Genetic Conditions- ABC Flashcards
Autosomal Dominate
Marfan Neurofibromatosis Achondropasia (homgygote lethal) Polycystic kidney Ectrodactyly Tuberous Sclerosis Digeorge (22q11.2) Huntington
Autosomal Recesive- main genetic syndromes
Cystic Fibrosis Sickle Cell Disease Tay-Sachs SMA Hemachromotosis (looks autosomal dominate - carrier frequency is very high) Lysosomal storage conditions congenital adrenal hyperplasia
x-linked
OTC -most common urea cycle disorder/ammonia
Hemophilia
Fragile X
DMD
Beckwith Wedimann Syndrome
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
Imprinting genetics
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.
Germ Line Mosicism -common conditions
severe OI
DMD
Mitocondrial inheritance
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,[
Trinucleotide repeat
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
Things you’ll see on karyotype that you won’t on anuploidy screening
Translocation Inversion Isochromosomes Marker Insertions Ring
SMA
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
Alpha Thal
Screen with low MCV
most common in SE asia
4 absent- barts (hydropic)
1 missing- silent carrier
carrier frequency in jews CF tay sac canavan familial dysautonomia Gaucher
CF 1/25 tay sac 1/30 canavan 1/40 familial dysautonomia 1/30 Gaucher 1/13
Tay-Sachs partner testing
- inital screen
- follow-up
Hex A enzymatic activity
Sequencing
CVS- associated risks
contraindications- infections ( test for transcervical) 1/300-1 % risk SAB infection bleeding (TC) Fluid leakage confined placenta mosiacism (1-2%)
What chromosomes do methylation mater (imprinting) ?
6,7,11,14,15
Karyotype vs microarray
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
moms criteria
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
Risk factors for anencephaly
folic acid deficiency diabetes obesity mxt VPA Carbamazepine 2-5% risk for recurrance
alobarholopros
- genetics
- prognosis
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
semilobar
lobar
Semi- absent csp, fused frontal lobes, thalami partially fused, microcephaly
lobar- absent csp, microcephaly, fused fornices, thalami separate
ventriculomegaly prognosis
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 %
sacrocoxegeal teratoma
cystic better than solid
Tumor vol/fetal weight >0.12 is bad
staging based on internal external
30-50 % mortality
Cleft lip
genetics
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%
micrognathia
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
hypoplastic left heart
aortic stenosis
coarctation
mitral valve stenosis
shone syndrome- MV/AV stenosis, supravalvular aortic stenosis
cardiac tumor differential
rhabdomyoma fibroma hemangioma myxoma pericardial teratoma
Increased NT ddx- possible anomalies
cardiac anomaly 15% if >5.5 mediastinal compression (increase venous pressure) CDH skeletal dysplasia arthrogryposis collagen disorders
Lissencephaly - what genetic disorder are you primarily concerned about ?
Miller Dieker- microdeletion
IUGR with ambigous genitalia - what syndrome
SLO - low estriol. inborn error of cholesterol synthesis.ranging from mild intellectual disability and behavioural problems to lethal malformations
autosomal recessive
absent corpus callosum - genetic concern
acardia syndrome (female) dominant X-linked manner. However, most cases are de novo. Intellectual delay, retinal differance, seizures, acc
non-immune hydrops- genetic concerns
>50% have genetic anomaly many- lysosomal storge disease alpha thal anuploidy noonan heart defect associated genes
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
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)
why is microarray standard?
10% SAB
13% stillbirth
and 5% ultrasound anomalies will have an abnormal array when karyotype is normal .
Single gene causes of recurrent miscarriages
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
Whats increased based on paternal age
Acondroplasia apert syndrome (acrocephalosyndactyly) crouzon syndrome FGFR2- cranial facial pfiffer sydrome (skeletal) MEN type 2 Progeria noonan
Genetics associated with infertility
fragile x CF Myotonic dystrophy Kennedy disease Karagener syndrome Klinefelter syndrome sex chromosomes
maternal congenital heart disease and cardiomyopathy - genetic considerations
noonan 22q 11.2
what can cause gain of function mutations?
missense mutations
what causes loss of function autosomal dominant
dominant negative
1/2 normal level- phenotype
tumor supression
Clinical heterogenieity
occurance of clinically different phenotypes from mutations in the same gene
locus heterogeneity
production of identical phenotypes by mutations in two or more different genes (noonan, craniosynotosis)
compound heterozygosity
different types of mutations in the same gene that act as homozygote
CDH- prognosis and genetics
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
multicystic dysplastic kidney- primary genetic concern
meckle gruber (renal, encephalocele, polydactyly) -lethal
T13/18
XX with ambigous genitalia- causes
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
46 xy ambigous genetalia
androgen insensitivity
17 alpha hydroxylase
leydig cell hypoplasia
5-alpha-reductase
Omphalacele -genetics
if there is abnormal genetics:
75% T18
25% T13
-methlyation testing for Beckwith Wediman (imprinted 11p5.5)
what is this: hitch hiker thumb clubbed foot cleft palate cauliflower ears scoliosis short long bones
dystrophic dysplasia- autosomal recessive
recurrance risk of clubbed foot
3-5%
Ratios in skeletal dysplasias
chest/AC <0.8 bad
FL/AC <0.16
FL/Foot <1 ( skeletal dysplasia)
bent bone dysplasia ddx
campomelic dysplasia Kyphomelic dysplasia Thanatophoric dysplasia osteogenesis imperfecta (Broken bones) short rib polydactyly femoral hypoplasia hypophosphatasis stuve -wiedeman
what is this bent bones ambigous genitalia normal clavicales bell shaped chest hypoplastic scapula
campomelic dysplasia- sox9 mutation - 90% die
warfarin syndrome
fgr, nasal bone hypoplasia, depressed nasal bridge, stippled epiphyses, IVH
Lithium teratogenicity
ebstein
Thalidomide teratogenicity
micromelia
mxt teratogenicity
folate antagonist
calvaria hypoplasia
craniofacial
limb defects
Primary anti-epileptic concerns in pregnancy
valproic acid
carbamazepine
- NTD
Triplet repeat diseases
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
Fragile x carriers phenotypes
ataxia
short term memory loss
premature ovarian failure
Fragile x stabilizers
AGG repeats
gene for marfans
- problem for anesthesia
fibrillin
- dural ectasia
loeys-Dietz syndrome
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)
vascular ED
autosomal dominant
COL3A1
uterine rupture
aortic rupture
baby- club foot/amniotic bands
vascular anomalies- problems with epidural
deliver at 34-37
Cesaeran ALWAYS
turner syndrome aortic dissection risk
-pregnancy management
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
Myotonic Dystrophy in pregnancy
congenital MD pph prolonged 2nd stage risk for heart conduction abnormalities increased sensitivity to opioids/anesthesia increased risk for pneumonia
Skeletal dysplasia of mother in pregnancy
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)
Osteogenesis imperfecta in pregnancy- (mother)
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
Acondroplasia in pregnancy (mother)
autosomal dominant
FGFR3
baseline PFT’s
anesthesia consult
cesarean recommended
Diseases where autosomal recessive diseases have some manifestation in heterozygotes
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
Hardy weinburg equilibrium
large population no mutations no selection random mating no migration
Genetic heterogeneity
same phenotype different mechansiums
williams syndrome
7 q`11.23 deletion elastin gene growth facial differances aortic stenosis GI abnormalities hypercalcemia rectal prolapse/constipation premature graying outgoing/ mild delay
