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Prenatal genetics > Week 6: Carrier screening > Flashcards

Week 6: Carrier screening Flashcards

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1
Q

T/F ACOG says carrier screening should be offered to every pregnant person

A

True!

Ideally should be performed before pregnancy

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2
Q

T/F Carrier screening can replace newborn screening

A

False!

Carrier screening does not replace newborn screening and newborn screening does not replace the potential value of carrier screening

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3
Q

Should cystic fibrosis screening be offered to everyone or just certain ethnic groups?

A

Everyone

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4
Q

Main feature of cystic fibrosis? What gene causes?

A

-Buildup of thick, sticky mucus leading to progressive respiratory system damage and chronic digestive problems
-Most men with CF have congenital bilateral absence of the vas deferens (CBAVD)
-Gene: CFTR
-Over 2,000 mutations reported, deltaF508 most common

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5
Q

What is the carrier frequency for CF in white population?

A

1/25

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6
Q

What is something that not all labs report for CF carrier screening that can affect the severity and penetrance?

A

T and TG tract

In patients with 5T, the length of the TG tract affects the potential severity and penetrance

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7
Q

What T tract is clinically significant? Which T tracts do not impact gene function?

A

5T tract clinically significant

7T and 9T don’t impact function

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8
Q

What TG tract is clinically benign? What TG tracts are relevant for for severity?

A

10TG clinically benign

11TG, 12TG, 13TG more relevant

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9
Q

Describe generally genotype-phenotype correlation for CF in relation to pancreatic function and pulmonary function

A

-Some correlation between genotype and phenotype seen in context of pancreatic function
-Severity of pulmonary disease among individuals with identical genotype varies

-Severity of variant R117H depends on presence of variation in the poly T tract

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10
Q

Describe the effect for patients who have a CF-causing variant plus a p.Arg117His and the 5T variant in cis?

A

Patients usually develop lung disease of CF, moderate/severe mutation

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11
Q

Describe the effect for patients who have a CF-causing variant plus a p.Arg117His and the 7T variant or 9T variant?

A

Highly variable phenotype ranging from mild lung disease to asymptomatic

Often not reported on carrier screening

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12
Q

Who should SMA carrier screening be offered to?

A

Anyone pregnant or considering pregnancy

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13
Q

Describe SMA

A

-Degeneration of the spinal cord motor neurons that leads to atrophy of skeletal muscle and weakness, eventual respiratory failure
-Different types of SMA with different onset and progression
-SMN1 gene adjacent to SMN2 gene (SMN2 disease modifier)

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14
Q

If a lab performing SMA carrier screening looked for presence/absence of SMN1 gene, what could be missed?

A

Point mutations could be missed! These could still cause disease

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15
Q

What is a silent carrier of SMA?

A

When someone carriers two copies of SMN1 in cis and has no copies present on other allele

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16
Q

Describe the gene product produced by SMN2

A

-Some portion of SMN2 transcripts create full length stable protein but most is unstable
-The number of copies of SMN2 which can offset malfunctioning SMN1 genes determines SMA severity and the patient’s age of onset- but not 100% predictive

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17
Q

What type of changes in hemoglobin occur related to hemoglobinopathies?

A

Qualitative changes!

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18
Q

What type of changes in hemoglobin occur related to thalassemias?

A

Quantitive changes!

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19
Q

What is the prevalence of sickle cell trait among African Americans?

A

1/10

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20
Q

Briefly describe HbC disease

A

-Hemoglobin C disease: variant in HBB leads to decreased solubility of RBCs=microcytic and abnormally shaped RBCs
-May be asymptomatic for some
-More severely affected patients can experience anemia and splenomegaly
-Affected individuals may be increased risk for infection and pain

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21
Q

T/F hemoglobin variants are always inherited in silo

A

-False! HbC disease can be inherited with other hemoglobin variants
-HbSC: typically milder course than HbSS

22
Q

What does screening for hemoglobinopathies look like?

A

-Hemoglobin electrophoresis: measuring levels of various hemoglobins
-HBB gene sequencing

23
Q

Briefly describe result of alpha thalassemia on hemoglobin

A

-Whole gene deletions in HBA1/HBA2 most common cause
-Alpha thal causes reduced production of alpha chains
-Due to shortage, beta tetramers are produced (hemoglobin H)
+This is an unstable
hemoglobin!

24
Q

What ethnicity has the highest carrier frequency of alpha thalassemia?

A

Southeast Asian: 1/7

25
Q

Is the risk greater for individuals of Asian background or African background to have a child affected with Hb Bart (incompatible with life)?

A

Greater risk for Asian population- more likely to carry mutations in cis

26
Q

Briefly describe the result of beta thalassemia on hemoglobin

A

-Beta thal causes reduced production of beta chains= alpha tetramers produced=unstable hemoglobin

27
Q

Regarding thalassemias, what lab values may indicate whether to be suspicious of trait?

A

-Low MCV
-High A2

Sequencing is best screening test for thalassemias, especially alpha thal

28
Q

Who should receive carrier screening for fragile X?

A

-Recommended for females with family hx of fragile X-related disorders or intellectual disability suggestive of fragile X
-If female has unexplained ovarian insufficiency or failure or elevated FSH level before age 40yr

29
Q

What gene variant causes fragile X?

A

-CGG repeats in FMR1
-Rarely point mutations or deletions

30
Q

What are the ranges for CGG repeats for normal, gray zone/intermediate, premutation, and full mutation related to fragile X?

A

-Normal: <45
-Gray zone: 45-54
-Premutation: 55-200
-Full mutation: >200

31
Q

What risk is associated with the gray zone/intermediate repeat length range for fragile X?

A

Someone in gray zone at risk for having child that is not affected with fragile X but could get premutation

32
Q

At how many maternal CGG repeats does the risk increase for probable expansion to full mutation in child?

A

55 repeats

33
Q

What is the main risk factor for expansion in fragile X?

A

-Number of maternal repeats
-Other factors: AGG interruptions, fetal sex

AGG interruptions can help stabilize repeats!
AGGs generally don’t help after 90 repeats tho (high risk for expansion)

34
Q

What is fragile X-associated tremor/ataxia syndrome (FXTAS)?

A

-Development of intention tremor and progressive cerebellar ataxia after age 50
-Affects ~46% of male ~12% female PM carriers

35
Q

What is fragile X-associated primary ovarian insufficiency (FXPOI)?

A

-Cessation of menses prior to age 40
-Occurs in ~20% women with a PM

36
Q

T/F at the time of CVS, methylation has been established and can reliably be measured

A

False!
At the time of CVS methylation has not been established and probably just need to go with amniocentesis

37
Q

What disorders should we think about screening for with European ancestry?

A

Cystic fibrosis
SMA

38
Q

What disorders should we think about screening for with French Canadian and Cajun ancestry?

A

Tay-Sachs
Cystic Fibrosis

39
Q

What disorders should we think about screening for with Hispanic ancestry?

A

Cystic Fibrosis
Beta Thalassemia
SMA

40
Q

What disorders should we think about screening for with Mediterranean ancestry?

A

Beta thalassemia
Alpha thalassemia
Cystic fibrosis
Sickle cell

41
Q

What disorders should we think about screening for with African ancestry?

A

Sickle cell
Alpha thalassemia
Beta thalassemia
Cystic fibrosis
SMA

42
Q

What disorders should we think about screening for with Ashkenazi Jewish ancestry?

A

Gaucher disease
Cystic fibrosis
Tay-Sachs disease
Fam. dysautonomia
Canavan disease
SMA
And more!

43
Q

What disorders should we think about screening for with Asian ancestry?

A

Alpha thal
Beta thal
SMA
Cystic fibrosis

44
Q

Briefly describe Tay Sachs disease

A

-Lysosomal storage disorder leading to neurodegenerative changes and fatal health complications
-Features: progressive weakness, loss of motor skills, declined visual attentiveness, increased exaggerated startle response
-Cherry red spot in eye
-Gene: HEXA
Carrier frequency AJ: 1/30
-Carrier frequency French Canadian: 1/50

45
Q

What does treatment look like for Tay Sachs?

A

Supportive care

46
Q

Briefly describe Gaucher disease

A

-Gene: GBA
-Lysosomal storage disorder leading to buildup of lipids specifically within bone marrow, spleen, liver
-Treatment: ERT, total splenectomy, supportive care
-Carrier frequency AJ: 1/15

47
Q

Describe the association between carrier status for Gaucher disease and Parkinson’s

A

-Potential relationship with Parkinson’s disease
-At this point, carrier status serves as a risk factor for PD due to reduced penetrance
-PD in GBA carriers is essentially indistinguishable from sporadic, potentially slightly earlier onset (~5yr)

48
Q

In individuals with Ashkenazi Jewish ancestry, does Tay Sachs or Gaucher disease have higher carrier frequency?

A

Gaucher disease has higher carrier frequency in AJ population

49
Q

Going above and beyond ancestry or population based carrier screening is referred to as what?

A

“expanded carrier screening”

50
Q

What results can yield from carrier screening?

A

Only pathogenic and likely pathogenic variants routinely reported

Prenatal genetics (9 decks)

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