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ABGC > Carrier Screening Conditions > Flashcards

Carrier Screening Conditions Flashcards

1
Q

alpha thalassemia

A

-common in SE asian (1 in 20) and African (1 in 3-1 in 20) ethnicity
-reduced alpha globin produced
+hydrops fetalis/Hb Bart in severe cases-zero alpha globin copies
+HbH disease causes hemolytic anemia-1 copy alpha globin
+trait carrier has mild anemia and cis v. trans arrangement affects risk for kids-2 copies
+silent carrier-3 copies

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2
Q

beta thalassemia

A

-common in Mediterranean (1 in 25), Hispanic (1 in 30-1 in 50), SE asian (1 in 60) and African (1 in 10-1 in 75) ethnicity
-mutation or loss of beta globin production
+causes imbalance in globin production-excess alpha chains
-leads to precipitate and ineffective erythropoiesis
+ increased HbA2 seen because of decreased beta globin

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3
Q

sickle cell anemia

A
  • common in African (1 in 10) and mediterranean (1 in 40) ethnicity
  • mutation of beta globin chain
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4
Q

CF carrier rates

A
  • Hispanic (1 in 46)
  • Caucasian and Mediterranean (1 in 25)
  • AJ (1 in 24)
  • African (1 in 65)
  • Asian (1 in 94)
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5
Q

CF genetics

A

-CFTR gene
-greater than 1500 mutations identified
+70% affected patients have > or = to 1 deltaF508 mutation
+23 mutations on pan-ethnic panel
-limited genotype-phenotype correlation
-incidence of 1/2500-1/3500

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6
Q

CF testing and diagnosis

A

-familial testing for known variants
-identification of carriers by population-based screening
-NBS
+normal does not necessarily rule it out, can also see false positives
-sweat test=gold standard
-abnormal nasal potential difference + clinical features
-two genetic mutations + clinical features
+GT not always diagnostic due to sensitivity
*sputum cultures not sensitive or specific

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7
Q

CF implications

A

-shortened lifespan: 40y, also most common AR lethal disorder in caucasians
-damage to many organ systems-lungs, GI, pancreas, skin, liver, reproductive organs
+non-classic symptoms: pancreatitis, CBAVD (80% w/CFTR mutation)
+2-3% risk when echogenic bowel seen prenatally
-50% risk for diabetes

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8
Q

poly pyrimidine tract

A

-within intron 8
-comes in 5T, 7T, 9T
+carriers with one WT mutation and 5T more likely to have CBAVD
+5T enhances severity of mild (ex: R117H) mutation
-longer thymine repeats increase effective mRNA splicing

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9
Q

SMA/Werdnig Hoffman dz implications

A

-most common inherited cause of infant death
-progressive symmetrical, proximal muscle weakness and degeneration of lower motor neurons in spinal cord and brainstem (anterior horn cells)
+without signaling from neurons, muscles weaken
+develop loss of of head and neck and motion control

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10
Q

SMA genetics

A

-mutation of SMN1 on 5q-complete loss of four exon 7 and 8 copies
+95-98% patients with homozygous deletions
+2% de novo (rare compared to other AR conditions)
+no intragenic mutations
-carrier status: 1-carrier, 2-reduced risk, 3-reduced risk
-cis vs trans arrangement can affect outcomes-NOT detected on carrier screening, but g. 27134T>G SNP absence helps
-SMN2 copies can modify severity-3+ copies=lessened phenotype
-incidence of 1 in 11000

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11
Q

SMA types

A
  • Type 1: classic, most common, most severe with onset <6mo and death at 2-3y
  • Type 2: onset 6-12mos, sit, but can’t walk
  • Type 3: onset >12mos-learn to walk
  • Type 4: adult onset after 30y
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12
Q

SMA carrier rates

A

-caucasian-1 in 47
-AJ-1 in 67
-Asian-1 in 59
-Hispanic-1 in 68
+greater number of 2 copy carriers, higher residual risk
-African-1 in 72
+greater number of 3 copy carriers, but reduced detection makes 2 copy carrier residual risk less understood
-Asian Indian-1 in 52
*overall considered 1 in 54 carrier rate

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13
Q

Fragile X genetics

A

-mutation of FMR1 gene and intronic CGG repeats
+silencing of FMR1 gene function by abnormal methylation
+anticipation by expansion of maternal permutation during meiosis
-1 in 250 carrier risk without family hx

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14
Q

Fragile X full mutation

A

200+ CGG repeats

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15
Q

Fragile X premutation

A

55-200 CGG repeats
+high risk of expansion in offspring
+56 is the smallest known permutation to have expanded

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16
Q

Fragile X intermediate/gray zone

A

45-55 CGG repeats

+no risk of having an affected child, but predisposes next generation

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17
Q

Fragile X mutation negative

A

<45 CGG repeats

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18
Q

AGG interruptions

A
  • modify risk of expansion in permutation carriers

- increased numbers of repeats stabilize more

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19
Q

Fragile X symptoms

A

-mostly causes males to have dysmorphic features, autism & ID, cryptorchidism
+due to lyonization females can have normal development (25%), milder phenotype (50%), or severe “full mutation” presentation (25%); 50% risk for some level of ID
-premutation carriers at risk to have POI (20% POI cases), FXTAS (75% risk for male carriers, 8-16.5% for female carriers)
+increased number of repeats may increase risk for premutation condition onset

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20
Q

children of males with Fragile X

A

tend to have intermediate repeats

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21
Q

AJ carrier screening

A

-founder mutations in certain conditions for EE Jewish ancestry
+carrier frequency 1 in 3 for conditions recommended to be tested

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22
Q

Non-AJ Jewish ancestry screening

A
  • ex: sephardic, mizrahi
  • similar to pop-based carrier screening
  • higher risk for hemoglobinopathies
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23
Q

AJ carrier frequencies

A
  • CF-1 in 24
  • familial dysautonomia and Tay-Sachs- 1 in 30
  • Gaucher dz 1-1 in 15
  • canavan-1 in 57
  • others (MSUD, Joubert, familial hyperinsulinism, FA, MPSIV, NPD-A, GSD1A, Usher 1F+III, Walker-Warburg, Bloom, nemaline myopathy, dihydrolipoamide dehydrogenase deficiency
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24
Q

Tay-Sachs testing

A

-enzyme analysis of leukocytes/WBCs
+has to be leukocytes if patient pregnant or on BC
+identifies carriers with less common mutations
+can identify pseduodeficiency and intermediate alleles
-panel genetic testing
+only picks up a few founder mutations
+should follow enzyme analysis to determine expected phenotype

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25
Q

HbA

A

alpha2, beta2

26
Q

HbA2

A

alpha2, delta2

27
Q

HbF

A

alpha2, gamma2

-more prevalent prenatally or when beta globin mutated

28
Q

beta globin mutations

A

affects structure and quantity of produced chain

29
Q

HgS

A

-sickled cells frisbee shaped

30
Q

HgC

A

-RBCs are like “ball pit balls”

31
Q

HgEE

A
  • common in Asian populations

- causes slight anemia and hepatosplenomegaly

32
Q

beta + mutations

A

maybe splicing mutations in beta globin, sometimes functions

33
Q

beta 0 mutations

A

no function of beta globin, usually nonsense mutations

34
Q

normal MCV

A

<80

35
Q

alpha-beta thal

A

double heterozygotes with lessened symptom severity because the ratios of globin chains aren’t as different

36
Q

hemoglobinopathy testing

A

-need CBC, heme-elec

+this can differentiate between affected, carrier and unaffected

37
Q

Tay-Sachs genetics

A

-mutations in HEXA disrupt beta-hexosaminidase function
+housekeeping gene in all tissues
+GM2 gangliosides no longer broken down

38
Q

Tay-Sachs types

A 
-Type 1-infantile
\+onset prior to 6m
\+death by 3-5y
-Type 2-juvenile
\+evident by 2-10y
\+death by 10-15y
-Type 3-late/adult
\+evident in adolescence or adulthood
\+variable presentation
\+neuropsychiatric sequelae, sometimes misdiagnosed as MS or only psychiatric abnormality
39
Q

G269S mutation

A

found only in late onset Tay-Sachs in combination with a null mutation

40
Q

infantile Tay-Sachs phenotype

A

toxic accumulation of GM2, especially in spinal cord and brain
+cherry-red spot
+loss of milestones
+development of blindness, deafness, etc

41
Q

Sephardic Jewish carrier testing

A
  • beta-thal
  • Tay-Sachs (Moroccan Jews)
  • familial mediterranean fever (N. African and Iraqi Jews, milder phen in AJ)
  • G6PD deficiency (Kurdish Jews)
  • GSD3 (North African Jews)
  • hereditary inclusion body myopathy (Iranian+Persian Jews)
42
Q

CF treatment and management

A

*earlier intervention improved IQ points, nutrition, but screened children had worse CXR in one study
-daily respiratory therapy (often mechanical), digestive enzymes, medications to improve lung function
-some targeted therapies
+G551D gating abnormality drug that allows CFTR protein to go into body-slight improvement in pulmonary function, reduced infection
-greater nutrition has better prognosis
-prescription of antibiotics for infection

43
Q

repeat size in maternal FMR1

A

lower numbers of CGG repeats in premutation reduces the risk for expansion in a child

44
Q

POI in Fragile X carriers

A

women with POI or elevated FSH of unknown cause before 40y should be offered FRAX carrier screening
-20x more likely than general population with FRAX permutation

45
Q

orphan diseases

A
  • incidence of <1 in 2000
  • 5000-7000 different types
  • affect 6-8% of world population
  • 80% genetic
46
Q

conditions to be excluded from ECS

A
  • adult onset conditions

- high incidence with low penetrance (ex: MTHFR)

47
Q

CF and lung disease cycle

A

-impaired airway clearance occurs due to sticky mucous
+simple osmosis cannot occur to allow cilia to beat
-unusual and characteristic bacterial colonization of the airway
+CF mucous is a great medium (carbs)
-inflammatory response generated
+neutrophils try to release proteolytic enzymes and oxygen free radicals causing epithelial damage
-collateral damage of response is tissue damage, which then further impairs clearance abilities

48
Q

CF classes

A

-I: complete protein absence (null), missense, nonsense and terminating
+G542X, R553X, W1282X
-II: full length protein produced, but cannot reach epithelial surface
+delF508, N1303k
-III: protein produced, but chloride conduction fails
+G551D
-IV: impaired function at cell surface, “conduction”, milder phenotype
+R117H
-V: splicing anomalies, decreased protein production, milder phenotype
+3489+10T>C

49
Q

CF clinical features

A
  • chronic sinopulmonary disease (ENT, pulmonology)
  • GI or nutritional abnormalities, FTT
  • disease in first degree relative
  • meconium ileum followed by confirmatory testing
50
Q

modifier genes in CF

A

-can partially relay phenotype variability in individuals with identical mutations
+TGFB: cytokine involved in injury response and wound healing
+mannose binding lectin: effects body’s ability to handle bacteria
+intestinal disease modifiers (meconium ileus)

51
Q

CF heterozygous advantage

A

-possibly thought to be related to salmonella infection resistance, resistance to toxin-mediated diarrhea

52
Q

beta-globin nonsense mutations

A

these mutations in exon 3 of the gene cause a severe AD anemia caused by the dominant negative effects of the abnormal protein

53
Q

deltaF508

A

CFTR mutation that significantly effects protein folding
-failure to fold properly causes copies to be stuck in ER, for homozygotes this means no protein reaches the cell membrane

54
Q

SMA new deletions

A

in most cases due to crossing over in paternal spermatogenesis

55
Q

Canavan disease

A

-AR mutations of ASPA gene
+increased incidence in AJ pop
-severe infantile form causes leukodystrophy
-affected children often fail to meet milestones, have hypotonia, FTT
-feeding and swallowing difficulties, seizures and sleep disturbance are also common
-macrocephaly is also seen

56
Q

Bloom syndrome

A

-AR mutation in BLM gene affecting RecQ helicase activity
-rare affecting only a few hundred individuals 1/3 of whom are AJ
-phenotype includes:
+short stature with persistent LBW
+skin abnormalities such as butterfly rash of face, hypo and hyperpigmentation and teleangectasias (even in the eyes); majorly increased cancer risk
+high pitched voice
+long, narrow facies, micrognathia, prominent ears and nose
+increased risk for diabetes, recurrent infection, COPD and infertility

57
Q

Joubert syndrome

A
  • AR mutation of 30 genes affects primary cilia function
  • Molar tooth sign brain anomaly on ultrasound
  • hyperpnea or apnea in infancy
  • ID and DD
  • dysmorphic features: broad forehead, ptosis, hypertelorism, arched eyebrows, triangle shaped mouth, low-set ears
  • ocular motor apraxia, sometimes coloboma or retinal dystrophy
  • PCKD, nephronophthisis and endocrine problems
58
Q

beta thal major

A

-B0,B0 in HBB
+causes ineffective erythropoiesis
-usually presents between 6-12mo during switch off of predominantly HbF
-can cause pallor, jaundice, irritability, FTT and hepatosplenomegaly
-heart enlargement and misshaping of the bones may also occur
-requires regular transfusions and chelation therapy
+w/o this leads to severe anemia, BM hyperplasia causing classic facies, GR, heart failure and death
+iron overload leads to endocrine issues, additional heart stressors, skin pigmentation and cirrhosis

59
Q

beta thal intermedia

A
  • B+B+ or B+B0, or B+ with 2+alpha genes on one or both chromosomes, or B+ with dominant thal gene, or persistence of HbF
  • reduced alpha/beta imbalance, increased gamma chain production (higher HbA2, HbF)
  • typical onset between 2-7y, anemia can worsen sometimes ex: puberty
  • splenomegaly, bony changes, delayed puberty, thin with normal height
  • transfusions and chelation not required, but improve QoL
60
Q

SCD

A
  • SS mutations in HBB
  • anemia caused by premature breakdown of RBCs
  • jaundice
  • pain crises when sickled cells get “stuck” can lead to damage of heart, lungs, brain, kidneys and spleen related to reduced oxygen flow
  • pulmonary hypertension in 1/3 patients
  • management: antibiotics and hydroxyurea to reduce the risks of infection and crises, pain management during crises
61
Q

alpha thal

A

-AR mutations of HBA1, HBA2
+loss of allele function leads to a reduction in the produced Hb and anemia
-anemia can cause pallor, fatigue, weakness
-management for HbH can include transfusions during crises and chelation

ABGC (34 decks)

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