LEC40: Inborn Errors of Development: Genetics of Congenital Anomalies

Question 1

key developmental pathways in inborn errors of development

Answer 1

1) RAS/MAPK
2) Sonic Hedgehog, SHH
3) Fibroblast Growth Factor Receptor, FGFR

Question 2

dysmorphology?

Answer 2

study of human congenital anomalies (birth defects), esp those affecting the morphology (anatomy) of the individual

aka study of abnormal form

Question 3

anomaly?

congenital anomaly?

Answer 3

devaition from the usual, something different, peculiar, abnormal

**congenital anomaly: **something that’s unusual & different at birth

Question 4

how common are major and minor congenital anomalies in newborns?

Answer 4

major: 2-3%
minor: 15%

Question 5

what % of infant deaths are because of anomalies?

Answer 5

20-30% infant deaths, 30-50% pediatric deaths

Question 6

how common are anomalies?

Answer 6

congenital anomalies: present in >2000 inherited conditions

multiple congenital anomalies: present in more than 1000 inherited conditions

Question 7

major anomaly?

Answer 7

significant cosmetic, medical, & surgical consequence

eg: congenital heart disease, cataract

Question 8

minor anomaly?

Answer 8

insignificant consequence, normal variant; don’t create functional problem; is cometic, removable

eg: skin tag, single palmar crease, overlapping toes

Question 9

what are ectopic cordis, neural tube defect, diaphragmatic hernia examples of?

Answer 9

major anomalies

Question 10

what are accessory nipple, double whorl, polydactyl examples of?

Answer 10

minor anomalies

Question 11

if see many isolated minor anomalies on physical exam, what could it indicate?

Answer 11

major anomaly

Question 12

most common isolated anomalies?

Answer 12

heart, craniofacial region, limbs, genitalia, nervous system

Question 13

categories of isolated anomalies?

Answer 13

deformation, disruption, dysplasia, malformation

depends on etiologic factors involving various developmental processes, intrinsic and external forces, or diff tissues

Question 14

what is deformation?

Answer 14

developmental process is normal

mechanical force alters structure, causes anomaly

eg: oligohydramnios can be secondary to renal hypoplasia, breech presentation or internal forces cause neuromuscular abnormality

Question 15

what are potter’s fascies and clubbed feet examples of?

Answer 15

deformation

Question 16

disruption?

Answer 16

developmental process is normal, but interrupted

usually caused by placental problem insufficiency

for ex., causes vascular accident, b/c of amniotic band sequence or fetal cocaine exposure

Question 17

porencephaly?

Answer 17

example of vascular disruption so fetal brain doesn’t develop

Question 18

malformation?

Answer 18

morphological, macroscopic defect from an intrinsically abnormal developmental process

sign of a genetic disorder

Question 19

holoprosencephaly, congenital heart disease, neural tube defect, cleft lip and palate are examples of?

Answer 19

malformation

Question 20

dysplasia?

Answer 20

abnormal microscopic tissue organization & development

eg: skeletal or connective tissue dysplasias; ectodermal dysplasias

Question 21

categorizations of multiple anomalies?

Answer 21

sequence, syndrome, association

Question 22

sequence?

Answer 22

series of congenital anomalies derived from a single anomaly

can be part of a syndrome, or an isolated event

“domino effect”

Question 23

pierre robin sequence is example of?

Answer 23

series

primary anomaly: micrognathia

leads to superior displacement of tongue

leads to failure of palatal shelves to close

leads to “U” shaped cleft and glossoptosis

Question 24

syndrome?

Answer 24

recognizable pattern of anomalies, presumed to be causally related, and NOT due to a sequence

> 700 human genetic syndroms have craniofacial anomalies

> 500 human genetic syndromes have limb abnormalities

Question 25

trisomy 13 is an example of?

Answer 25

syndrome bilateral cleft, emphalaceal, polydactely very fatal, usually baby isn't born

Question 26

sequence vs. syndrome?

Answer 26

sequence: single origin results in variably expressed group of secondary and tertiary defects; entire cascade of events is known syndrome: groups of anomalies containing multiple malformations and/or sequences which are variably expressed, results in overall pattern of anomalies; pathogenic relationship of group of anomalies not always understood

Question 27

association?

Answer 27

group of congenital anomalies that oc-occur more frequently that expected by chance unknown etiology i.e. VACTERL

Question 28

what is VACTERL

Answer 28

association V: vertebral anomalies/dysgenesis, vascular anomalies A: anal atresia C: cardiac anomalies T: tracheo-esophageal (T-E) fistula E: esophageal atresia R: renal anomalies, radial dysplasia L: limb anomalies

Question 29

breakdown of causes of human congenital anomalies?

Answer 29

50-60%: unknown etiology 20-25%: multifactorial 7-10%: environmental agents **8%: mutant genes ** **7%: chromosomal defects**

Question 30

most common environmental teratogen? characteristics?

Answer 30

fetal alcohol syndrome physical impairment results from alcohol exposure during pregnancy leading cause of intellectual disability growth retardation, microcephaly, mental retardation, short palpebral fissures, short nose, smooth philtrum, thin upper lip, small distal phalanges and hypoplastic finger nails, cardiac defects

Question 31

tertagogens?

Answer 31

exposure during pregnancy that has harmful effect on developing fetus

Question 32

examples of teratogenic exposures?

Answer 32

phenylalanine - maternal pheylketonuria glucose - maternal diabetes TORCH infections anticonvulsants (hydantoins, valproate) retinoic acid embryopathy

Question 33

what is maternal PKU? what does it cause?

Answer 33

syndrome per environmental exposure to phenylalanine growth retardation, mental retardation, microcephaly, cardiac anomalies

Question 34

what does maternal diabetes cause re: syndrome in fetus?

Answer 34

environmental cause of syndrome macrosomia, hypoglycemia, hypocalcemia, CNS anomalies, cardiac anomalies, caudal regression

Question 35

non syndromic/isolated anomalies caused by?

Answer 35

genes which cause rare developmental syndromes i.e. Van der Woude syndrome

Question 36

cleft lip and palate is ex. of? when is it most common?

Answer 36

common isolated anomaly cleft lip pallet (CLP) is more common than cleft lip alone (CLA), and bilateral is more common tha unilateral more common in males incidence higher in asian, latino, native american descent

Question 37

van der woude is? example of?

Answer 37

autosomal dominant cleft lip and palate disorder w/ mutations in DNA binding domain give away: lip pits and cleft lip/cleft palate 70% caused by mutation in IRF6 gene

Question 38

examples of allelic heterogeneity in IRF6?

Answer 38

interferon regulatory factor, IRF6 70% mutations in IRF6 = cause of Van der Woude syndrome but genetic variants in IRF6 also assoc w/ popliteal pterygium syndrome, excess skin on extremities and contraction of arms/knees

Question 39

what causes non-syndromic/isoalted cleft lip and palate?

Answer 39

IRF6 V274I overtransmission so polymorphism, rare variance, in general population valine confers triple recurrents risk risk allele!

Question 40

types of disease proteins in developmental disorders?

Answer 40

txn factors: 25-34% enzymes: 19 structural proteins: 18 receptors: 9 tumor suppressors: 5

Question 41

what is homeobox gene cluster?

Answer 41

transcription factor homeobox genes are organized v. close to each other chromasomally, have spatial expression; number them based on expression in flies, mice

Question 42

hox gene mutations cause?

Answer 42

syndromes lower number = more cranial, so head, higher numbers = more caudal syndromes, tail

Question 43

what are implicated in syndromes of congenital anomalies?

Answer 43

mutations in genes coding for txn factors, enzymes, structural proteins, receptors, tumor suppressors

Question 44

what do mutations in a pathway affect?

Answer 44

development of multiple organ systems, b/c pathways/processes are utlized many times in diff tissues through organism's lifetime

Question 45

muations of factors in FGFR3 pathway causes?

Answer 45

1) long bones of skeleton, causes limb development issues - achondroplasia, hypochondroplasia, skeletal issues result 2) craniosynostosis syndromes - skull doesn't fuse properly

Question 46

craniosynostosis syndromes classification? cause?

Answer 46

FGFR mutation autosomal dominant syndromes genetic heterogeneity phenotypic variability gain of function mutations

Question 47

what is craniosynostosis?

Answer 47

premature fusion of skull bones makes head particular shape depending on FGFR mutation and which head shape results

Question 48

how do clinicians redefine/reclassify conditions?

Answer 48

by relating phenotype w/ the genotype

Question 49

mutations in genes/compoents of a common developmental pathway/process may result in?

Answer 49

overlapping phenotypic features way that researchers relate phenotype w/ genotype to redefine, reclassify dysmorphic conditions

Question 50

what does knowing syndrome's molecular basis allow?

Answer 50

targeted therapy

Question 51

what are RASopathies?

Answer 51

clincally overlapping syndromes all based on RAS pathway defects, cannot always tell 1 from another based on clinical observations Noonan syndrome, costello syndrome, cardiofacial cutaneous syndrome

Question 52

characteristics of RASopathies?

Answer 52

autsosomal dominant, sparse, brittle hair, ASD, pulmonic stenosis, hypertrophic cardiomyopathy, ectodermal skin changes, +/- intellectual handicaps

Question 53

examples of SHH pathway problems? what does this illustrate?

Answer 53

that mutations in inductive signals involved in establishing cell fates and pattering in developing embryo can cause phenotypically similar syndromes Holoprosencephaly, Greig Cephalopolysyndactyly, Pallister Hall Syndrome, GLI3 mutations examples of this re: SHH

Question 54

what do phenotypes of SHH pathway mutations have in common?

Answer 54

genetic heterogeneity / autosomal dominant midline defects polydactyly, syndactyly

Question 55

what does mTOR pathway control? mutations in it cause?

Answer 55

mTOR pathway: promtoes growth mutations in mTOR: related to overgrowth, predisposition to cancer

Question 56

what causes tuberous sclerosis? what is research into it?

Answer 56

normally, dimerizing of hamartin, tuberin inhibits Rheb GDP which inhibits mTOR pathway if have mutation in one of these proteins, hamartin or tuberin, get signaling of mTOR pathway, therefore tumor growth

Question 57

treatment for tuberous sclerosis?

Answer 57

targeted therapy: mTOR inhibitors

Question 58

examples of developmental signaling pathways?

Answer 58

fibroblast growth factor, glial cell-derived neurotrophic factor, notch, P13K-LKB1, RAS/MAPK, SHH, TGF-beta, Tumor Necrosis factor, Wnt (wingless-type)

Question 59

what do whole exome/genome, expression, epigenetic sequencing or mutageneis screens show?

Answer 59

new pathways/networks of interacting environmental and genetic factors involved in normal variation in morphology and abnormal development

Question 61

relationship between TWIST and FGFR?

Answer 61

TWIST is an inhbitor of FGFR if LOF of TWIST, get FGFR gain of function