Carrier Screening

Question 1

Who should be carrier screening be offered to?

Answer 1

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

Question 2

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

Answer 2

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

Question 3

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

Answer 3

CF and SMA

Question 4

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

Answer 4

screen for conditions offered to everyone in general population

CF, SMA, Fragile X

Question 5

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

Answer 5

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

Question 6

What’s incidence of CF carriers in European populations?

Answer 6

1/2500

Question 7

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

Answer 7

follow the more mild variant

Question 8

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

Answer 8

CFTR

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

Question 9

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

Answer 9

sequencing +del/dup of CFTR gene

Question 10

What’s the incidence of SMA? Carrier freq?

Answer 10

1/10,000

1/40-1/60

Question 11

How is SMA classified?

Answer 11

based on age and maximum function attained?

Question 12

95-98% of those with SMA are?

Other 2-5%?

Answer 12

homozygous for a deletion of SMN1 exon 7

compound het, deletion + point mutation

Question 13

What percent of SMA variants are de novo?

Answer 13

2%

Question 14

What can lead to a more milder phenotype in SMA?

Answer 14

increased SMN2 copy number

Question 15

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

Answer 15

3-4%

each SMN1 I is in cis

SNP in intron 7 (more likely)

Question 16

When should we screen for Fragile X?

Answer 16

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

Question 17

What is characteristic of individuals with FXS?

Answer 17

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

Question 18

What can we see in FXS premutation carries?

Answer 18

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

Question 19

FXS is caused by:

Answer 19

expansion of CCG repeats in FMR-1 gene

Question 20

What’s the mechanism of FXS?

Answer 20

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

Question 21

What are the ranges of CCG repeats in FXS?

Answer 21

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

Question 22

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

Answer 22

AGG

decreases chances of expansion when inherited

only effective if <80 CCGs

Question 23

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

Answer 23

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

condition is usually relatively common, ethnicity based

Question 24

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

Answer 24

Tay-sachs
Canavan
CF
familial dysautonomia
Gaucher
SMA
etc.

Question 25

What types of screening is completed for Tay-Sachs?

Answer 25

exnsyme-based DNA based

Question 26

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

Answer 26

Hexosaminidase A 98%

Question 27

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

Answer 27

HEXA targeted genotyping (8 common mutants) -> 94% full sequencing = 99%

Question 28

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

Answer 28

diverse groupw of inhierited blood disorders hemoglobin electrophoresis

Question 29

What are some of the Beta-globinopathies? Gene?

Answer 29

Beta-thal (Major, Intermedia, MInor/Carrier) Sickle cell (HbS) sickle/beta-thal Other(HbC, HbE, HbD, and more) HBB

Question 30

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

Answer 30

HBA1/2

Question 31

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

Answer 31

aa/aa

Question 32

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

Answer 32

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

Question 33

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

Answer 33

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

Question 34

How can we screen for hemoglobinopathies?

Answer 34

- CBC with MCV - Hemoglobin electrophoresis - targeted mutation - sequencing

Question 35

What are some challenges w/ ethnicity based screening?

Answer 35

``` pop admixture uncertain ancestry adoption defining options for Jewish screening consanguinity Labor and cost ```

Question 36

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

Answer 36

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

Question 37

How is ECS done?

Answer 37

panel-based (size/# of genes is lab based) offer same panel to all pts

Question 38

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

Answer 38

- 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

Question 39

What are the benefits of ECS?

Answer 39

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

Question 40

LImitations and challenges for ECS?

Answer 40

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