will see anomalies elsewhere as well

Question 17

Syndromes related by Pathway

Answer 17

“Ras-opathies”
Different genes mutated in same pathway
All increase risk of cancer

Question 18

Normal Developmental Processes (list)

Answer 18

Fundamental problem
Proliferation
Differentiation
Migration
Apoptosis
Rac1

Question 19

Fundamental Problem (development)

Answer 19

Turn a single cell (fertilized egg) into a fully and normally developed organism

Question 20

Proliferation (development)

Answer 20

Increase cell number by division

Question 21

Differentiation (development)

Answer 21

Formation of specialized cell types

Question 22

Migration (development)

Answer 22

Cells move in characteristic patterns

Question 23

Apoptosis

Answer 23

Cells die in the characteristic patterns

Question 24

Rac1

Answer 24

Multiple roles in cellular functions, including actin cytoskeleton organization, cell adhesion, migration, proliferation, and apoptosis in mammalian cells

Question 25

Probability

Answer 25

Inbred strains of mice, genetically identical

The same formin gene mutation causes renal aplasia in only 20% of the carriers of the mutation

What explains the difference in the occurrence in affected vs. unaffected?

Question 26

Cell Proliferation

Answer 26

Needed for growth to occur

Excess cell reproduction causes abnormally large body structures, often with abnormal function

No karyotype needed, cell increase on one side

Ex. Hemihyperplasia

Question 27

Human Tumors

Answer 27

Dysfunctional p53 proteins

Functional p53: tumor suppressor protein

Cell cycle clock, Cyclins, CDK

Inhibitory proteins like p53 induce cell death

Question 28

Differentiation

Answer 28

Hematopoiesis- specification, fate

Nerve cells don’t make hemoglobin and red blood cells don’t make synaptic proteins

Stem cells and gene therapy

Changes are due to epigenetic changes, not mutations of DNA

Question 29

Cryptorchidism

Answer 29

Failure of descent of the testes

Caused by abnormalities in hormones, nerves or connective tissues

Reported in 350 syndromes

Question 30

Apoptosis

Answer 30

Programmed cell death, essential to morphogenesis

During development, apoptosis is main cell death type
Adulthood: apoptosis maintains homeostasis (i.e in gut, blood, CNS)
30% of original cells form organism

Question 31

Apoptosis Examples

Answer 31

Rat eye lens: partial apoptosis removes nuclei in a process called nuclear death, leaving remainder as functional lens
Heart: cell death needed for 4 chambers
Genitalia: degeneration of ducts: mullerian ducts regress in males, wolffian ducts regress in females
Hands

Question 32

Apoptosis: Hands

Answer 32

Classic example of apoptosis

Removal of interdigital webs

Rac1: overlap of functions

Question 33

Cellular Migration

Answer 33

Add from lecture

Question 34

Neuronal Migration

Answer 34

Heterotopias: normal neurons in wrong place

Periventricular nodular heterotopia (PNH)-most common, neurons that never migrate
Genes involved:
FLNA (most common)
LIS1 (lissencephaly)
DCX (doublecortin)

Question 35

Tuberous sclerosis

Answer 35

Hamartomas (tumors): abnormally firm areas of cortex, Cardiac Rhabdomyoma (lumpy heart)

Skin and nail findings: ungual fibroma (nails), facial angiofibroma, ashleaf spots

Seizures
Genes: TSC1, TSC2

Question 36

Body Patterning: Laterality

Answer 36

Situs Solitus- normal positioning of organs

Situs Inversus- mirror, primary ciliary dyskinesias, Kartagener’s

Situs Ambiguous- mixed, ZIC3 (10% familial cases)

Question 37

Body Patterning: Hox

Answer 37

HOX genes: regional selection of developmental fate (limbs and vertebrae patterning, craniofacial structure and innervation)

Expressed along the dorsal axis from the hindbrain to the tail

Question 38

HOX Genes

Answer 38

Temporal colinearity:
3’ HOX genes expressed earlier than 5’ genes

Spatial colinearity: 3’ HOX genes expressed more anteriorly than 5’ genes

Question 39

HOX Genes (human examples)

Answer 39

Anterior- Head
HOXA 1: athabaskan brainstem dysgenesis

Posterior- Tail
HOXA 11: radioulnar synostosis with amegakaryocytic thombocytopenia

Question 40

PAX Genes

Answer 40

Transcription regulators
Initiate and orchestrate eye development
May function as proto-oncogenes
Human aniridia: PAX-6

WAGR: aniridia-wilms tumor association
PAX-6 deletion (contiguous deletion)
Wilms tumor due to loss of WT1 gene

Question 41

PAX Genes and Eye Development

Answer 41

Waardenburg Syndrome (I-IV)

Type I: PAX3, autosomal dominant
Heterochromia- no vision problems
Hypertelorism: widely set eyes
White forlock and deafness

Type IV: Hirschsprung disease, aganglionic megacolon

Question 42

Sonic Hedgehog/SHH

Answer 42

Holoprosencephaly (alobar, semilobar, lobar)
Clefting
Missing/malformed midline structures (thalami, olfactory bulbs, optic bulbs, pituitary)
Cyclopia
Single central incisor (teeth)
Absent frenulum
Narrow spread eyes

Question 43

Genetics and Dysmorphology

Answer 43

Goals of evaluation: prognosis, management options and recurrence risk estimate

How to study?
Patients as they present, animal models

Question 44

Congenital Anomalies

Answer 44

2-3% of all newborns
Leading cause of neonatal morbidity and mortality (20% of infant deaths, 10% NICU admissions, 25-35% of deaths)
Pediatrics admissions: 25/30% have major birth defect

Question 45

Normal Development

Answer 45

Single fertilized cell becomes human with 10^13 to 10^14

Several hundred cell types

Dozens of tissues