B8.066 Preconceptual and Prenatal Genetic Screening and Counseling Flashcards
prenatal
pertaining to the state of pregnancy at any gestational age prior to delivery
preconception
any person (men and women) with reproductive potential
chromosomal disorders
affect number or structure of chromosomes
- Down Syndrome
- del22q11.2 (digeorge)
genetic disorders
affect the structure and function of genes
- cystic fibrosis
- tay sachs
preconception care
identifiation of conditions that could affect a future pregnancy or fetus and that may be amenable to intervention
what is included in preconception care?
family planning and pregnancy spacing current meds nutrition immunization status review of med, surg, psych history socioeconomic, educational, and cultural context exercise history family history* genetic screening/testing* substance abuse OB/GYN history
recommended genetic carrier screening
CF
spinal muscular atrophy
hemoglobinopathies
fragile x
genetic conditions based on eastern /central european jewish descent
genetic conditions based on founder mutations
recommendation for CF carrier screening
offer to all women who are considering pregnancy or are currently pregnant
which groups have the highest carrier rates of CF?
Ashkenazi Jewish
Non-hispanic white
CFTR protein
25 exons
250,000 bp
1480 aa
transmembrane Cl- channel > complex product
considerations for CF screening
- populations with lower carrier frequencies also have higher rates of atypical mutations (aka easier to catch mutations in populations with more prevalence)
- 80% of men with congenital bilateral absence of the vas deference have CFTR mutations
what do you do if an individual screens positive as a carrier for CF
DO NOT use a common mutation panel for their partner….need to do full sequencing
what populations are most at risk of SMA
caucasian
ashkenazi jewish
asian
what is the normal gene structure of SMA?
SMN1 + SMN 2 on each chromosome
SMN2 produces a functional product, but at a very low amount, doesn’t contribute much to disease process
most common SMA genetic mutation
93%
missing SMN1 on both chromosomes
due to crossing over event that excises SMN1 in each parent
less common SMA genetic mutation
6%
1 chromosome with SMN1 missing
1 chromosome with mutations that makes SMN1 nonfunctional
very rare SMA genetics mutation
1 in 1000
happens in consanguineous relationships
SMN1 on both chromosomes have mutations that make them nonfunctional
ways that you can be a carrier for SMA
carrier of deletion
carrier of mutation
2+0 carrier
what is a 2+0 carrier of SMA and why is this an issue
these people have 2 SMN1 copies on 1 chromosome and a deleted SMN1 on the other chromosome; but still technically have 2 copies
carrier screening typically only looks for # of SMN1 copies, so this person can appear to be normal on screening
how could you recognize a 2+0 carrier
look for a g.27134 T>G mutation in one of the copies
more common in african american populations
carrier screening recommendation for hemoglobinopathies
a CBC with RBC indices should be performed on all women who are currently pregnant to assess not only their risk of anemia, but also allow assessment for risk of a hemoglobinopathy
*ideally offered before pregnancy
B globin gene cluster
chromosome 11
gamma product > contributes to Hb F
delta product > contributes to HbA2
beta product > contributes to HbA
alpha globin gene cluster
chromosome 16
zeta 1&2
alpha 1&2
most common hemoglobinopathies
sickle cell/ hemoglobin variants of the B chain
B Thalassemia
a Thalassemia
how do you screen for hemoglobinopathies
hemoglobin electrophoresis should be performed in addition to a CBC if there is suspicion of a hemoglobinopathy based on ethnicity (african, mediterranean, middle eastern, southeast asian, west indian)
what would indicated B-Thalassemia trait on CBC and Hb electrophoresis
MCV < 80
increased HbA2 (>3.5%)
-indicates that not enough B chain is being made
what would indicated a-Thalassemia trait on CBC and Hb electrophoresis
MCV <80
no iron deficiency
what do you do if you find an a or B thalassemia trait?
test partner!
what other lab finding would lead to testing a partner for hemoglobinopathies
clinically significant Hb variant on electrophoresis
-cant detect absence, only abnormal product
who should be screened for fragile x premutation
women with a family history of fragile x related disorders or intellectual disability suggestive of fragile x syndrome
women with unexplained ovarian insufficiency or failure before age 40
CGG repeat levels in fragile x
normal : 5-44
intermediate: 45-54 (at risk for expansion only to premutation)
premutation: 55-200 (increased risk for FXTAS and POF)
full mutation: 201 and up (fragile x syndrome)
role of AGG interruption within maternal FMR1 gene
reduces the risk of offspring with fragile x
most common disorders in ashkenazi jewish populations
gaucher disease CF tay sachs familial dysautonomia canavan disease
less common, but severe disorders in the ashkenazi jewish populations
fanconi anemia
niemann-pick type A
bloom syndrome
mucolipidosis IV
what are some qualifications for disorders to be selected for expanded carrier panels
carrier frequency of 1 in 100 or greater
have a well defined phenotype
have a detrimental effect on quality of life
cause cognitive or physical impairment
require surgical or medical intervention
have early onset
screened conditions should be able to be diagnosed prenatally
should not include disorders of adult onset
purpose and target population of screening tests
purpose: to detect potential disease indicators
target population: large numbers of asymptomatic, but potentially at risk individuals
**sensitive
purpose and target population of diagnostic tests
purpose: to establish presence/absence of a disease
target population: symptomatic individuals to establish diagnosis, or asymptomatic individuals with a positive screening test
**specific
screening for chromosome abnormalities in the first trimester
nuchal translucency nasal bone ductus venosus tricuspid defects maternal serum screening
nuchal translucency testing
performed by US between 11w and 13w6d
normal is under 2.5-3 mm depending on gestational age
increased NT
associated with cardiac defects and chromosome abnormalities
nasal bone testing
screening for presence or absence only
low nasal bridge associated with some chromosome abnormalities
maternal serum screening in 1st trimester
PAPP-A
BhCG
AFP (placental, not fetal, different from AFP done in 2nd trimester to test for neural tube defects)
purpose of maternal serum testing in 1st trimester
adjusts risk for trisomies 18 and 21
components of maternal serum screening in 2nd trimester for chromosomal abnormalities
hCG
AFP
DIA
uE3
how are maternal serum levels analyzed
multiples of means
normal distributions of affected and unaffected individuals
AFP levels in down syndrome
low
AFP levels in spina bifida
high
function of maternal serum screening in 2nd trimester for chromosomal abnormalities
performed between 15w and 22w6d
correct assessment of gestational age is critical for interpretation
detection for trisomy 21, 18 and neural tube defects
screening options for chromosome abnormalities that can be done in all trimesters
non-invasive prenatal screening
may be performed anytime after 10 weeks of gestation
cfDNA analyzed in fetus and mother
functions of screening methods for chromosome abnormalities that can be done in all trimesters
screens for trisomy 13, 18, 21 and abnormal numbers of sex chromosomes
may be used to detect microdeletions (del22q11.2, cri-du-chat (5p), angelman/ prader willi, wilf hirshorn (4p), and 1p36 deletion syndrome)
can screen for all chromosomes!!!
diagnostic testing for chromosome abnormalities and genetic disorders
amniocentesis
chorionic villus sampling
amniocentesis
after 15 weeks
chorionic villus sampling
between 10-14 weeks
what can fetal cells be used for after amniocentesis/ chorionic villus sampling
chromosome analysis microarray analysis single gene analysis analyte analysis (only amnio) WES, WGS
