LEC40: Inborn Errors of Development: Genetics of Congenital Anomalies Flashcards Preview

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Flashcards in LEC40: Inborn Errors of Development: Genetics of Congenital Anomalies Deck (61):
1

key developmental pathways in inborn errors of development

1) RAS/MAPK

2) Sonic Hedgehog, SHH 

3) Fibroblast Growth Factor Receptor, FGFR

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dysmorphology?

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

aka study of abnormal form

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anomaly?

congenital anomaly?

devaition from the usual, something different, peculiar, abnormal 

congenital anomaly: something that's unusual & different at birth

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how common are major and minor congenital anomalies in newborns?

major: 2-3% 

minor: 15% 

5

what % of infant deaths are because of anomalies?

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

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how common are anomalies?

congenital anomalies: present in >2000 inherited conditions 

multiple congenital anomalies: present in more than 1000 inherited conditions

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major anomaly?

significant cosmetic, medical, & surgical consequence 

eg: congenital heart disease, cataract

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minor anomaly?

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

eg: skin tag, single palmar crease, overlapping toes

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

major anomalies

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

minor anomalies

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

major anomaly

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most common isolated anomalies?

heart, craniofacial region, limbs, genitalia, nervous system

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categories of isolated anomalies?

deformation, disruption, dysplasia, malformation 

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

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what is deformation?

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

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

deformation

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disruption?

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 

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porencephaly?

example of vascular disruption so fetal brain doesn't develop

 

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malformation?

morphological, macroscopic defect from an intrinsically abnormal developmental process 

sign of a genetic disorder 

 

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

malformation

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dysplasia?

abnormal microscopic tissue organization & development

eg: skeletal or connective tissue dysplasias; ectodermal dysplasias

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categorizations of multiple anomalies?

sequence, syndrome, association 

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sequence?

series of congenital anomalies derived from a single anomaly 

can be part of a syndrome, or an isolated event

"domino effect"

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pierre robin sequence is example of?

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

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syndrome?

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

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trisomy 13 is an example of?

syndrome 

bilateral cleft, emphalaceal, polydactely 

very fatal, usually baby isn't born 

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sequence vs. syndrome?

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

27

association?

group of congenital anomalies that oc-occur more frequently that expected by chance 

unknown etiology 

i.e. VACTERL 

28

what is VACTERL

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

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breakdown of causes of human congenital anomalies?

50-60%: unknown etiology

20-25%: multifactorial 

7-10%: environmental agents 

8%: mutant genes 

7%: chromosomal defects

30

most common environmental teratogen?

characteristics?

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

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tertagogens?

exposure during pregnancy that has harmful effect on developing fetus

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examples of teratogenic exposures?

phenylalanine - maternal pheylketonuria 

glucose - maternal diabetes 

TORCH infections 

anticonvulsants (hydantoins, valproate) 

retinoic acid embryopathy

33

what is maternal PKU? 

what does it cause?

syndrome per environmental exposure to phenylalanine 

growth retardation, mental retardation, microcephaly, cardiac anomalies

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what does maternal diabetes cause re: syndrome in fetus?

environmental cause of syndrome

macrosomia, hypoglycemia, hypocalcemia, CNS anomalies, cardiac anomalies, caudal regression 

35

non syndromic/isolated anomalies caused by?

genes which cause rare developmental syndromes 

i.e. Van der Woude syndrome

36

cleft lip and palate is ex. of?

when is it most common?

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

37

van der woude is? example of?

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 

 

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examples of allelic heterogeneity in IRF6?

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

39

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

IRF6 V274I overtransmission 

so polymorphism, rare variance, in general population 

valine confers triple recurrents risk 

risk allele! 

40

types of disease proteins in developmental disorders?

txn factors: 25-34% 

enzymes: 19

structural proteins: 18 

receptors: 9 

tumor suppressors: 5

41

what is homeobox gene cluster?

transcription factor 

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

 

42

hox gene mutations cause?

syndromes 

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

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what are implicated in syndromes of congenital anomalies?

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

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what do mutations in a pathway affect?

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

45

muations of factors in FGFR3 pathway causes?

1) long bones of skeleton, causes limb development issues - achondroplasia, hypochondroplasia, skeletal issues result 

2) craniosynostosis syndromes - skull doesn't fuse properly

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craniosynostosis syndromes classification? cause?

FGFR mutation

autosomal dominant syndromes

genetic heterogeneity

phenotypic variability 

gain of function mutations 

47

what is craniosynostosis?

premature fusion of skull bones 

makes head particular shape depending on FGFR mutation and which head shape results

48

how do clinicians redefine/reclassify conditions?

by relating phenotype w/ the genotype 

49

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

overlapping phenotypic features 

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

50

what does knowing syndrome's molecular basis allow?

targeted therapy 

 

51

what are RASopathies?

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 

 

52

characteristics of RASopathies?

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

53

examples of SHH pathway problems? what does this illustrate?

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 

54

what do phenotypes of SHH pathway mutations have in common?

genetic heterogeneity / autosomal dominant

midline defects 

polydactyly, syndactyly 

55

what does mTOR pathway control? mutations in it cause?

mTOR pathway: promtoes growth 

mutations in mTOR: related to overgrowth, predisposition to cancer

56

what causes tuberous sclerosis? 

what is research into it?

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

57

treatment for tuberous sclerosis?

targeted therapy: mTOR inhibitors 

 

58

examples of developmental signaling pathways?

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

59

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

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

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61

relationship between TWIST and FGFR?

TWIST is an inhbitor of FGFR 

if LOF of TWIST, get FGFR gain of function 

 

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