3. Developmental Genetics Flashcards
Define and discuss the basic classifications used in dysmorphology (objective)
Answer later
Discuss the basic principles of morphogenesisdevelopment (objective)
Answer later
Discuss broadly some of the clinical syndromes seen in human developmental biology, including the associated genes (objective)
Answer later
Congenital Anomalies (frequency)
Undescended testicles and heart defect most common
Cleft palate, craniosynostosis, syndactyly
Deformation
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
Disruption
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
Dysplasia
Abnormal organization of cells into tissue (seen microscopically)
Abnormal migration of cells
Not in use as widely currently
Malformation
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
Syndrome
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)
Sequence
One or more secondary morphologic anomalies known or presumed to cascade from a single malformation, disruption, dysplasia, or deformation
Anomaly
An anatomic (microscopic and macroscopic) phenotype that represents a substantial departure from the appropriate reference population
Phenotypic Heterogeneity
Different mutations in a gene
Hypochondroplasia (H)
Thanatophoric dysplasia (T)
Achondroplasia (A)
Non-specificity of cleft lip/palate
Isolated cleft lip/palate
Vs.
Syndromic cleft lift/palate (EEC syn.)
Syndromic will see anomalies elsewhere as well
Syndromes related by Pathway
“Ras-opathies”
Different genes mutated in same pathway
All increase risk of cancer
Normal Developmental Processes (list)
Fundamental problem Proliferation Differentiation Migration Apoptosis Rac1
Fundamental Problem (development)
Turn a single cell (fertilized egg) into a fully and normally developed organism
Proliferation (development)
Increase cell number by division
Differentiation (development)
Formation of specialized cell types
Migration (development)
Cells move in characteristic patterns
Apoptosis
Cells die in the characteristic patterns
Rac1
Multiple roles in cellular functions, including actin cytoskeleton organization, cell adhesion, migration, proliferation, and apoptosis in mammalian cells
Probability
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?
Cell Proliferation
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
Human Tumors
Dysfunctional p53 proteins
Functional p53: tumor suppressor protein
Cell cycle clock, Cyclins, CDK
Inhibitory proteins like p53 induce cell death
Differentiation
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
Cryptorchidism
Failure of descent of the testes
Caused by abnormalities in hormones, nerves or connective tissues
Reported in 350 syndromes
Apoptosis
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
Apoptosis Examples
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
Apoptosis: Hands
Classic example of apoptosis
Removal of interdigital webs
Rac1: overlap of functions
Cellular Migration
Add from lecture
Neuronal Migration
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)
Tuberous sclerosis
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
Body Patterning: Laterality
Situs Solitus- normal positioning of organs
Situs Inversus- mirror, primary ciliary dyskinesias, Kartagener’s
Situs Ambiguous- mixed, ZIC3 (10% familial cases)
Body Patterning: Hox
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
HOX Genes
Temporal colinearity:
3’ HOX genes expressed earlier than 5’ genes
Spatial colinearity: 3’ HOX genes expressed more anteriorly than 5’ genes
HOX Genes (human examples)
Anterior- Head
HOXA 1: athabaskan brainstem dysgenesis
Posterior- Tail
HOXA 11: radioulnar synostosis with amegakaryocytic thombocytopenia
PAX Genes
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
PAX Genes and Eye Development
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
Sonic Hedgehog/SHH
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
Genetics and Dysmorphology
Goals of evaluation: prognosis, management options and recurrence risk estimate
How to study?
Patients as they present, animal models
Congenital Anomalies
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
Normal Development
Single fertilized cell becomes human with 10^13 to 10^14
Several hundred cell types
Dozens of tissues
