Genetic Conditions- ABC

Question 1

Autosomal Dominate

Answer 1

Marfan
Neurofibromatosis
Achondropasia (homgygote lethal)
Polycystic kidney 
Ectrodactyly
Tuberous Sclerosis
Digeorge (22q11.2)
Huntington

Question 2

Autosomal Recesive- main genetic syndromes

Answer 2

Cystic Fibrosis
Sickle Cell Disease
Tay-Sachs
SMA
Hemachromotosis (looks autosomal dominate - carrier frequency is very high)
Lysosomal storage conditions
congenital adrenal hyperplasia

Question 3

x-linked

Answer 3

OTC -most common urea cycle disorder/ammonia
Hemophilia
Fragile X
DMD

Question 4

Beckwith Wedimann Syndrome

Answer 4

Uniparental disomy
Omphalocele and macroglossia
overgrowth - large kidneys
ear creases
childhood tumors- wilms/hepatobastoma
4-5% of IVF pregnancies 
epigentic changes with embryo in media 
chromosome 11 (genes IGF2, CDKN1c, H19, KCNQ1OT1

Question 5

Imprinting genetics

Answer 5

Prader willi
- deletion of paternal copy
-imprinting defect
- maternal UPD
1/15000
"prader no father"
-hypotonic, poor suck, failure to thrive, developmental delays, hypogonad, obesity 

Angelman syndrome 
no maternal chromosome
severe developmental delays
multiple seizures
progressively worsening 
deletion of maternal locus, parental uniparental disome
imprinting disorder.

Question 6

Germ Line Mosicism -common conditions

Answer 6

severe OI

DMD

Question 7

Mitocondrial inheritance

Answer 7

MELAS-Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes
Leber’s hereditary optic neuropathy
mito encephalomyopathy with ragged red muscle fibers
(varying degrees)
- heart/skeletal muscle/CNS
myoclonus, seizures, cerebellar ataxia, myopathy,[

Question 8

Trinucleotide repeat

Answer 8

huntington ( autosomal dominate)CAG/ HD- dad expansion

myotonic dystrophy (autosomal dominate) CTG/DMPK- mom anticipation
>50 symptoms at 50 (cataracts)
>90 myotonia (can’t let go) age 20-30
>1000 congenital

Fragile x CGG/FMR- maternal anticipation
- expansion methylates gene and there is no expression
60-200 premutation - bigger mutation high risk for expansion.
>100-50%
AGG triplets stabilize the gene
female- premature ovarian failure

Fedrich’s ataxia
Spinocerebellar ataxia

Question 9

Things you’ll see on karyotype that you won’t on anuploidy screening

Answer 9

Translocation 
Inversion
Isochromosomes
Marker
Insertions
Ring

Question 10

SMA

Answer 10

ACOG recommends that all people get SMA testing.
#1 killer for kids under 2
2nd most common autosmal recessive
weakness- pulmonary complications
SMN1 (5q13)- more copies are better! (miss 4% of carriers that have 2 in cis)
SMN2 (5q13) - modifies

Question 11

Alpha Thal

Answer 11

Screen with low MCV
most common in SE asia
4 absent- barts (hydropic)
1 missing- silent carrier

Question 12

carrier frequency in jews
CF 
tay sac
canavan
familial dysautonomia
Gaucher

Answer 12

CF 1/25
tay sac 1/30
canavan 1/40
familial dysautonomia 1/30
Gaucher 1/13

Question 13

Tay-Sachs partner testing

• inital screen
• follow-up

Answer 13

Hex A enzymatic activity

Sequencing

Question 14

CVS- associated risks

Answer 14

contraindications- infections ( test for transcervical) 
1/300-1 % risk 
SAB
infection
bleeding (TC)
Fluid leakage
confined placenta mosiacism (1-2%)

Question 15

What chromosomes do methylation mater (imprinting) ?

Answer 15

6,7,11,14,15

Question 16

Karyotype vs microarray

Answer 16

Karyotype-
balanced translocation
Roberstonian translocation (concerns for T21)
Ring?

Microarray (6-7% more) 
-90 percent of genetic cases are missed! 
microdeletions/duplications 
now can detect triploidy 
? mosaicism 

SNP- homozygosity

Question 17

moms criteria

Answer 17

Inclusion criteria
 Singleton 
Upper MMC boundary at T1-S1
 Evidence of hindbrain herniation
 GA 19.0-25.9 weeks at randomization
 Normal karyotype 
Maternal age >18 years

10 Major exclusion criteria 
Fetal anomaly unrelated to MMC
 Severe kyphosis 
Risk of PTB (short cervix, prior PTB) Placental abruption
 BMI >35 
Contraindication to prenatal surgery

Question 18

Risk factors for anencephaly

Answer 18

folic acid deficiency
diabetes
obesity
mxt
VPA
Carbamazepine 
2-5% risk for recurrance

Question 19

alobarholopros

• genetics
• prognosis

Answer 19

chromosomal 25-50%
SLO-inborn error of cholesterol synthesis. It is an autosomal recessive,
meckel Gruber
Aicardi/Fryns- CDH
DiGeorge
- diabetic 1%

risk for IUFD
50% die by 5 mo
80% die by 1 year

Question 20

semilobar

lobar

Answer 20

Semi- absent csp, fused frontal lobes, thalami partially fused, microcephaly

lobar- absent csp, microcephaly, fused fornices, thalami separate

Question 21

ventriculomegaly prognosis

Answer 21

worse with
progression
>12
much worse >15 - 50% have severe long term neurologic sequelae

x-linked
spina bifida
Septo-Optic dysplasia
CMV
Aneulopidy 

isolated in about 40 %

Question 22

sacrocoxegeal teratoma

Answer 22

cystic better than solid
Tumor vol/fetal weight >0.12 is bad

staging based on internal external

30-50 % mortality

Question 23

Cleft lip

genetics

Answer 23

1:1000
most genetic causes are single gene
- trecher collins (midline), CHARGE (deaf and blind), skeletal disorder, Zellweger (leukodystrophies), Oculo-Auriculo-Vertebral,
Ectrodactyly–ectodermal dysplasia–cleft syndrome

unilateral 10% associated anomalies ,

bilateral- 35% with other anomalies

Recurrance risk can be 50%

Question 24

micrognathia

Answer 24

inferior facial angle (straight down from nasal depresion and the angle of the chin/upper lip)
Fronto/naso/mental (forehead-nose-chin)
- determine if EXIT is helpful

Question 25

hypoplastic left heart

Answer 25

aortic stenosis coarctation mitral valve stenosis shone syndrome- MV/AV stenosis, supravalvular aortic stenosis

Question 26

cardiac tumor differential

Answer 26

``` rhabdomyoma fibroma hemangioma myxoma pericardial teratoma ```

Question 27

Increased NT ddx- possible anomalies

Answer 27

``` cardiac anomaly 15% if >5.5 mediastinal compression (increase venous pressure) CDH skeletal dysplasia arthrogryposis collagen disorders ```

Question 28

Lissencephaly - what genetic disorder are you primarily concerned about ?

Answer 28

Miller Dieker- microdeletion

Question 29

IUGR with ambigous genitalia - what syndrome

Answer 29

SLO - low estriol. inborn error of cholesterol synthesis.ranging from mild intellectual disability and behavioural problems to lethal malformations autosomal recessive

Question 30

absent corpus callosum - genetic concern

Answer 30

acardia syndrome (female) dominant X-linked manner. However, most cases are de novo. Intellectual delay, retinal differance, seizures, acc

Question 31

non-immune hydrops- genetic concerns

Answer 31

``` >50% have genetic anomaly many- lysosomal storge disease alpha thal anuploidy noonan heart defect associated genes ```

Question 32

``` Risk for genetic anomaly with these findings: cystic hygroma AV canal Omphalocele Duodenal atresia bladder outlet obstruction hydrocephaly cardiac defects meningomyelocele anencephaly encephalocele limb reduction clubfoot facial clefts CNS Skeletal ```

Answer 32

``` cystic hygroma >50% 45X AV canal 40% 21 Omphalocele 30% (13/18) Duodenal atresia 30% (21) bladder outlet obstruction 20% (13/18) hydrocephaly 10% (13/18/21/triploid) cardiac defects 10% (many) meningomyelocele 7% (18) anencephaly 2% encephalocele 10% limb reduction 8% (18) clubfoot 6% (xxy, xxx, 12/21) facial clefts 1% (13/18 22q) CNS 15% ( abnormal array) Skeletal 14% (abnormal array) ```

Question 33

why is microarray standard?

Answer 33

10% SAB 13% stillbirth and 5% ultrasound anomalies will have an abnormal array when karyotype is normal .

Question 34

Single gene causes of recurrent miscarriages

Answer 34

``` alpha thal x linked dominant/lethal- IP chondordysplasia punctata goltz Rett- normal psychomotor development during the first 6 to 18 months of life, followed by a developmental "plateau," and then rapid regression in language and motor skills Aicardi ``` Anticipation- Maternal myotonic dystrophy

Question 35

Whats increased based on paternal age

Answer 35

``` Acondroplasia apert syndrome (acrocephalosyndactyly) crouzon syndrome FGFR2- cranial facial pfiffer sydrome (skeletal) MEN type 2 Progeria noonan ```

Question 36

Genetics associated with infertility

Answer 36

``` fragile x CF Myotonic dystrophy Kennedy disease Karagener syndrome Klinefelter syndrome sex chromosomes ```

Question 37

maternal congenital heart disease and cardiomyopathy - genetic considerations

Answer 37

noonan 22q 11.2

Question 38

what can cause gain of function mutations?

Answer 38

missense mutations

Question 39

what causes loss of function autosomal dominant

Answer 39

dominant negative 1/2 normal level- phenotype tumor supression

Question 40

Clinical heterogenieity

Answer 40

occurance of clinically different phenotypes from mutations in the same gene

Question 41

locus heterogeneity

Answer 41

production of identical phenotypes by mutations in two or more different genes (noonan, craniosynotosis)

Question 42

compound heterozygosity

Answer 42

different types of mutations in the same gene that act as homozygote

Question 43

CDH- prognosis and genetics

Answer 43

lung to head ratio >1.4 better prognosis, liver - worse prognosis 40-50% with Cardiac anaomaly genetic anomaly is common - Fryns- AR, pallister-killian, cornelia de lange- AD X-linked, donnai- barrow

Question 44

multicystic dysplastic kidney- primary genetic concern

Answer 44

meckle gruber (renal, encephalocele, polydactyly) -lethal T13/18

Question 45

XX with ambigous genitalia- causes

Answer 45

CAH (21 hydroxylase, 11 b hydroxylase 3B hydroxysteroid- adrenals don't make cortisol- no feedback, overproduce androgens- problems with electrolytes) meds, viralizing tumor MRI may show ovaries and uterus Aneuploidy- T13, triploid XXY Robinow- skeletal Aarskog- skeletal SLO- 7 dehydroxycholesterol (CNS, syndactyly) WAGR -Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability. Deletion Campomelic dysplasia Deny Drash - kidneys and genitalia 90% wilms tumor

Question 46

46 xy ambigous genetalia

Answer 46

androgen insensitivity 17 alpha hydroxylase leydig cell hypoplasia 5-alpha-reductase

Question 47

Omphalacele -genetics

Answer 47

if there is abnormal genetics: 75% T18 25% T13 -methlyation testing for Beckwith Wediman (imprinted 11p5.5)

Question 48

``` what is this: hitch hiker thumb clubbed foot cleft palate cauliflower ears scoliosis short long bones ```

Answer 48

dystrophic dysplasia- autosomal recessive

Question 49

recurrance risk of clubbed foot

Answer 49

3-5%

Question 50

Ratios in skeletal dysplasias

Answer 50

chest/AC <0.8 bad FL/AC <0.16 FL/Foot <1 ( skeletal dysplasia)

Question 51

bent bone dysplasia ddx

Answer 51

``` campomelic dysplasia Kyphomelic dysplasia Thanatophoric dysplasia osteogenesis imperfecta (Broken bones) short rib polydactyly femoral hypoplasia hypophosphatasis stuve -wiedeman ```

Question 52

``` what is this bent bones ambigous genitalia normal clavicales bell shaped chest hypoplastic scapula ```

Answer 52

campomelic dysplasia- sox9 mutation - 90% die

Question 53

warfarin syndrome

Answer 53

fgr, nasal bone hypoplasia, depressed nasal bridge, stippled epiphyses, IVH

Question 54

Lithium teratogenicity

Answer 54

ebstein

Question 55

Thalidomide teratogenicity

Answer 55

micromelia

Question 56

mxt teratogenicity

Answer 56

folate antagonist calvaria hypoplasia craniofacial limb defects

Question 57

Primary anti-epileptic concerns in pregnancy

Answer 57

valproic acid carbamazepine - NTD

Question 58

Triplet repeat diseases

Answer 58

huntington CAG/HD autosomal dominant <36/ >40 -worse from dad fragile x CGG/FMR1 x linked <60/>200 Myotonic dystrophy CTG/DMPK autosomal dominant <30/80-2000 Friedrich Ataxia AAG/FRDA autosomal recessive <34/>36-100

Question 59

Fragile x carriers phenotypes

Answer 59

ataxia short term memory loss premature ovarian failure

Question 60

Fragile x stabilizers

Answer 60

AGG repeats

Question 61

gene for marfans - problem for anesthesia

Answer 61

fibrillin - dural ectasia

Question 62

loeys-Dietz syndrome

Answer 62

similar to marfans - baby can have cleft - cervical spine instability vag delivery with operative delivery or c-section due to root dilation ( same as marfans)

Question 63

vascular ED

Answer 63

autosomal dominant COL3A1 uterine rupture aortic rupture baby- club foot/amniotic bands vascular anomalies- problems with epidural deliver at 34-37 Cesaeran ALWAYS

Question 64

turner syndrome aortic dissection risk -pregnancy management

Answer 64

1-2% Cardiac MRI within 2 years of pregnancy Higher risk of preeclampsia/FGR Pregnancy contraindicated: history of aortic dissection ASI>2.0-2.5 cm dependent on BAV aortic coarctation transverse artch elongation hypertension

Question 65

Myotonic Dystrophy in pregnancy

Answer 65

``` congenital MD pph prolonged 2nd stage risk for heart conduction abnormalities increased sensitivity to opioids/anesthesia increased risk for pneumonia ```

Question 66

Skeletal dysplasia of mother in pregnancy

Answer 66

``` heritability safety/mode of delivery anesthesia management cardiopulmonary status less weight gain up to 20 lb decrease fluid rates pelvic anatomy assessment ``` avoid operative delivery if concern for baby (c-section not indicated)

Question 67

Osteogenesis imperfecta in pregnancy- (mother)

Answer 67

autosomal dominant most of the time increased fracture risk blue sclera late onset hearing loss COL1A1/COL1A2 anesthsia consult consider mode of delviery Increased hernia risk

Question 68

Acondroplasia in pregnancy (mother)

Answer 68

autosomal dominant FGFR3 baseline PFT's anesthesia consult cesarean recommended

Question 69

Diseases where autosomal recessive diseases have some manifestation in heterozygotes

Answer 69

ataxia telangiectasis- increased risk for cancer sickle cell- resistance to malaria homocystinuria- increased vascular disease a-1 antitrypsin- increased risk for pulmonary disease Gaucher - increased ris for parkinson

Question 70

Hardy weinburg equilibrium

Answer 70

``` large population no mutations no selection random mating no migration ```

Question 71

Genetic heterogeneity

Answer 71

same phenotype different mechansiums

Question 72

williams syndrome

Answer 72

``` 7 q`11.23 deletion elastin gene growth facial differances aortic stenosis GI abnormalities hypercalcemia rectal prolapse/constipation premature graying outgoing/ mild delay ```