Carrier Screening Flashcards
Who should be carrier screening be offered to?
all patients: preconception, seeking infertility care, and during 1st or early 2nd trimester
What sort of reproductive decisions are available to those with carrier screening?
IVF with PGT-M donor gamete(s)/embryo adoption prenatal dx w/ CVSA or amnio -> prepare for birth, palliative care, etc. not having children
What conditions do ACMG and ACOG say everyone should be screened for (2017)?
CF and SMA
What is the idea behind population-based carrier screening? Ex?
screen for conditions offered to everyone in general population
CF, SMA, Fragile X
What are the criteria for something to be included in population-based screening?
disorder is clinically severe
high frequency of carriers in screened population
availability of reliable test with high specificity and sensitivity
availability of prenatal dx
testing is voluntary
What’s incidence of CF carriers in European populations?
1/2500
If an individual with CF has tow different variants, their phenotype will:
follow the more mild variant
What gene is responsible for CF? What types of testing is done?
CFTR
most common mutations or full gene sequencing can be completed w/ del/dup
What the best way to find CF variants no matter the population?
sequencing +del/dup of CFTR gene
What’s the incidence of SMA? Carrier freq?
1/10,000
1/40-1/60
How is SMA classified?
based on age and maximum function attained?
95-98% of those with SMA are?
Other 2-5%?
homozygous for a deletion of SMN1 exon 7
compound het, deletion + point mutation
What percent of SMA variants are de novo?
2%
What can lead to a more milder phenotype in SMA?
increased SMN2 copy number
What percent of the population are silent SMA carriers? How’s this happen? How can we detect these?
3-4%
each SMN1 I is in cis
SNP in intron 7 (more likely)
When should we screen for Fragile X?
FHx of FXS
FHx of unexplained intellectual disability, DD, or autism
women with ovarian insufficency or failure or an elevated FSH <40y w/o known cause
men or women experiencing late onset intention tremor and idiopathic cerebellar ataxia
What is characteristic of individuals with FXS?
- moderate ID in males, mild in females
- autistic-like features
- long narrow face, prominent ears
- marco-orchidism
- joint laxity
What can we see in FXS premutation carries?
FXPOI (ovarian insufficency)
FXTAS (late onset >50y, M>F)
neuropsychriatric disorder and developmemntal and cognitive profile (anxiety, bipolar, depression, etc.)
FXS is caused by:
expansion of CCG repeats in FMR-1 gene
What’s the mechanism of FXS?
expansion of FMR1 leads to methylation -> lack of expression -> phenotype
What are the ranges of CCG repeats in FXS?
<45: unaffected
45-54: intermediate
55-200: premutation
>200: full mutation
What other tri-nucleotide repeat impacts FMR1 stability? How? Up to what # of CCG?
AGG
decreases chances of expansion when inherited
only effective if <80 CCGs
What is the concept behind targeted-population-based carrier screening?
screening limited to particulat gropus o fpeople determined to be at higher risk for specific genetic disorders
condition is usually relatively common, ethnicity based
What types of conditions are often included in targeted-population-screening- for AJ pops?
Tay-sachs Canavan CF familial dysautonomia Gaucher SMA etc.
What types of screening is completed for Tay-Sachs?
exnsyme-based
DNA based
What enzyme is screened for in Tay-sachs? DR with enzyme screening?
Hexosaminidase A
98%
What gene is sequenced in Tay-Sachs? Different methods and DRs?
HEXA
targeted genotyping (8 common mutants) -> 94%
full sequencing = 99%
What are the hemoglobinopathies? What method is often used to detect thes?
diverse groupw of inhierited blood disorders
hemoglobin electrophoresis
What are some of the Beta-globinopathies? Gene?
Beta-thal (Major, Intermedia, MInor/Carrier)
Sickle cell (HbS)
sickle/beta-thal
Other(HbC, HbE, HbD, and more)
HBB
What gene(s) are associated with alpha-thalassemia?
HBA1/2
What genotype would you expect in a normal individual for HBA1/2?
aa/aa
What genotype would you expect in a carrier individual for HBA1/2? (3 types)
silent: aa/a-
carrier (trans): a-/a-
carrier (cis): aa/–
What two severe conditions are associated with alpha-thal genes? treats?
HbH (a-/–) -> monthly blood transfusions
Bart disease or hydrops fetalis (–/–) -> significant anemia, requires fetal blood transfusion, must be caught 1st tri
How can we screen for hemoglobinopathies?
- CBC with MCV
- Hemoglobin electrophoresis
- targeted mutation
- sequencing
What are some challenges w/ ethnicity based screening?
pop admixture uncertain ancestry adoption defining options for Jewish screening consanguinity Labor and cost
What’s the rationale behind carrier screening (expanded)?
single gene conditions are collectively common (10% of pediatric admission and 20% of infant mortality)
- 1/280 births impacted by mendelian disorder
- rare conditions can be prevetned, or early treatment can be offered
- carriers creening whole pop may cost less than treating affected children
How is ECS done?
panel-based (size/# of genes is lab based)
offer same panel to all pts
What types of conditions does the ACMG say should be in ECS?
- disease should cause at-risk ppl to consider prenatal dx
- -profound: shortend lifespane, ID
- -severe: detath in early adulthood, impaired mobility or mlaformation of internal organ
- -moderate: neurosensory impairment, immune deficiency, cancer, mnetal illness, dysmorphic features
disease w/ variable expressivity or incomplete penetrance should be transparnet and OPTIONAL
pts must provide consent for conditions that are adult-onset in offspring
What are the benefits of ECS?
testing for multiple conditions
address admixture, ancestral uncertainty
potentilly customizable panels
potential for reduced costs
40-60% screen positive rate if sequenced
identifies risk couples
LImitations and challenges for ECS?
routine hematology and biochem remain guideline-driven gold standard for hemoglobinopathise and tay-sachs
residiual carrier risks still present
increased screen positive rate
incidental findings
