developmental genetics Flashcards
when does gastrulation occur
14-28 days
what is gastrulation
rearrangement of a single layer into a trilaminar structure
trilaminar structure of gastrulation?
ectoderm, mesoderm, and endoderm
what major structural feature forms in the gastrulation phase
primitive streak
neurlation?
folding process that turns the nueral plate into the neural tube
what type of birth defects does neurlation cause
neural tube defects
where does neurulation close at
5 diff sites
what does the ectoderm separate into during neurlation
neural tube, epidermis, and neural crest cells
when is the mesoderm formed
gastrulation
what does the notochord do?
induce neural tube and body axis
what does the dorsal mesoderm give rise to?
axial skeleton, skeletal muscle, and CT
what does the intermediate mesoderm give rise to?
kidneys and GU
what does the lateral mesoderm give rise to?
heart, viscera, body wall
what does the mesoderm consist of
notochord, dorsal mesoderm, intermediate mesoderm, lateral mesoderm, and head mesenchyme
what layer of the trilamina causes many birth defects
mesoderm
what does the endoderm form
lining of digestive tract, respiratory tree, middle ear, thymus, thyroid, and parathyroids
purpose of primitive streak
crate A/P axis
what does nodal expression do
initiates and maintains primitive streak
purpose of Hox genes
position cells and tissues
mutations in Hox genes leads to…
abnormalities of limb formation
what is situs solitus
normal axis formation
what is situs inversus
body is a mirror image- appendix on left side
what is situs ambiguous/heterotaxy
same on both sides ex: left and right lung both have 3 lobes
what is craniofacial development regulated by
Hox genes
1st MC birth defects? 2nd MC birth defects?
heart then limb
what embryonic later is limb formation derived from
mesoderm
what influences distal progression of limb
apical ectodermal ridge
what does the Apical ectodermal ridge stimulate proliferation of
mesodermal cells
what does the zone of polarizing activity specify
anterior and posterior information
what is key for thumb/finger differentiation
zone of polarizing activity
what occurs in Holt Oram Syndrome
malformations in radial, thenar, and carpal bones, congenital heart disease, cardiac conduction disease
what side of the body is Holt Oram Syndrome more severe in
left
what type of congenital heart defects do ppl with Holt Oram Syndrome have
ASD and VSD
what can cardiac conduction disease progress to
complete heart block with or without atrial fibrillation
what gene is the mutation on in holt oram synd
TBX5
organ formation?
Common cells and tissues “collaborate” for a unified function
what is skeletal formation dependent upon
osteoblasts
what is skeletal formation regulated by
transcription factor RUNX2
what do RUNX2 mutations cause
cleidocranial dysostosis
clinical features of cleidocranial dysostosis
Open fontanelle, Hypertelorism, Absent clavicles
what do PAX 6 gene mutations cause
aniridia (no iris)
what do Pax 6 gene mutations cause
small eye
ectopic expression?
Can manipulate the gene to express in a different location
example of ectopic expression?
pax 6 mutations
what are malformation defects due to
Defects due to intrinsically abnormal development
how do malformations arise
genetic, teratogens, and fetal environment
examples of syndromes with malformations?
TAR syndrome
Fanconi anemia
Polydactyly
what are deformation defects due to
nondisruptive mechanical force, resulting in abnormal form or position; extrinsic factor
what causes deformations
Uterine constraint
Malformation or disruption may contribute
how is the prognosis for deformations
good! spontaneous resolution and internal fixation
examples of syndromes with deformations?
plagiocephaly, metatarsus adductus (clubfeet)
when do deformations occur
Post-conception!
what is a disruption defect due to
disruptive mechanical force
is disruption genetic
no
what are the effects of disruption
lasting effects since tissue can’t grow back
examples of disruptions
amniotic bands
dysplasia?
Anomalous organization of cells or tissues
2 types of dysplasia?
localized and genralized
tell me about localized dysplasia
Severity depends on extent of involvement; genetic at cellular level
tell me about generalized dysplasia
Usually genetic, and heritable with variable expressivity
examples of dysplasias
skeletal dysplasias
what type of inheritance pattern are skeletal dysplasias
autosomal dominant; usually new mutations
what type of disorder is usually parinatal letal
skeletal dysplasias
when are skeletal dysplasias detectable
in utero
spine?
spondylo
epiphyseal?
ossification separated from shaft by epiphyseal cartilage
metaphyseal?
growth area between epiphyses and diaphyses
diaphyseal?
shaft
localized rhizomatic dysplasia?
humerus is shorter than forearm
femur shorter than leg
localized mesomelic dysplasia?
radius/ulna or tibia/fibula are short
localized acromelic dysplasia?
hand/foot
localized micromelic dysplasia?
whole limb
what is Thanatophoric dysplasia
long trunk and very short curved limbs,flat ossification centers of the vertebral bodies, femora and other bones are very short and usually curved
what is achondroplasia
rhizometric shortening of long bones, trident hand shape, bowing bc of bone length discrepancy
most mutable position in genome
achondroplasia gene
natural history of achondroplasia
Normal intelligence Motor delays (hypotonia, large head)
adult height of someone with achondroplasia
50 inches
complications of acholdroplasia
Otitis media (midface hypoplasia), Respiratory problems and apnea, Foramen magnum compression, Midface hypoplasia, Hydrocephalus
diff btwn achondroplasia and hypochondroplasia?
similar features of achondroplasia but less pronounced, diagnosed at later age, height 50-65 inches, inc incidence of learning probs and ID
mutations in thanatophoric dysplasia, acholdroplasia, and hypochondroplasia are in what gene
FGFR3
what determines if someone gets thanatophoric dysplasia, acholdroplasia, or hypochondroplasia
point mutation location within the gene
what are skeletal dysplasias AKA
fibroblast growth factors (FGF)
what are Craniosynostoses
Premature closure of the cranial sutures
name the different skeletal dysplasias
craniosynostoses, thanatophoric dysplasia, acholdroplasia, and hypochondroplasia
what are mutations from Craniosynostoses in
FGFR1, FGFR2, FGFR3, TWIST
what are the different paracrine signaling families
FGF, hedgehogs, Wingless (Wnt), transforming growth factor beta (TGRB)
pathway of sonic hedgehog
SHH activates PTCH
active PTCH inhibits SMO
what is SHH invoolved in
axis formation
what do mutations in SHH cause
holoprosencephaly
clinical features of holoprosencephaly
Cyclopia
Central maxillary incisor
Cyclopia?
lack of 2 brain hemispheres
what is Smith-Lemli-Opitz syndrome an abnormality in
cholesterol metabolism; Deficiency in 7-dehydrocholesterol (7DHC) reductase
clinical features of Smith-Lemli-Opitz syndrome
Small head and body size
Intellectual disability
Ambiguous genitalia
Y-shaped 2/3 toe syndactyly
clinical features of Gorlin syndrome/Nevoid basal cell carcinoma syndrome
Multiple basal cell carcinomas
Macrocephaly
Jaw keratocysts
what do mutations in PTCH cause
Gorlin syndrome/Nevoid basal cell carcinoma syndrome
what do mutations in GLI3 cause
Greig Cephalopolysyndactyly syndrome
clinical features of Greig Cephalopolysyndactyly syndrome
Preaxial polydactyly, Macrocephaly, Seizures, hydrocephalus, and intellectual disability in severe cases
clinical features of Rubinstein-Taybi syndrome
Broad and angulated thumbs and big toes, Postnatal small head and body size, Mod-severe intellectual disability
mutations in CREBBP cause what
Rubinstein-Taybi syndrome
what axis formation are wingess (wnt) responsible for
dorsal/ventral
what organs do wingless (wnt) form
brain, muscle, gonads, and kidneys
what disordesr are wingless (wnt) responsible for
disorders of limb structure and gonadal development
what are Transforming Growth Factor β (TGFBs) associated with formation of
bones
name some RAS opathies
noonan syndrome, LEOPARD syndrome, Costello syndrome, cardio-facio–cutaneous syndrome, NMF1
PTPN11 mutations are associated with what
noonan syndrome
common genetic form of short stature?
noonan syndrome
MC heart defect in noonan
pulmonic stenosis
features of noonan
short stature, congenital heart defects, undescended testicles, minor learning difficulties
mutations in PTPN11, also RAF1 and BRAF are associated with…
LEOPARD
LEOPARD?
Lentigines (freckles) ECG abnormalities Ocular hypertelorism Pulmonic stenosis Abnormal genitalia Retardation of growth Deafness, sensorineural
features of Cardiofaciocutaneous synd
CHD, sparse/curly hair, sparse/absent eyebrows, ID, risk for neoplasia (Acute lymphoblastic leukemia)
Mutations in BRAF, MAP2K1, MAP2K2, KRAS are assoc with what
Cardiofaciocutaneous
clinical features of Costello syndrome
Severe postnatal feeding difficulties Short stature Intellectual disability Curly, sparse fine hair Congenital heart disease
HRAS mutations are seen in what
costello synd
features of NMF1?
Café-au-lait (coffee with cream) spots
Benign nerve tumors called neurofibromas
Freckling in the inguinal (groin) or axillary (armpit) regions
Eye changes
Learning problems or intellectual disability
what happens to the symptoms of NMF over time
they get worse; progressive
inheritance pattern of NMF 1?
autosomal dominant
in order for a tumor suppressor gene to be mutated what needs to occur
both copies must be mutated
in order for a proto-oncogene to be mutated what needs to occur
only one copy must be mutated
what do protooncogenes do
encourage growth
with a germline mutation, what cells are mutated
ALL cells start out with a SINGLE hit
Knudson’s Two-Hit Hypothesis is genotypically _____ and phenotypically______
dominant, recessive
is variable expressitivity quantitative or qualitative
qualitative
is penetrance quantitative or qualitative
quantitative
variable expressitivity?
you have the symptoms but to what degree
penetrance?
do you have symptoms or not?
transcription factors
Regulate when and how much a gene is transcribed
what are many CT disorders caused by
EMP dysfunction
EMP disorder examples?
Marfan syndrome
Collagenopathies including Ehlers-Danlos syndrome
Williams syndrome
mutation in FBN1 causes what
marfan syndrome
marfan features
Tall, thin body
long limbs
retinal detachment
risk for aortic root dilation and/or dissection
trmt for marfan heart issues?
beta blockers, Losartan
