Carrier Screening Conditions Flashcards
alpha thalassemia
-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
beta thalassemia
-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
sickle cell anemia
- common in African (1 in 10) and mediterranean (1 in 40) ethnicity
- mutation of beta globin chain
CF carrier rates
- Hispanic (1 in 46)
- Caucasian and Mediterranean (1 in 25)
- AJ (1 in 24)
- African (1 in 65)
- Asian (1 in 94)
CF genetics
-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
CF testing and diagnosis
-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
CF implications
-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
poly pyrimidine tract
-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
SMA/Werdnig Hoffman dz implications
-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
SMA genetics
-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
SMA types
- 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
SMA carrier rates
-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
Fragile X genetics
-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
Fragile X full mutation
200+ CGG repeats
Fragile X premutation
55-200 CGG repeats
+high risk of expansion in offspring
+56 is the smallest known permutation to have expanded
Fragile X intermediate/gray zone
45-55 CGG repeats
+no risk of having an affected child, but predisposes next generation
Fragile X mutation negative
<45 CGG repeats
AGG interruptions
- modify risk of expansion in permutation carriers
- increased numbers of repeats stabilize more
Fragile X symptoms
-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
children of males with Fragile X
tend to have intermediate repeats
AJ carrier screening
-founder mutations in certain conditions for EE Jewish ancestry
+carrier frequency 1 in 3 for conditions recommended to be tested
Non-AJ Jewish ancestry screening
- ex: sephardic, mizrahi
- similar to pop-based carrier screening
- higher risk for hemoglobinopathies
AJ carrier frequencies
- 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
Tay-Sachs testing
-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
HbA
alpha2, beta2
HbA2
alpha2, delta2
HbF
alpha2, gamma2
-more prevalent prenatally or when beta globin mutated
beta globin mutations
affects structure and quantity of produced chain
HgS
-sickled cells frisbee shaped
HgC
-RBCs are like “ball pit balls”
HgEE
- common in Asian populations
- causes slight anemia and hepatosplenomegaly
beta + mutations
maybe splicing mutations in beta globin, sometimes functions
beta 0 mutations
no function of beta globin, usually nonsense mutations
normal MCV
<80
alpha-beta thal
double heterozygotes with lessened symptom severity because the ratios of globin chains aren’t as different
hemoglobinopathy testing
-need CBC, heme-elec
+this can differentiate between affected, carrier and unaffected
Tay-Sachs genetics
-mutations in HEXA disrupt beta-hexosaminidase function
+housekeeping gene in all tissues
+GM2 gangliosides no longer broken down
Tay-Sachs types
-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
G269S mutation
found only in late onset Tay-Sachs in combination with a null mutation
infantile Tay-Sachs phenotype
toxic accumulation of GM2, especially in spinal cord and brain
+cherry-red spot
+loss of milestones
+development of blindness, deafness, etc
Sephardic Jewish carrier testing
- 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)
CF treatment and management
*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
repeat size in maternal FMR1
lower numbers of CGG repeats in premutation reduces the risk for expansion in a child
POI in Fragile X carriers
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
orphan diseases
- incidence of <1 in 2000
- 5000-7000 different types
- affect 6-8% of world population
- 80% genetic
conditions to be excluded from ECS
- adult onset conditions
- high incidence with low penetrance (ex: MTHFR)
CF and lung disease cycle
-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
CF classes
-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
CF clinical features
- chronic sinopulmonary disease (ENT, pulmonology)
- GI or nutritional abnormalities, FTT
- disease in first degree relative
- meconium ileum followed by confirmatory testing
modifier genes in CF
-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)
CF heterozygous advantage
-possibly thought to be related to salmonella infection resistance, resistance to toxin-mediated diarrhea
beta-globin nonsense mutations
these mutations in exon 3 of the gene cause a severe AD anemia caused by the dominant negative effects of the abnormal protein
deltaF508
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
SMA new deletions
in most cases due to crossing over in paternal spermatogenesis
Canavan disease
-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
Bloom syndrome
-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
Joubert syndrome
- 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
beta thal major
-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
beta thal intermedia
- 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
SCD
- 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
alpha thal
-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
