GENETICS Flashcards
Fanaroff 10, 11,12,14,15,16 11 edition
number of chromosomes in humans
23 pair of chromosomes
autosomes
identical chromosomes (22 pairs in both genders)
women homologous chromosomes
XX
men nonhomologous chromosomes
XY
linear DNA
histones (protein) form of chromatin
centromere
short arm (p arm) and long arm (q arm)
metacentric chromosome
arm length is equal
submetacentric chromosome
one arm is longer than the other
acrocentric
p arm is neglected (example: 13,14,15,21,22)
telomeres
the ends of each chromosome
karotype
analyze chromosomes
chromosome disorders
structural or numerical
advanced maternal age
35 or more at the expected date of confinement
numerical abnormalities
triploidy and tetraploidy; aneuploidy;
triploid
three sets of chromosomes (69 total); fertilization by two sperm; rarely born alive; poor survival
tertaploid
96 chromosomes, fetus miscarried in the first trimester
aneuploidy
any genotype in which total chromosome number is not a multiple of 23
monosomy
type of aneuploidy; only one representative of particular chromosome; not viable expect TURNER syndrome (monosomy X)
trisomy
type of aneuploidy; three copies of particular chromosome ; chromosomes 13, 18, 21, X, and Y compatible with life
structural abnormalities
chromosomal breakage followed by anomalous reconstruction; balance or unbalanced; deletions, insertions, ring chromosomes, isochromosomes, translocation
Robertsonian translocation
two acrocentric chromosomes lose their short arms and fuse near the centrometric region; phenotypically normal but have risk of producing unbalanced gametes involving chromosome 21 (downs)
single-gene disorders
4000 diseases; Mendelian inheritance; types: autosomal dominant disorders, autosomal recessive disorders, sex-linked disorders
alleles
variants of gene
autosomal dominant disorders
vertical pattern of transmission (phenotype in every generation); 50% risk; example: osteogenesis imperfecta;
advanced paternal age
40+, not clear;
autosomal recessive disorders
individual possessess two mutant alleles that were inherited from heterozygous parents; horizontal transmission (appears in more than one member of the family: sibllings); example: cystic fibrosis
consanguineous unions
mating between individuals who are second cousins or closer
sex-linked disorders
hemophilia A; X-linked recessive disorder; male disorder
Non-Mendelian patterns of inheritance
mitochondrial inheritance; epigenetics and uniparental disomy; trinucleotide repeat expansion
mitochondrial inheritance
maternal inheritance, replicative segregation, and heteroplasmy; examples: CNS or MS systems: MERRF, MELAS, NARP, LHON, MNGIE; dysfunction of high energy consuming organs like brain, muscle, heart, kidneys; poor growth, muscle weakness, loss of coordination, developmental delay;
epigenetics
modification of genes that determines whether a gene is expressed or not
imprinting
phenomenon in which genetic material is differently expressed depending on whether it was inherited from FOB or MOB
uniparental disomy
inheritance of a pair of homologous chromosomes from one parent (normally one chromosome is inherited from each parent); example: Prader-Willi syndrome; Angelman syndrome
trinucleotide repeat expansion
mutations occur and get passed on to next generation; ; examples: congenital myotonic dystrophy, Huntington disease, Friedreich ataxia, fragile X syndrome
Fragile X Syndrome
1 in 4000; at risk for adult onset cerebellar dysfunction; family and personal HX of delay or retardation or tremor should get screened for it
Multi-factorial Inheritance /Complex
genetics, environmental and gene-gene interactions; examples: neural tube defects(NTD): spina bifida and anencephaly;
Complex Inheritance: ANENCEPHALY
forebrain, meninges, bone and skin are absent; stillborn
CompleX Inheritance: NTD
incomplete fusion of vertebral arches; lack of folic acid,
Teratogens
medications, maternal conditions, infections
all or non period
first two weeks after conception; lethal or no adverse effect
diagnostic imaging
ionizing radiation; ; dental xray ok(less than 5 rad); exposure more than 10 rad increase rick for malformations; iodinated contrast: might effect fetal thyroid); MRI not contradicted; US not contradicted
congenital abnormalities occur in
3-4% live births
congenital abnormalities categories
malformation, deformation, disruption
malformation
intrinsic abnormalities in the genetic programs controlling development;
deformation
extrinsic factors physically imprinting on otherwise normal tissue;
arthrogryposis
contractures of the extremities due to prolonged leakage of AF resulting in fetal crowding
disruptions
consequence of fetal tissue destruction: vascular insufficiency or mechanical damage
ultrasound examination categories
limited(placental location), standard(18-20 weeks check up), specialized/targeted(fetal ECHO)
first trimester US (10-13.6 weeks)
confirm pregnancy, estimate GA, evaluate pelvic anatomy; aneuploidy screening: nuchal transluency (70% downs) ; in the future might be replaced by NIPS;
second trimester US (15-22.6 weeks)
fetus anatomy : fetal number, presentation, cardiac activity, AF and placental characteristics; fetal organ survey
triple screen
maternal serum AFP, hCG, unconjugated estriol
cell free DNA screening
maternal blood screen; non-invasive prenatal screening (NIPS)-cant replace prenatal diagnosis;
NIPS non invasive prenatal screening
tests for aneuploidy (trisomy), (not recommended for microdeletions,) deletions and duplications
Serum Alpha-fetoprotein (AFP)
(15-20 weeks); screens for NTDs; false positive if contaminated with blood
screening for hemoglobinopathies
CBC early in pregnancy; for all women; if at rick then test FOB
carrier screening for Cystic Fibrosis
mutation of chromosome 7; s&s: chronic pulmonary disease, pancreatic insufficiency, liver disease; CTFR gene;
Jewish Carrier Screening
Ashkenazi heritage
carrier screening for Spinal Muscular Atrophy (SMA)
progressive neuromuscular disease resulting from degeneration of spinal alpha neurons; offered to all couples
diagnostic modalities
chorionic villus sampling (CVS), amniocentesis, cordocentesis
Chorionic Villus Sampling
small sample of the placenta; 10-13 weeks; often same karyotype as fetus; NOT for Alpha-fetoprotein, NOT for NTDs;
Amniocentesis
withdrawal of AF (20-30 ml) from the uterine cavity; prenatal genetics and lung maturity; 15-22 weeks; used to test NTDs, FISH
karyotyping
Giemsa stain; analysis of banding pattern; advantage: whole genome analyzed at one time
FISH
fluorescence microscopy; advantage: can be applied to non-dividing and dividing cells; ; disadvantage: structural abnormalities can be missed;
microarray technology
gene expression analysis; detect smaller changes than karyotype;
future in PRENATAL diagnostics
next generation sequencing, WES and WGS;
Assisted Reproductive Technologies
IVF
Genetic Evaluation and Counseling
family and personal HX; ethnic background; tetatogen exposure; abnormal US; previous pregnancy loss
Fetal Imaging Techniques
B-mode: standard (confirmation of cardiac activity and fetal movement; M-mode (arrhythmia, myocardial contractility, pericardial effusions); doppler US (color and power): sound and color; three-dimensional US;
diagnostic US energy
bioeffects: heating and cavitation;
application of US
genetic screening, assisted reproduction(complications), multiple gestation(3% of all pregnancies); standard method for recognition of fetal anomalies
US fetus with Downs anomalies
endocardial cushion defect, duedenal atresia, small atrioseptal and vantriculoseptal cardiac defects; thickened nuchal fold
monochorionic TTTS
shared perfusion: restricts growth and AF production in the donor, and causes volume overload, cardiac dysfunction, polyhydramnios in the reciepient
Twin Reversed Arterial Perfusion TRAP
“pump twin” vs “acardiac/parabiotic twin” flow in the artery and veins are reversed
sonographic measurements and US parameters
basis for accurate GA and detection of fetal growth abnormalities
Biparietal diameter
parietal bone calsification in 12 week; closest correlation with GA in the 2nd trimester
US fetal growth assessment/ fetak biometry
BPD (biparietal diameter), head circumference, abdominal circumference, femoral length; no golden standard, in third semester usually undetected
Placental abnormalities US
US is ultimate diagnosis for placental DX; placental location;
funic
umbilical cord
vasa previa
fetal vessels overlying the os
placenta previa
common source of severe third semester bleeding
Amniotic Fluid Volume
16weeks done by renal production; 24h turnover; 1000ml
polyhydramnios
malformations of esophagus and upper GI, inhibited fetal swallowing, aneuploidy, intermittent renal obstruction, maternal DM, TTTS, dwarfisms, fetal hydrops; usually idiopathic; more than 2000ml
oligohydramnios
after membrane rupture, urogenital anomalities; maternal dehydration; meds: indomethacin, ACE inhibitors;
cervical length US
correlates with duration of gestation; under 25mm increase premature labor; cerclage
doppler US
identification and localization of blood flow; abnormal doppler US presese growth restriction and maternal HPT complications;
Biophysical Profile (BPP)
non-invasive US-based clinical tool; (1) tidal fetal breathing, (2)AF pocket (3)three fetal movements (4)fetal tone (5) reactive NST
Hydrocephalus
raised intracranial pressure, not done by US; does NOT happen with NTDs;
fetal ventriculomegaly
10mm
Meningomyelocele and Chiari Malformation (type II)
downward displacement of the hindbrain;
“lemon sign”
altered appearance of calvarium; 18-24 weeks; DX of spina bifida
“banana sign”
abnormal cerebral positioning; DX of spina bifida
anencephaly
absence of normal brain; 10 weeks; alpha fetoprotein very elevated; cause abnormal prolongation of pregnancy; no survival
encephalocele
extracranial protrusion of brain tissue
holoprosencephaly
malformation of brain resulting from early failure of division; trisomy 13; 11-14 weeks, butterfly sign
Choroid Plexus Cyst
usually resolve by early 3rd trimester; normal karyotype; associated with trisomy 18
spine US
3D imaging; sacrococcygeal tetratomas (SCTs) congenital germ cell tumors; uncomplicated SCTs prognosis is excellent;
head and neck US
14 weeks; orbits, facial clefting; nasal bones;
cystic hygroma US
mass arising from neck and occipital region secondary to lymphatic malformation; monosomy X;
heart US
18-22 weeks; four chambers and great arteries at 13-14 weeks;
GI US
esophageal atresia and Tracheoesophageal Fistula; small bowel obstruction( “double-bubble”, trisomy 21) anterior abdominal wall defect (omphalocele, gastroschisis); Diaphragmatic hernia and thoracic lesion (fluid filled intrethoracic bowel loops, mass effect on lungs causing: pulmonary hypoplasia, and secondary pulmonary HPT; fetal hydrops (accumulation of fluid); gallbladder and bile ducts
GU US
kidneys 12-14 weeks; bladder;
Potter syndrome
prolonged oligohydramnios, characteristic facial apperance, limb deformities, pulmonary hypoplasia
anhydramnios
no measurable fluid in the bladder
pyelectasis
dilation of the renal pelvis, 4-7mm
hydronephrosis
dilation of the renal pelvis 1cm
MS US
skeletal dysplasia (falling below 3SD measure)
phocomelia
extreme generalized limb reduction or absence
micromelia
overall limb shorthening
rhizomelia
proximal reduction (femurs and humeri)
mesomelia
more distal reduction (forearms and lower legs)
acromelia
most distal reduction (hands and feet)
dysostosis
absence of various skeletal portions
two vessel umbilical cord
restricted growth, serial third trimester examination recommended
antepartum
testing done remote from delivery
intrapartum
testing done during labor
antepartum fetal surveillance
MOB subjective assessment “kick counts”; non-stress test (NST), CST, Biophysical profile, AF volume assessment; doppler flow velocimetry; if normal then usually performed on weekly basis
what alteres fetal biophysical paremeters?
hypoxemia and acidosis
non-stress test
NST: monitor FHR for up to 40 minutes, observe for HR accelerations; peak up 15bpm and last 15 sec; usually starts at 32-34 weeks
contraction stress test
CST: evaluate FHR in response; to maternal contractions; MOB had at least 3* 40 sec contractions in 10 minute period
biophysical profile
NST and US; 30 minute period, score can be only even number: 0-10;
AF volume assessment
US: measuring and adding the maximal vertical pockets of fluid
Doppler flow velocimetry
evaluation of fetus with possible IUGR
fetus respiratory acidosis
carbon dioxide accumulates secondary to impaired clearance by the lungs/placenta;
respiratory vs metabolic acidosis
check base deficit; high base deficit is caused by metabolic process
metabolic processes
more concerning than respiratory; excess tissue lactate generation; longer time to correct; result of prolonged or severe deprivation of oxygen, triggers lactate production in fetal tissues
respiratory acidosis
low umbilical ph, low 1-minute apgar; faster to correct through proper ventilation
continuous electronic FHR monitoring
externally and internally(contradicted with hepatitis and HIV);
continuous FHR recordings
FHR baseline 110-160bpm;
primary response to hypoxemia
tachycardia secondary to sympathetic discharges
FHR variability
fluctuation in FHR baseline of two cycles per minute or greater, with irregular amplitude and inconstant frequency
FHR accelerations
periodic elevations above baseline, always reassuring; but absence is not concerning
FHR decelerations
episodic decreases below the baseline; “early”: increases in intracranial pressure; “variable”:systemic vascular resistance; “late”: hypoxemia ; recurrent(50%) or prolonged(2 minutes)
early decels
shallow and symmetric, gradual in onset and recovery same time as the peak of contraction; Cushing reflex; unrelated to fetal oxygenation and acid-base balance
variable decels
abrupt onset and abrupt return to baseline; vary in shape, duration, and depth; associated with compression of umbilical cord(can lead to presence of umbilical cord compression, oligohydramnios, prolapse of cord through the cervix); maternal position changes can solve “decels”
late decels
more gradual onset and return baseline (30sec); occur after the contraction; caused by hypoxemia and tissue level hypoxia; resolved my positional change, oxygen supplementation, two mechanisms of action ;)
fetal tracing categories
category I: normal (110-160, moderate variability, absence of late and variable decels; early decels ok, accelerations may or may not be present
category II: indeterminate tracing
category III: abnormal (absent baseline with any of these:-recurrent late decels, recurrent variable decels, bradycardia; and sinusoidal pattern
how to manage patterns during labor?
rule out immediate delivery: cord prolapse, placental abruption, or uterine rupture
rule out meds and MOB BP
rule out frequent contractions not allowing for recovery (oxytocin)
change maternal position: lateral recumbent
give supplemental oxygen
give fluids: amnioinfusion
The Developmental Origins of Health and Disease / DOHaD
field of study that explores the relationship between exposure to environmental stressors during critical periods of fetal development and adverse health outcomes that occur across a lifetime; originally published by Baker
preconceptual effects
epigenome; maternal and paternal exposures
epigenetics
study of phenotypic changes occurring in the absence of modification of DNA sequence; genomic imprinting; mechanism: DNA methylation, alternation of expression patterns in micro RNA, modification of histone proteins
genomic imprinting
silencing of one parental allele leading to monoallelic gene expression; differential expression of specific genes according to parental origins
maternal exposure
active smoking; environmental toxicants; DES (given to prevent miscarriage) can cause your offspring infertility
paternal exposure
environmental toxicants: pesticides, can cause offspring infertility and/or cancer, and birth defects
maternal body burden
adipose tissue stores chemicals, bones store lead and fluoride; PCBs ; Lead
maternal exposures concurrent with pregnancy
occupation and paraoccupational: lead, mercury, pesticides, organic solvents, ionizing radiation; air pollution; drinking water; diet
pathways of fetal exposure
placenta-dependent: by crossing the placenta
placenta- independent: radiation, heat, noise,
fetal pharmacokinetics
absorption: increase in progesterone prolongs gastric emptying, slows GI; hyperventilation…then increases overall exposure
distribution: increased fat, increased fluid volume, AF, prolongs elimination….causing prolonged overall exposure
metabolism: increase, ontogeny of fetal phase I and phase II metabolism in the liver, genetic polymorphisms in drug metabolizing enzymes
specific exposure
cigarette smoking, ethanol, pesticides, Bisphenol A, S, f; Phthalates, organic solvents,
epigenetic transgenerational inheritance
epimutations in the germline (egg or sperm) that are passed to future generations and leads to variations in phenotypic expressions
active cigarette smoking during pregnancy
reduced fertility, placental dysfunctions, spontaneous abortions, IUGR, PTL, congenital anomalities, SIDS
Fetal Alcohol Spectrum Disorder vs FAS
extreme end spectrum: characteristic facial features, and neurodevelopmental impairment
pesticides
neurotoxins; endocrine disruptors, immunotoxicants, carcinogens
BPA and phthalates (PVC)
plastic, BPA- estrogeic, PVC-anti-androgenic
Organic solvents
household cleaning supplies, teratogens
“normal” fetal growth
10-90 percentile for GA
SGA
less than 10 percentile
IUGR
all fetuses with evidence of malnutrition or in utero growth restriction, can include infants above 10 percentile; 10% of all live born infants; suboptimal nutrient and oxygen provision to the fetus, often secondary to poor placental perfusion; fetal growth less that its genetic potential
complications of IUGR
short: hypoglycemia, hyperbili, hypothermia, RDS
long: neurodevel delays, cardiometabolic (obesity, DM2, CV disease)
asymmetric IUGR
decrease in intrauterine nutrition and oxygen; nutrients go to vital organs: brain and heart; disproportionately HC compared to weight; manifests in third semester; “head-sparing”; more common; placental insufficiency
symmetric IUGR
proportionately low measurements of HC, weight and length; less common; detected earlier in pregnancy, genetics or chromosomal; pregnancy infections (rubella, TORCH, malaria)
etiology of IUGR
maternal, fetal, placental, environmental factors, or combination
fetal IUGR
asymmetric: genetics;
symmetric: chromosomal trisomy 13, 18, 21; structural
maternal IUGR
asymmetric: age, parity, race, nutrition; medical conditions and DX,
symmetric: advanced maternal disease: severe HPT
environmental IUGR
asymmetric: teratogen exposure, substance abuse, altitude, assisted reproductive technology
symmetric: infectious disease(malaria, rubella, CMV, syphilis)
placental IUGR
multiple gestation, insufficiency(most common of all for IUGR), placental disorders and umbilical cord abnormalities;
pathophysiology IUGR
chromosomal (decrease number of fetal cells); hormones: insulin, thyroid, adrenal, pituitary
antenatal screening IUGR
maternal and family HX; maternal physical exam (fundal height measurment); fetal US (four biometric measurements) : best predictor- abdominal circumference; Doppler velocimetry: umbilical artery (absent or reverses end-diastolic flow)
hypoglycemia IUGR
suboptimal glycogen stores, impaired gluconeogenesis; formula, gavage, IVF
hypothermia IUGR
decreased brown fat; exogenous heat (incubator)
RDS IUGR
pulmonary vascular remodeling; support respiratory care
NEC IUGR
especially AEDF and REDF; exclusive breast milk, trophic feeds
other issues DX with IUGR
IVH, electrolyte abnormalities, jaundice/polycythemia, abnormal immunity
adaptive mechanisms and intrauterine environment
create finely crafted “thrifty” phenotype that may tip towards a disease state
imprinting disorders due to IVF
Beckwith-Wiedemann, Angelman, Prader-Willi syndromes, hypomethylation syndrome
low weight and slow growth pattern followed by exponential growth during childhood causes what?
metabolic syndrome
postnatal “catch-up” growth
result in adiposity (too much white adipose tissue), sets adults for metabolic syndrome, DM, and coronary artery disease
mismatch concept
the earlier the deprivation phase is followed by catch-up growth, the more significant the consequences in adult life
placental abnormalities and adult chronic disease
HPT and CHD
Gestational DM and long-term effect on offspring
obesity, insulin resistance, DM2
high estrogen in pregnancy effects on offspring
high estrogen in advanced maternal age, twins and LGA can cause PIH, cancer
chronic antenatal and postnatal stress
neurodevelopmental impairments;
tocometry
contractions monitoring
