Cram 4 Flashcards
r i s k o f s e x c h r o mo s o me a ne u p l o i d y w i t h I C S I ?
1 % - ma y b e d u e t o u nd e r l y i ng s e x c h r o mo s o me a ne u p l o i d y i n f a t h e r o r d u e t o I C S I itself.
I f a f e t u s h a s a nu c h a l t r a ns l u c e nc y i nc r e a s e d t o 2 s t a nd a r d d e v i a t i o ns a t 1 1 - 1 4 w e e k s , t h e mo s t l i k e l y k a r y o t y p e f i nd i ng i s
normal karyotype -ri sk of aneupl oi dy i ncreased, but normal outcome sti l l most likely
AR disorders of increased frequency for prenatal carrier screening?-Mediterranean
beta thal : 1/25 al pha thal : /140 (trans) si ckl e cel l : 1/4
AR disordersof increased frequencyforprenatal carrierscreening?-African American
sickle cell: 1/12 alpha thal: 1/30 (trans) Hb C: 1/50 beta thal: 1/65 G6PD-A: 1/10males
AR disordersof increased frequencyforprenatal carrierscreening?-Non-Hispanic Caribbean, W. Indian
sickle cell: 1/12 Hb C: 1/30 alpha thal: 1/30 (trans)
AR disordersof increased frequencyforprenatal carrierscreening?-West African
sickle cell: 1/6 Hb C: 1/25 alpha thal: 1/30 (trans)
AR disordersof increased frequencyforprenatal carrierscreening?-Hispanic (Mexican;Central Amer’n)
beta thal: 1/40
AR disordersof increased frequencyforprenatal carrierscreening?-Asian
alpha-thal:1/20(*cis)beta thal:1/50
AR disordersof increased frequencyforprenatal carrierscreening?-Southeast Asian
al pha-thal : >1/20 (*ci s) beta thal : 1/30
AR disordersof increased frequencyforprenatal carrierscreening?-Asiansubcont (India, Pakistan)
beta thal: 1/50
AR disorders of increased frequency for prenatal carrier screening?-middle eastern
beta thal: 1/50
Sickle cell disease
SS (60-70%); SC, S/beta-thal -anemi a (by 4-5 mo, normocyti c, normochromi c) -
i nf e c t i o n ( mo s t c o mmo n c o mp l ‘ n, p r e v e nt w i t h p e ni c i l l i n p r o p h y l a x i s e a r l y o n) - v a s o - occlusive dis. (50% by 1y, most by 6y) —painful bone/joint crises (ER complaint) —pulmonary crises (50%, hosp’l admis’n) —painful abd’l crises -other: cardiac, CNS,dactylitis,pripaism,oculardis.,renal complic’ns-dx:IEF (usuallyforNBS); HLPC;molecularforprenatal dx-tx:penicllinprophylaxis,vaccination,oral hydration, folate supplements, avoid hypoxia/exhaustion/temp extremes -
Hb Bart disease
on-immunefetal hydrops-usuallydeathinneonatal period -all fouralpha globingenes deleted -really only occurs inasians (b/c cis)
Hb H disease
2 alpha globingenes deleted -mild to moderate microcytic hypochromic hemol yti c anemi a -mi l d j aundi ce -herpatospl enomegal y -thal assemi a-l i ke bone changes -live into adulthood tx - avoid sulfonamides, antimalarias (to prevent h e mo l y s i s ) - mo ni t o r f o r h e mo l y s i s d u r i ng f e v e r - f o l a t e s u p p l ‘ n - t r a ns f u s i o n i f needed during pregnancy
alpha thal trait, silent carrier
“trait” -2 deleted -microcytosis, hypocrhomia, normal % HbA2, Hb F (vs. beta thal trai t) “si l ent carri er” -one del eted -no phenotype
beta-thal major
d x : mi c r o c y t i c , h y p o c h r o mi c a ne mi a ; a b nl p e r i p h e r a l b l o o d s me a r w nu c l e a t e d RBC;reduced HbAwincreased HbA2and Hb F -severeanemiaand hepatosplenomegaly by 6mo-2yo -ironoverload by 10yo -FTT and reduced lifespantx- BMT isHLA-matched sib;if not - regulartransfusionstomaintainHb at 100g/L -chelationto reduce ironoverload and prevent growth retard’n, failure of sexual matur’n
beta-thal intermedia
mi l d e r a nd l a t e r s y mp t o ms - r a r e l y ne e d t r a ns f u s i o n - a t r i s k f o r i r o n o v e r l o a d d u e t o increased intestinal absorptionof excess ironfromineffective hematopoiesis
beta-thal minor(carrier)
asymptomatic ormildlyanemic -MCV<79-MCH<27-Hb<7-minorRBC morphological changes
beta-thal causes
beta-not: complete absence of beta globingenes; increased gamma globinchains beta-plus: variable reductioninbeta globinchains. pheno: mild to severe HbE: thalassemicstructural betachainvariantthatactivatesacrypticRNAsplicesite. Hb E/beta-thal compoiund het - oftensevere, but canbe mild oreven asymptoamtic. HbE/HbE - unaffected.
what makesbeta-thal milder?
HPFH and alpha-thal trait
cystic fibrosis
me d i a n s u r v i v a l : 3 5 y . l o ng e r i f p a nc r e a t i c s u f f i c i e nt d x : - N B S - i nc r e a s e d immunoreactive trypsinogeninblood spot -sweat chloride (positive in>90% of pt) -Cl >50mEq/Lon2occasions-transepithelial nasal potential difference- moleculartesting
f r a g i l e x p r e v a l e nc e , c a r r i e r r a t e s
full mtn:-1/1250males-1/200femalespre-mtn:-1/150women-1/755men
FXTAS phenotype and penetrance?
-short-termmemory loss, executive fxndeficits, cognitive decline -late-onset, progressive cerebellarataxia and intentiontremor, parkinsonism, peripheral neuropathy, lower-limproximal muscle weakness, autonomic dysfxn-age-related penetrance: —50-59 - 17% —60-69 - 38% —70-79 - 47% —>80 - 75%
e mp i r i c r e c u r r e nc e r i s k s f o r d e a f ne s s
i b of deaf chi l d w heari ng parents —-18% —-14% i f GJB2(c26) rul ed out -o f f s p r i ng o f d e a f p e r s o n a nd h e a r i ng p e r s o n - - - 1 0 % ( b / c c o u l d b e A D ) - - - t e s t f o r
GJB2 -offspring of deaf couple with no evident AD syndrome —15%
SAB chromosomal abnlts
50-70% of SAB have chromosomal abnl ts -45,X, tri somy 16 most common; al so other t r i s o mi e s - i f p r e v i o u s S A B w i t h c h r o mo s o ma l e a b nl t , g r e a t e r r i s k f u t u r e a ne u p l o i d y -aneuplody less likely inPOCs of couples with recurrent miscarriage (vs. sporadic SABs)
thrombophilia and miscarriage
- t w o me t a - a na l y s e s f o u nd i nc r e a s e d 1 s t t r i me s t e r S A B a nd l a t e r p g l o s s a s s ‘ d w i t h -factorVLeidenand -prothrombinG20210A-(but C, S, antitrhombinII NOT ass’d)
CF carrierfrequencyand detectionrate -northerneuropean-southerneuropean-AJ j e w s - o t h e r p o p ‘ ns
northerneuropean: 1/25, 85-90% -southerneuropean: 1/25, 70% -AJ: 1/26, 97% - others <=70% —asians - 30% —Hispanic 57%
a s t h e a g e o f a s u b s e t o f w o me n u nd e r g o i ng a ne u p l o i d y s c r e e ni ng i nc r e a s e s , w h a t happens to the detectionrate and false positive rate?
both increase. example: -overall 75% detec’nrate, 5% FPR -20yo: 45% detec’n rate, 3% FPR -40yo: 92% detec’nrate, 40% FPR
aneuploidyscreeningdetectionratesand falsepositiverates(fordownsyndrome)
-2nd tri quad: 82%, 7% -1st tri NT + serum: 86%, 4% -1st + 2nd tri: 93%, 2.6% (cut off of 1/270)
what is the 2nd tri analyte patternif gestatinal age > dating?
high AFP (b/c AFP goes up across GA) low hCG (b/c hCF goes downacross GA) highuE3(b/c uE3goesup)nl orslighltyhihinhibin(b/c flat)
what is the 2nd tri analyte patternif gestational age < dating
low AFP (b/c AFP goes up across GA) high hCG (b/c hCG goes down) low uE3 (b/c uE3goesup)nl orslightlylowinhibin(b/cflat)
A R d i s o r d e r s - c a r r i e r s c r e e ni ng s h o u l d b e o f f e r e d t o A J i nd i v i d u a l s ?
Gaucher, type 1 - 1/18 - 4 mtns - 90% detectionrate CF - 1/24 - several mtn- 97% DR Tay-Sachs - 1/31 - 3+ mtn- 97% DR fam’l dysautonomia - 1/32 - 1 mtn- 99% fanconi anem. C - 1/89 - 1 mtn- 99% niemanpick A - 1/90 - 3 mtn- 97% bloom- 1/107 - 1 mtn- 99% mucolipidosis Iv - 1/127 - 1 mtn- 95%
w h a t i s t h e r i s k o f s e r v e r e a b no r ma l i t y o r mo r t a l i t y r e l a t e d t o a g e ne t i c d i s o r d e r i n tehfirst child of first cousins?
6% 3% background + and addi ti onal 3%
what analytes are abnormal in2nd tri screening with anencephaly
AFP isupuE3maybedown
N S G C r e c o mme nd a t i o ns f o r g e ne t i c c o u ns e l i ng a nd s c r e e ni ng o f c o ns a ng u i ne o u s coupl es.
consganguineous=2nd cousinsorcloser-recommend thoroughfhxwithfollow-up of significant findings-noadditional screeningortestingbeyond what other copules get. -first cousins —excess mortality risk to offspring 4% —excess birth defect risk to offspring 2% (i.e. 5-6% total) -first-degree relatives —excess mortality18%—excessbirthdefects9%—overall riskforadverseoutcomeis 1 7 - 3 1 % - r i s k f o r a d v e r s e h e a l t h o u t c o me i s g r e a t e s t i n 1 s t y r o f l i f e
fetal alcohol syndrome
growth retardation-microcephaly -mental retardation-short palpebral fissures - short nose-smoothphiltrum-thinupperlip-small distal phalanges-hypoplastic f i ng e r na i l s - c a r d i a c d e f e c t s
maternal PKU
growth retard’n-mental retard’n-microcephaly -cardiac anomalies
maternal diabetes
marosomi a -hypogl ycemi a, hypocal cemi a -CNS anomal i es -cardi ac anomal i es - caudal regression
retinoic acid embryopathy
-anotia, microtia -ipsilateral facial nerve paralysis -CNS and cardiac anomalies
hydantoin(anticonvulsant) embryopathy
-growthretard’n-mental retard’n-largeanteriorfontanelle-metopicridge,hypertelorism-short nose, falt bridge -small nails, distal phalanges -arch
f i ng e r t i p p a t t e r n
pottersequence
primary anomaly: obstructionof urinary tract ->renal disease->oligohydramnios and compression-potter’s facies - flat nasal bridge, retrognathia
pierre robinsequence
p r i ma r y a no ma l y i s mi c r o g na t h i a - > s u p e r i o r d i s p l a c e me nt o f t o ng u e - > f a i l u r e o f palatal shelves to close->U shaped cleft and glossoptosis -ass’d with SOX9 disregulation-50% of cases are part of a genetic syndrome —50% of that is Sti ckl er, most have eye i nvol vement (penetrant as newborn) —22q11.2 i s onl y hal f a s c o mmo n a s S t i c k l e r
what is a deformation?
-compressionorbiomechanical distortionof analreadynormallyformed bodypart -usually occurs at 8-10 weeks -developmental process is normal -mechanical force alters structure -ex. club foot, plagiocephaly, torticollis, contractures, dimples, joint dislocations
what is a disruption?
compression/biomechanical distortionof analreadyformed (ortobeformed) normal body part to such anextreme that the resulting defect looks like an a no ma l y - v a s c u l a r a c c i d e nt i s mo s t c o mmo n - e x . o l i g o d a c t y l y d u e t o a mni o t i c bands, cleft palate due to glossoptosis, web neck due to nuchal edema
cleft lip w/wo palate and cleft palate alone
CP alone is twice as likely to be part of a genetic syndrome (25-40% vs. 10-25%) -CL/P: M:F=2:1; CP: M:F=1:2 -recurrence risk: —sporadic CP: 1% —sporadic CLP:1-5%(higherforbilateral thanunilateral)-CLP variesinprevalenceacross populations (most commoninasians) -CLP and CPA canbe ass’d with conductive hearing loss
X-linked disorders with male lethality
aicardi syndrome-goltz syndrome(focal dermal hypoplasia)-incontinentia pi gmenti -rett syndrome -chondrodyspl asi a punctata
alpha-1-antitrypsindeficiency chromosome 14
i nhi bi tor of neutrophi l el astase -pul monary emphysema (hets and homozygotes) - hepati c ci rrhosi s (homozygotes) -dx by el ectrophoresi s –M al l l el - nl - 95% of whites–Z allele(glu342lys)-10-15%activity,impairedreleasefrom hepatocyts(livertoxicity)-proteinhasmultipleN-linked glycosylationsites
(contribute to heterogeneity of bands onIEF) -Z allele likely had a single origin —null alleles-onlylungdisease,noliverdisease-tx:nosmoking,antioxidant, transpl antati on, al pha-1-at augmentati on
polycystic kidneydisease
AR - infantile, dilated collecting ducts, hepatic fibrosis, one locus -AD - adult,two+ loci, liverand pancreatic cysts, hepatic fibrosis, diverticula, heart valve
defects, aneurysms —-AD is most common(1-2/1000)
components of humangenome
1.5-2% protei n-codi ng genes 26% i ntrons 12% mi scel l aneous uni que sequences 8% miscellaneous 50% repeats —20% LINEs —13% SINEs
A J c o nd i t i o ns f o r s c r e e ni ng - T a y - S a c h s
-GM2 gangliosidosis (hexosaminidase alpha-subunit deficiency), LSD -AJ carrier rate: 1/28, 93% detectionrate -normal at birth -onset <10mo, fatal <6yo - hyperacusi s/exagerated startl e -hypotoni a -herry red spot of macul a -sei zures -MR -blindness -AJ alleles: G269S, 1278insTATC, 1421+1G>C inIVS12
A J c o nd i t i o ns f o r s c r e e ni ng - C a na v a n d i s e a s e
-LSD -neurodegenerative -dx depends onvery high conc’nN-acetyl aspartic acid (NAA) inurine -no cure, life expectancy typically <10y -onset 3-5mo -macrocephaly, head l ag, dev. del ay, hypotoni a -i nteract soci al l y, not abl e to si t, stand, tal k -AJ c a r r i e r f r e q 1 / 4 0 , 9 7 % d e t e c t i o n r a t e - A J mt n: Y 2 3 1 X , E 2 8 5 A
AJARdiseasesforcarriertesting-familial dysautonomia
-sensory autonomic neuropathy III -decreased sensitivity to pain, temperature - ‘cardiovascularinstability’-recurrent pneumonias, vomiting crises, GI dysfunction- usually normal intelligence -progressive neuronal dgeneratin- hypotonia, lack of balance -life-threatening with high mortality rate - 60% reach 20yo -AJ carrier freq 1/30, 99% detectionrate -AJ mtn2507+6T>C inIVS20 R696P
AJARdiseasesforcarriertesting-Fanconi AnemiatypeC
most commonof the rare inherited bone marrow failure syndromes -progressive BM failure -increased risk of malignances (AML, solid tumors) -malformationof forearmand thumbs -short stature -skinpigmentation, hearing loss, developmental delay -pancytopenia infirst decade -increased chromosome breakage -AJ carrier freq 1/80, 99% detectionrate -AJ mtn: IVS4+4A>T
A J A R d i s e a e s f o r c a r r i e r t e s t i ng - mu c o l i p i d o s i s I V
severe psychomotordelaybyend of 1y-progressive retinal degenerationand corneal cloudinginfirstdecade-MR,mostneverspeak,walk-strabismus-AJ carrierrate 1/127, 95% detectionrate
A J A R d i s e a s e s f o r c a r r i e r t e s t i ng - N i e ma nn p i c k t y p e A
-LSD -lack of acid phingomyelinase -sphingomyelinaccumulates in reticuloendothelial and othercell typesthroughout body;accumulationin ganglioncells of CNS leads to death -FTT ininfancy, jaundice, hepatosplenomegaly -progressive neurodegenerationleading to death by 3yo -AJ carrierfreq: 1/180, 95% detectionrate
A J A R d i s e a s e s f o r c a r r i e r t e s t i ng - a k a v o n G i e r k e d i s e a s e ; G S D 1 a
-deficiency of microsomal glucose-6-phosphatase activity (final setp of glycogenolysis and gluconogenesis) -normal at birth -low blood sugar, enlarged liver, retarded growth, abnl blood biochemprofile -primary symptoms improve w age-after20-30yo-livertumors/cancer,chronicrenal disease,gout,lownl IQ-tx - d i e t a r y , ma i nt a i n b l o o d g l u c o s e l e v e l s - A J c a r r i e r f r e q 1 / 7 1 , 9 4 % d e t e c t i o n rate
A J A R d i s e a s e s f o r c a r r i e r t e s t i ng - B l o o m s y nd r o me
typical facial appearance and short stature -increased chromosome breakage and s i s t e r c h r o ma t i d e x c h a ng e - h i g h e r r i s k f o r mu l t i p l e c a nc e r s - A J c a r r i e r f r e q 1 / 1 0 2 ,
97% detectionrate -tx: preventive - avoid sunlight and x-rays; BM
A J A R d i s e a s e s f o r c a r r i e r t e s t i ng - G a u c h e r d i s e a s e t y p e 1
L S D - A J c a r r i e r f r e q 1 / 1 8 ( h i g h e s t o f a l l A J c o nd i t i o ns ) - t y p e 1 - no n- ne u r o p a t h i c glucocerebrosidase deficiency -hepatosplenomegaly, fractures, cypoenia, pulmonary disease -ERT, most effective is started inpresymptoamtic stage - vari abl e age of onset (i nto adul thood) -dx shoul d be made by ezyme acti vi ty
techniquesfordetectingspecificsmall mutations(small deletions,missense, etc.)
dot blots (pt dna onblot, hybridize probes) -reverse dot blots (used more) (mt and wt probes onblot, hybridize pt dna) -OLA - oligo ligationassay (olgos matching mtnand wt, if anneals will be ligated and product produced) -ARMS - a l l e l e - s p e c i f i c P C R - o nl y r u ns i f p r i me r s ma t c h ( o ne p r i me r f o r W T , o ne f o r mt n) - s e q u e nc i ng ! e s p e c i a l l y i f d o n’ t ne e d h i g h t h r o u g h p u t p a r a l l e l t e s i t ng ( i . e . f a mi l y mtnvs. carrierscreening)
techniqusfordetectingdeletionsand duplications
MLPA - mutiplex ligationprobe amplication; PCR inlog phase to allow for quantificaiton(betterfordupsand carriersthansouthernand PCR)- mayneed to c o nf i r m o r c h e c k i f S N P a t p r o b e b i nd i ng s i t e i s c a u s e o f a p p a r e nt d e l e t i o n - a r r a y ( b e t t e r f o r d u p s a nd c a r r i e r s t h a n s o u t h e r n a nd P C R ) - P C R - mu l t i p l e x ( e x . D M D ) - d u p s d i f f i c u l t o t d e t e c t , e a s i e r i f d o ne i n l o g p h a s e ; ne e d t o c o nf i r m d u p s w i t h anothermethod -rtPCR forquantitiy(betterforheterozygotesthanstraight PCR)- sout hern
advantage of microsatellite repeats vs. restrictionfragment length polymoprhisms?
microsatellitesaremulti-allelicand arethereforeofteninformativeforlinkage
familial dysautonomia
feeding difficulties -episodic vomiting -autonomic neuropathy – insensitivity to pain, temp -absent tearing -absent fungiformsweating -IKBKAP gene -splicing mtn inAJ -AJ carrierrate - 1/32, 99% detectionrate
NF1 featuresbyage
infancy/preschool –plexiformneurofibromas –tibial dysplasia –development - school age –optic glioma –lisch nodules –short stature –hypertension– scoliosis -adolescence –dermal neurofibromas -adulthood –cosmetic – malignancy–osteopenia
NF1 diagnostic criteria
2 o r mo r e o f . . . - a t l e a s t 6 C A L ma c u l e s - - - 5 mm p r e - p u b e r t y - - - 1 5 mm p o s t - p u b e r t y - skin-fold freckles-twoormoreneurofribromas-oneplexiformneurofibroma-optic glioma-twoormoreirislischnodules-characteristicskeletal dysplasia(tibia, orbit)-affected FDR
NF2diagnostic criteria
bilateral vestibularschwannomasOR -FDR wNF2and anytwoof:meninigioma —glioma —schwannoma —juvenile posteriorsubcapsular
cataract/corti cal wedge opacity
TSC diagnostic criteria
Major-facial angiofibrma -forehead plaque -periunual fibroma -hypomelanotic macules (>3) -shagreenpatch -multiple retinal hamartomas -giant cell astrocytoma -subependymal nodul es -corti cal tumor -cardi ac rhabdomyoma (~50% of pt) -renal angiomyolipoma-lymphangiomyomatosisMinor-dental enamel pits- hamartomatousrectal polyps-bonecysts-whitemattermigrationlines-gingival fibromas -non-renal hamartomas -retinal achromic patch -confetti skinlesions - renal cysts(histologic)DefiniteTSC:-twomajor-onemajor,twominorProbable
VHL
hemangi obl astoma (cerebel l um, reti na, spi nal cord) -pheo -renal cel l carci noma - endolympathic sac tumor
Basal cell nevus(Gorlin)syndrome
macrocephaly -basal cell nevi/carcinomas -rib anomalies -cysts inmandible - medul l obl astoma -AD -patched mutati ons, tumor supressor gene
syndromes ass’d wi th hol oprosencephal y
syndromes ass’d wi th hol oprosencephal y
chromosomal (50% of cases)-pallister-hall -rubinstein-taybi -kallman-SLO- meckel -others
friedreich ataxia
ataxia, impaired positionand vibrationsensation-loss of DTR’s, pes cavus, extensorplantars-HCM,diabetes-AR,GAAinintron,nl 5-33,premutation34-65, mtn66-1700-5% compund het forpoint mtn-impaired mito’l Fe metabolism
CADASIL
-cerebral arteriopathy w subcortical infarcts and leukoencephalopathy -AD, notch3 gene (most are mi sssense mtns) -smal l artery occl usi ons > i schemi c epi sodes and strokes
w h a t d i s o r d e r i s c a u s e d b y a d e l e t i o n o n 1 7 p ? d u p l i c a t i o n?
d e l e t i o n - h e r e d t i a r y l i a b i l i t y t o p r e s s u r e p a l s i e s . d u p l i c a t i o n - C M T 1 A
newbornwith weakness, hypotonia, absent reflexes, tongue fasiculations. what’s t h e d i a g no s i s ?
SMAtype1 -almost all havetonguefasiculationsotherfeatures-onset >6mo- h y p o t o ni a a nd w e a k ne s s - l a c k o f mo t o r d e v ‘ t - t o ng u e f a s c i c u l a t i o ns - p o s t u r a l termorof thefingers(occasional)-mild contractures(oftenat knees)-absenceof tendonreflexes -no sensory loss -alert appearance -NORMAL INTELLECT and
cerebral function
cause of CMT1A??
duplicationon17p
linkage vs. association
linkage is studied infamilies; associations canbe studied inunrelated persons linkage is betweenloci- associations are betweenalleles -associations may imply a causal (physi ol ogi cal ) r’shi p, l i nkage does not
ataxia-telangectasia -specific DNA damange deficiency
-repairof doublestand DNAbreaks-avoid ionizingradiation
b l o o m - s p e c i f i c D N A d a ma g e d e f i c i e nc y
chromatid/chromosome breaks ontesting -avoid UV light, x-ray
X P - s p e c i f i c D N A d a ma g e d e f i c i e nc y
impaired ability to sense, excise, repare UV-induced damage -protect fromUV light,
whatconditionshavecataractsasafeature?
lowe syndrome -sticklersynd -myotonic dystrophy-galactosemia -NF2(juvenileposteriorsubcapsularlenticularopacity/juvenilecortical cataract)-congenital
rubella -chondrodysplasia punctata -hallermann-streiff
