Reproductive Carrier Screening

Question 1

What is carrier screening?

Answer 1

genetic testing carried out on an individual who is not known to have symptoms of a genetic condition but may have a variant within a gene associated with disease

Question 2

What are the two options for carrier screening?

Answer 2

sequential (female partner is screened first, then the male is screened for any positive results)
concurrent (both partners are tested at the same time)

Question 3

What factors should be included in informed consent for carrier screening?

Answer 3

purpose
voluntary nature of screening
range of symptoms and severity
risk of carrier status
inheritance pattern/risk of affected offspring
meaning of positive and negative results
factors to consider in decision-making
further testing necessary for prenatal diagnosis 
incidental findings

Question 4

What is the difference between genotyping and sequencing?

Answer 4

genotyping is an analysis of common mutations (historically carrier screening) whereas sequencing looks at the full gene (historically diagnostic)

Question 5

What features are associated with genotyping?

Answer 5

relatively cheap
relatively fast
straightforward results for pre-defined set of pathogenic variants

Question 6

What features are associated with sequencing?

Answer 6

expensive
time consuming
variants of uncertain significance (VUS)
coverage not complete

Question 7

Name some causes of high frequency of certain conditions in certain ethnic groups.

Answer 7

founder effect
genetic drift
historical/social factors
selective advantage of heterozygotes
consanguinity

Question 8

Provide examples for selective advantages for heterozygotes.

Answer 8

carriers of sickle cell have decreased rates of malaria

carriers of CF have decreased rates of cholera

Question 9

What is population bottleneck?

Answer 9

sharp reduction in size of population due to environmental events (famines, earthquakes, floods, etc.) or human activities (genocide, etc.)

Question 10

What is founder effect?

Answer 10

marked population decrease, migration, or isolation

Question 11

What is genetic drift?

Answer 11

change in frequency of an existing gene variant in a population due to random sampling of organisms (occurs for reasons unrelated to carrying the variant)

Question 12

What conditions are on reproductive screening for the general population?

Answer 12

CF
spinal muscular atrophy
Fragile X syndrome
Hemoglobinopathies

Question 13

What is CF?

Answer 13

mutation in the CFTR gene on chromosome 7
AR
chronic lung disease with GI malabsorption
frequent infections

Question 14

What is spinal muscular atrophy?

Answer 14

SMN1 copy number variant (number of SMN2 alleles can modify the phenotype) on chromosome 5
AR
characterizwd by progressive muscle weakness and atrophy due to degeneration of motor neurons in the spinal chord and brainstem

Question 15

What is fragile X syndrome?

Answer 15

FMR1 trinucleotide repeat expansion
X-linked- anticipation
most common inherited form of intellectual disability (moderate intellectual disability, developmental delay, autism, ADHD, poor eye contact, hand flapping, hand biting, tantrums)
characteristic facial appearance (large head, long face, prominent forehead and jaw, protruding ears)
about 50% of females with mutation causal of Fragile X are symptomatic

Question 16

Describe the correlation between repeats in Fragile X and the phenotypic expression.

Answer 16

<45 repeats: normal with no clinical features (stable)
45-54 repeats: intermediate with no clinical features (uncertain)
55-200 repeats: premutation with Fragile X tremor and ataxia syndrome, premature ovarian insufficiency (unstable)
>200 repeats: full mutation, Fragile X syndrome (unstable)

Question 17

What is Fragile X Tremor and Ataxia syndrome?

Answer 17

late onset neurodegenerative disorder characterized by cerebellar ataxia, intention tremor, short term memory loss, etc
40-45% of males with premutations older than 50 (penetrance is age related)
8-16.5% female premutation carriers

Question 18

What is Premature Overian Insufficiency?

Answer 18

cessation of menses prior to age 40

premutations account for 4-6% of cases (46,XX POI)

Question 19

How is Fragile X tested for?

Answer 19

AGG trinucleotide repeat genotyping (available for intermediate and small premutation allele carriers)

Question 20

When is screening for Fragile X recommended?

Answer 20

individuals who have a family history of it or unexplained intellectual disability
women experiencing fertility problems associated with elevated FSH levels

Question 21

What are hemoglobinopathies?

Answer 21

a group of disorders caused by the abnormal production or structure of the hemoglobin molecule
HBA1, HBA2, HBB genes
AR

Question 22

In what populations are hemoglobinopathies more common?

Answer 22

Mediterranean, African American, Caribbean, West African, West Indian, Mexican, Central American, Asian, Middle Eastern, and South Asian populations

Question 23

List examples of hemoglobinopathies.

Answer 23

sickle cell anemia, beta-thalassemia, hemoglobin C disease

Question 24

What are the steps for screening for hemoglobinopathies?

Answer 24

1. CBC- MCV and MCH
   quantitative hemoglobin electrophoresis
2. molecular testing (if clinically indicated)

Question 25

What is Beta Thalassemia?

Answer 25

reduced synthesis of the beta globin subunit

Question 26

Describe the different types of beta thalassemia.

Answer 26

thalassemia major: severe anemia, hepatosplenomegaly, failure to thrive
thalassemia intermedia: presents later with milder anemia
beta-thalassemia trait: Low mHgA, High HgA2, Low MCV

Question 27

What is sickle cell disease

Answer 27

group of disorders with at least one hemoglobin S allele (pGlu6Val) and a second pathogenic variant in the HBB gene
characterized by intermittent vaso-occlusive events, chronic hemolytic anemia, frequent infections, periodic episodes of pain, pulmonary hypertension, etc

Question 28

Describe the kinds of alpha thalassemia.

Answer 28

Hemoglobin Bart Syndrome: fetal onset, hydrops fetalis, severe anemia
Hemoblobin H disease: anemia, splenomegaly, mild jaundice, variable bone changes, etc

Question 29

All conditions grouped together as the Jewish Genetic Diseases exhibit a ________ phenomenon.

Answer 29

founder mutation

Question 30

What is Tay Sachs disease?

Answer 30

HEXA
AR
progressive neurodegenerative disorder characterized by progressive weakness, loss of motor skills, decreased attentiveness, increased startle response, seizures, blindness, spasticity, paralysis, and death

Question 31

Tay Sachs has two _______ that are ______.

Answer 31

pseudodeficiency alleles
not associated with disease, however are associated with degradation of the synthetic/artificial substrate used in enzyme activity analysis.

Question 32

What is the Dor Yeshorim program?

Answer 32

confidential premarital genetic screening program for Ashkenazi Jewish people used to reduce the risk of two carriers having affected children
standard panel tests for 10 conditions
optional panel tests for 7 conditions

Question 33

What indications would warrant screening of someone with Jewish descent?

Answer 33

one Jewish grandparent

if only one partner is Ashkenazi Jewish, offer them testing first and then the partner if carrier status is identified

Question 34

What Jewish Genetic Diseases are included in both the ACMG and ACOG standards of care?

Answer 34

Tay Sachs
Cystic Fibrosis
Canavan disease
familial dysautonomia

Question 35

What are the Joint Statement (2015) inclusion criteria for an expanded pan-ethnic carrier screening panel?

Answer 35

1. conditions screened for should encompass one or more of the following
   a. cognitive disability
   b. need for surgical or medical intervention
   c. effect on quality of life
   d. conditions in which prenatal dx may result in prenatal intervention to improve outcome/immediate care of newborn, delivery management, prenatal education of parents regarding special needs following birth

Question 36

What are the Joint Statement (2015) exclusion criteria for an expanded pan-ethnic panel?

Answer 36

a. condition is most often associated with an adult-onset phenotype and molecular testing cannot distinguish between childhood and adulthood onset
b. variants have a high allele frequency and low penetrance
c. most appropriate approach to screening is something other than molecular testing, often because of low penetrance
“variants of uncertain significance detected by sequencing should not be reported”

Question 37

What steps should be included in post-carrier screening counseling?

Answer 37

review info regarding any condition an individual was identified to be a carrier of (clinical presentation; inheritance pattern)
discuss residual risk
provide detailed info on prenatal diagnosis as well as options for IVF for at-risk couples (genotype/phenotype correlation)
encourage sharing of information with family memners
discuss perception of risk