Week 6: Carrier screening Flashcards
T/F ACOG says carrier screening should be offered to every pregnant person
True!
Ideally should be performed before pregnancy
T/F Carrier screening can replace newborn screening
False!
Carrier screening does not replace newborn screening and newborn screening does not replace the potential value of carrier screening
Should cystic fibrosis screening be offered to everyone or just certain ethnic groups?
Everyone
Main feature of cystic fibrosis? What gene causes?
-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
What is the carrier frequency for CF in white population?
1/25
What is something that not all labs report for CF carrier screening that can affect the severity and penetrance?
T and TG tract
In patients with 5T, the length of the TG tract affects the potential severity and penetrance
What T tract is clinically significant? Which T tracts do not impact gene function?
5T tract clinically significant
7T and 9T don’t impact function
What TG tract is clinically benign? What TG tracts are relevant for for severity?
10TG clinically benign
11TG, 12TG, 13TG more relevant
Describe generally genotype-phenotype correlation for CF in relation to pancreatic function and pulmonary function
-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
Describe the effect for patients who have a CF-causing variant plus a p.Arg117His and the 5T variant in cis?
Patients usually develop lung disease of CF, moderate/severe mutation
Describe the effect for patients who have a CF-causing variant plus a p.Arg117His and the 7T variant or 9T variant?
Highly variable phenotype ranging from mild lung disease to asymptomatic
Often not reported on carrier screening
Who should SMA carrier screening be offered to?
Anyone pregnant or considering pregnancy
Describe SMA
-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)
If a lab performing SMA carrier screening looked for presence/absence of SMN1 gene, what could be missed?
Point mutations could be missed! These could still cause disease
What is a silent carrier of SMA?
When someone carriers two copies of SMN1 in cis and has no copies present on other allele
Describe the gene product produced by SMN2
-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
What type of changes in hemoglobin occur related to hemoglobinopathies?
Qualitative changes!
What type of changes in hemoglobin occur related to thalassemias?
Quantitive changes!
What is the prevalence of sickle cell trait among African Americans?
1/10
Briefly describe HbC disease
-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
T/F hemoglobin variants are always inherited in silo
-False! HbC disease can be inherited with other hemoglobin variants
-HbSC: typically milder course than HbSS
What does screening for hemoglobinopathies look like?
-Hemoglobin electrophoresis: measuring levels of various hemoglobins
-HBB gene sequencing
Briefly describe result of alpha thalassemia on hemoglobin
-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!
What ethnicity has the highest carrier frequency of alpha thalassemia?
Southeast Asian: 1/7
Is the risk greater for individuals of Asian background or African background to have a child affected with Hb Bart (incompatible with life)?
Greater risk for Asian population- more likely to carry mutations in cis
Briefly describe the result of beta thalassemia on hemoglobin
-Beta thal causes reduced production of beta chains= alpha tetramers produced=unstable hemoglobin
Regarding thalassemias, what lab values may indicate whether to be suspicious of trait?
-Low MCV
-High A2
Sequencing is best screening test for thalassemias, especially alpha thal
Who should receive carrier screening for fragile X?
-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
What gene variant causes fragile X?
-CGG repeats in FMR1
-Rarely point mutations or deletions
What are the ranges for CGG repeats for normal, gray zone/intermediate, premutation, and full mutation related to fragile X?
-Normal: <45
-Gray zone: 45-54
-Premutation: 55-200
-Full mutation: >200
What risk is associated with the gray zone/intermediate repeat length range for fragile X?
Someone in gray zone at risk for having child that is not affected with fragile X but could get premutation
At how many maternal CGG repeats does the risk increase for probable expansion to full mutation in child?
55 repeats
What is the main risk factor for expansion in fragile X?
-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)
What is fragile X-associated tremor/ataxia syndrome (FXTAS)?
-Development of intention tremor and progressive cerebellar ataxia after age 50
-Affects ~46% of male ~12% female PM carriers
What is fragile X-associated primary ovarian insufficiency (FXPOI)?
-Cessation of menses prior to age 40
-Occurs in ~20% women with a PM
T/F at the time of CVS, methylation has been established and can reliably be measured
False!
At the time of CVS methylation has not been established and probably just need to go with amniocentesis
What disorders should we think about screening for with European ancestry?
Cystic fibrosis
SMA
What disorders should we think about screening for with French Canadian and Cajun ancestry?
Tay-Sachs
Cystic Fibrosis
What disorders should we think about screening for with Hispanic ancestry?
Cystic Fibrosis
Beta Thalassemia
SMA
What disorders should we think about screening for with Mediterranean ancestry?
Beta thalassemia
Alpha thalassemia
Cystic fibrosis
Sickle cell
What disorders should we think about screening for with African ancestry?
Sickle cell
Alpha thalassemia
Beta thalassemia
Cystic fibrosis
SMA
What disorders should we think about screening for with Ashkenazi Jewish ancestry?
Gaucher disease
Cystic fibrosis
Tay-Sachs disease
Fam. dysautonomia
Canavan disease
SMA
And more!
What disorders should we think about screening for with Asian ancestry?
Alpha thal
Beta thal
SMA
Cystic fibrosis
Briefly describe Tay Sachs disease
-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
What does treatment look like for Tay Sachs?
Supportive care
Briefly describe Gaucher disease
-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
Describe the association between carrier status for Gaucher disease and Parkinson’s
-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)
In individuals with Ashkenazi Jewish ancestry, does Tay Sachs or Gaucher disease have higher carrier frequency?
Gaucher disease has higher carrier frequency in AJ population
Going above and beyond ancestry or population based carrier screening is referred to as what?
“expanded carrier screening”
What results can yield from carrier screening?
Only pathogenic and likely pathogenic variants routinely reported
