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Molecular Diagnostics > Carrier Screening > Flashcards

Carrier Screening Flashcards

1
Q

Who should be carrier screening be offered to?

A

all patients: preconception, seeking infertility care, and during 1st or early 2nd trimester

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2
Q

What sort of reproductive decisions are available to those with carrier screening?

A 
IVF with PGT-M
donor gamete(s)/embryo
adoption
prenatal dx w/ CVSA or amnio -> prepare for birth, palliative care, etc.
not having children
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3
Q

What conditions do ACMG and ACOG say everyone should be screened for (2017)?

A

CF and SMA

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4
Q

What is the idea behind population-based carrier screening? Ex?

A

screen for conditions offered to everyone in general population

CF, SMA, Fragile X

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5
Q

What are the criteria for something to be included in population-based screening?

A

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

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6
Q

What’s incidence of CF carriers in European populations?

A

1/2500

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7
Q

If an individual with CF has tow different variants, their phenotype will:

A

follow the more mild variant

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8
Q

What gene is responsible for CF? What types of testing is done?

A

CFTR

most common mutations or full gene sequencing can be completed w/ del/dup

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9
Q

What the best way to find CF variants no matter the population?

A

sequencing +del/dup of CFTR gene

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10
Q

What’s the incidence of SMA? Carrier freq?

A

1/10,000

1/40-1/60

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11
Q

How is SMA classified?

A

based on age and maximum function attained?

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12
Q

95-98% of those with SMA are?

Other 2-5%?

A

homozygous for a deletion of SMN1 exon 7

compound het, deletion + point mutation

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13
Q

What percent of SMA variants are de novo?

A

2%

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14
Q

What can lead to a more milder phenotype in SMA?

A

increased SMN2 copy number

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15
Q

What percent of the population are silent SMA carriers? How’s this happen? How can we detect these?

A

3-4%

each SMN1 I is in cis

SNP in intron 7 (more likely)

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16
Q

When should we screen for Fragile X?

A

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

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17
Q

What is characteristic of individuals with FXS?

A
  • moderate ID in males, mild in females
  • autistic-like features
  • long narrow face, prominent ears
  • marco-orchidism
  • joint laxity
18
Q

What can we see in FXS premutation carries?

A

FXPOI (ovarian insufficency)
FXTAS (late onset >50y, M>F)
neuropsychriatric disorder and developmemntal and cognitive profile (anxiety, bipolar, depression, etc.)

19
Q

FXS is caused by:

A

expansion of CCG repeats in FMR-1 gene

20
Q

What’s the mechanism of FXS?

A

expansion of FMR1 leads to methylation -> lack of expression -> phenotype

21
Q

What are the ranges of CCG repeats in FXS?

A

<45: unaffected
45-54: intermediate
55-200: premutation
>200: full mutation

22
Q

What other tri-nucleotide repeat impacts FMR1 stability? How? Up to what # of CCG?

A

AGG

decreases chances of expansion when inherited

only effective if <80 CCGs

23
Q

What is the concept behind targeted-population-based carrier screening?

A

screening limited to particulat gropus o fpeople determined to be at higher risk for specific genetic disorders

condition is usually relatively common, ethnicity based

24
Q

What types of conditions are often included in targeted-population-screening- for AJ pops?

A 
Tay-sachs
Canavan
CF
familial dysautonomia
Gaucher
SMA
etc.
25
Q

What types of screening is completed for Tay-Sachs?

A

exnsyme-based

DNA based

26
Q

What enzyme is screened for in Tay-sachs? DR with enzyme screening?

A

Hexosaminidase A

98%

27
Q

What gene is sequenced in Tay-Sachs? Different methods and DRs?

A

HEXA

targeted genotyping (8 common mutants) -> 94%

full sequencing = 99%

28
Q

What are the hemoglobinopathies? What method is often used to detect thes?

A

diverse groupw of inhierited blood disorders

hemoglobin electrophoresis

29
Q

What are some of the Beta-globinopathies? Gene?

A

Beta-thal (Major, Intermedia, MInor/Carrier)

Sickle cell (HbS)

sickle/beta-thal

Other(HbC, HbE, HbD, and more)

HBB

30
Q

What gene(s) are associated with alpha-thalassemia?

A

HBA1/2

31
Q

What genotype would you expect in a normal individual for HBA1/2?

A

aa/aa

32
Q

What genotype would you expect in a carrier individual for HBA1/2? (3 types)

A

silent: aa/a-
carrier (trans): a-/a-
carrier (cis): aa/–

33
Q

What two severe conditions are associated with alpha-thal genes? treats?

A

HbH (a-/–) -> monthly blood transfusions

Bart disease or hydrops fetalis (–/–) -> significant anemia, requires fetal blood transfusion, must be caught 1st tri

34
Q

How can we screen for hemoglobinopathies?

A
  • CBC with MCV
  • Hemoglobin electrophoresis
  • targeted mutation
  • sequencing
35
Q

What are some challenges w/ ethnicity based screening?

A 
pop admixture
uncertain ancestry
adoption
defining options for Jewish screening
consanguinity
Labor and cost
36
Q

What’s the rationale behind carrier screening (expanded)?

A

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
37
Q

How is ECS done?

A

panel-based (size/# of genes is lab based)

offer same panel to all pts

38
Q

What types of conditions does the ACMG say should be in ECS?

A
  • 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

39
Q

What are the benefits of ECS?

A

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

40
Q

LImitations and challenges for ECS?

A

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

Molecular Diagnostics (6 decks)

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