Cram 6 Flashcards
mtDNA - size, number of genes?
16.5kb, 37 genes
which genetic conditions cancause oligospermia?
5% of menwith oligospermia have a karyotype abnormality. -unbalanced translocations are more commoninmenw oligospermia -47,xxy - non-obstructive oligo or a zoo
fasting plasma ammonia levels innormal, UCD, transient hyperammonemia of new born
normal - 15-35uM THAN - 4,750uM CPS - 1,000uM OTC - 1,100uM AS - 892 AL - 807 use citrulline and arginine to differentiate: citrulline -CPS &OTC - no/v. low citrulline -AS - vs. high (2656) citulline -AL - high citrulline (176) -THAN -
s l i g h t l y h i g h ( 5 4 ) v s . nl 6 - 2 0 a r g i ni ne : - C P S , O T C , A S , A L - l o w - T H A N - no r ma l ( 3 0 - 84)
risk forabnormal outcome in1st cousinmating?
3-5%, double the overall background risk of 2-3% (forstillbirth, neonatal death, c o ng e ni t a l ma l f o r ma t i o ns ) - i nc r e a s e d r i s k f o r 3 r d c o u s i ns o r mo r e d i s t a nt l y r e l a t e d is negligible (T&T)
L e i g h s y nd r o me , N A R P L e i g h - ma ny mi t o c h o nd r i a l g e ne s N A R P - M T - A T P 6 o nl y gene
Leigh and NARP (neurogenic uscle weakness, ataxia, RP) are part of a continuum of progressive neurodegenerative disorders -Leigh: –onset 3-12mo, oftenafter viral infection–decompensation(w lactic acidosis) inincurrent illness - ass’d w p s y c h o mo t o r e t a r d a t i o n o r r e g r e s s i o n - h y p o t o ni a , s p a s t i c i t y , mo v e me nt d i s o r d e r s (chorea), cerbel l ar ataxi a, peri pheral neuropathy, crani al nerve abnormal i ti es) – HCM –75%dieby2-3yo(usualyrespiratoryorcardiacfailure)-NARP –proximal neurogeni c muscl e weakness w sensory neuropathy, ataxi a, pi gmentary reti onopathy
relationshipbetweenmutationrateand fitnessforcalculations?
Mutationrate=sq(allelefrequency)=(1-f)(allelefrequency)
calculationof mtnrate fromfitness of x-linked recessive
SelectionAgainst X-Linked Recessive Mutations – If anX-linked phenotype is
benignand if affected males have normal fetuses, 1/3 of mutant alleles are in males and 2/3 are infemales. Whenselective disadvantage against males occurs, μ = s * q/3 Whens = 1, 1/3 of all copies a mutant gene are lost ineach generation and the disease is a genetic lethal condition.
biochemical lab finding ass’d with Lesch-Nyhansyndrome?
hi gh uri c aci d
biochemical lab finding ass’d with acute itnermittent porphyria?
high delta-aminolevulinic acid
biochemical lab finding ass’d with x-linked ardrenoleukodystrophy?
h i g h v e r y l o ng c h a i n f a t t y a c i d s
galactosemia
-jaundice,abnormal liverfunctiontests(LFTs),hyperbilirubinemia-bleeding diatheses, burising, coagulopathy -feeding problems -irritability, lethargy - sepsis** -cataracts** -elevated amino acids -hypoglycemia -renal fanconi syndrome -long term: —DD, esp. expressive language delay (‘verbal dyspraxia’) —motor delays (ataxia, tremor) —POF, hypergonadotropic hypogonadism, low bone density - t x : s t o p b r e a s t f e e d i ng , d a i r y ; s o y f e e d s ; c o ns d i e r s e p t i c r i s k ; t r e a t l i v e r d i s e a s e and jaundice
at what week inthe pregnancy to physiologic omphaloceles resolve by?
1 5 w e e k s . i f s e e n p r i o r t o t h a t a n o mp h a l o c e l e ma y b e c o mp l e t e l y no r ma l a nd doesn’t warrant further testing.
ismaternal diabetesass’d withanincreased risk forNTD?
yes
MSAFP at 2.5MoM detectionrate foropenneural tube defects?
80%
what percentage of balanced translocations are inherited?
70% (online review course)
what phenotype is seenwith 46,XY,del(9)(p24) ?
sex reversal
Which of the following parental karyotypes is associated with the lowest risk for having a livebornchild with a chromosome abnormality?a) 45,XX,der(13;14) (q10;q10) b) 46,XX,t(11;22)(q23.3;q11.2) c) 45,XX,der(14;21)(q10;q10) d) 46,XX,del (22)(q11.2;q11.2) e) 47,XX,+21
a) 45,XX,der(13;14)(q10;q10) –1% b) 46,XX,t(11;22)(q23.3;q11.2) –6% c) 45,XX,der(14;21)(q10;q10) – 12% d) 46,XX,del (22)(q11.2;q11.2) – 50% e) 47,XX,+21 – 50%
ASAFP + ultrasound -detectionratesforNTD and anencephaly?
- N T D - 9 8 - 9 9 % - a ne nc e a p h a l y - v i r t u a l l y a l l
reasonsforelevated AFAFP
NTD -underestimated gestational age -fetal death -twins -blood contamination -abdominal wall defects (omphalocele, gastroschesis)
whenis acetylcholinesterase present (AChE)?
withinopenNTD only(not closed, not abdominal wall defect)
what is the recommended dosage of folic acid -general population?-previous child withNTD?
-genpop: 0.4 mg/day -previous child: 4mg/day
CVS details
10-12 wks 6 days -0.5-1.5% mi scarri age ri sk (some studi es say comparabl e to amnio) -biochemical testing possible (onchorionic vili, not onamniocytes, ex. c o l l a g e n s t u d i e s f o r O I ) - C V S < 1 0 w e e k s - i nc r e a s e d r i s k t r a ns v e r s e l i mb abnormality
PUBS details
> 16 weeks -1-3% fetal loss rate -rapid karyotyping (48 hrs, tho less of an
advantagewithinterphaseFISH onamnioorcvs)-indications:mgmt of Rh compatibility, featal blood profile forgenetic conditons, detectionof infection, diagnosis of hemoglobinopathies, confirmationof CVS/amnio results
2nd tri screening - time window?
15 - 20 weeks
which markers have the strongest ass’nwith downsyndrome?
h C G a nd I nh i b i n A
MSAFP cutoff and detectionrates
2 . 5 M o M - 9 0 % o f a ne nc e p h a l y - 8 0 % o f N T D
when do you repeat MSAFP?
if it’s2-3MoM (depends on the center)
FISH resolution
1-100 kb
uE3associations
low indownsyndrome -low intrisomy 18 -very low (0-0.15 MoM) with: —-x-
l i nked i chthyi osi s (scal i ng ski n, corneal opaci ti es, hyperkeratosi s) —-SLOS (MR, mi c r o c e p h a l y , 2 - 3 t o e s y nd a c t y l y , ma l e s w h y p o g o na d i s m o r a mb i g u o u s g e ni t a l i a ) - —CAH —-maternal anti bi oti c or corti costeroi d therapy —anencaphl y
PWS - lacking ____ contribution of _____.
paternal, 15q11-13
Angel man- lacking _______ contribution of _________.
maternal, 15q11-13
timewindowforfirst trimesterscreen?
10-14 weeks
PWS etiology by frequency
pat 15q11-13 del (70%) mat UPD (30%) impriting center defect (5%) unknown
(<1%) single-gene mutation
Angelman etiology by frequency
mat 15q11-13 del (70%) single gene mutation- UBE3 (10%) pat UPD (3-5%)
unknowncase (10-15%)
AR diseases with de novo mutations
SMA 21-hydroxyl ase deficiency
NT>3mmass’d with?
tri 21, 18, 13-turner-triploidy-CHD -diaphragmatic hernia -skeletal dysplasiaarthrogryposis-noonansyndrome– if karyotypenormal offerdetailsultrasound and fetal echo
HD repeat ranges
<35 normal 35-39 intermediate <40 affected (T&T) <26 normal 27-35 intermediate,
mutable 36+ abnormal 36-39 - incomplete penetrance 40-60 HD, 100% penetrant
> 60 juvenile HD
HD repeat: _ _ _ in the ___ region of the gene
CAG incoding regi on(i .e. polyglutamine disorder)
what maternal serumanalyte patterns are ass’d with increased risks of IUGR, fetal demise, preeclampsia, placental dysfunction?
high AFP -high hCG (>2-3 MoM) -high Inhibin(>2-2.5 MoM) -low PAPP-A (<0.35-38 MoM)
Fragile X repeat ranges
<50 normal 50-58 intermediate 59-200 premutatoin 100-200 premutation with
100% of expanding to full mtninoogenesis >200 affected, hypermethylated
Fragile X repeat: _ _ _ in the _____ region of the gene.
CGG in the 5’ UTR
integrated vs sequential screening?
falsepositiverateishigherinsequential (9%vs.5%),detectionratesaresimilar c o nt i ng e nt a c h i e v e s a d e t e c t i o n a nd F P R s i mi l a r t o i nt e g r a t e d , b u t f e w w o me n come back forthe second draw
Myotonic dystrophy repeat ranges
<30 normal 50-80 may be mildly affected 80-2000 affected
twin pregnancy screening detection rates?
NT 75% with 7% false positive -integrated screening 45% with 5% false positive
Myotonic dystrophy: _ _ _ in the ________ region of the gene
CTG in the 3’ UTR
interpretationof serumscreening results GA: 15 weeks Maternal weight: 132 lbs Race: CaucasianIDDM: No Multiple gestation: No Maternal age at EDD: 34 yo AFP MoM: 4.75 uE3 MoM: 1.47 hCG MoM: 2.64
increased risk forNTD (b/c highAFP)increased risk forobstetric complications - IUGR, fetal demise, preeclampsia (b/c high AFP)
Friedreich ataxia repeat ranges
<34 normal 36-100 intermediate >100 affected
Friedreich ataxi a repeat: _ _ _ in the ______ region.
AAG in an intron
ultrasound sensitivityfordefects-ventral wall defects-urinarytract -NTD - c a r d i a c d e f e c t s - c l e f t l i p / p a l a t e - mi c r o e p h a l y - l i mb s
ventral wall defects - 92% -urinary tract - 91% -NTD - 80-90% -cardiac defects - 1 3 - 3 5 % ( 6 7 % i n t a r g e t e d 2 nd t r i u / s ) - c l e f t l i p / p a l a t e - 3 0 % - mi c r o e p h a l y - 27% - l i mb s - 25%
example of pseudoautosomal inheritance
dyschondrosteosis mutations i nSHOX or SHOXY (al so cause short stature) or
del eti ons in pseudoautosomal region Y pter-p11.2, Xpter-p22.32
what region of the X chromosome is critical for ovarian function?
xq13-q26
downsyndrome soft markers onultrasoudn?which has the biggest effect size/RR?
NT thickening (1st tri) -nuchal thickening (2nd tri) - biggest effect size/RR - cardiac defects -intracardiac echogenic focus -CPC (more ass'd w tri 18) - e c h o g e ni c b o w e l - s h o r t e ne d f e mu r a nd h u me r u s - d u d e na l a t r e s i a - p y e l e c t a s i s - 5 t h fingerclinodactyly
cleft lip+/- palate-ethnicityass’n?-ass’nwithothercongenital defects?- r e c u r r e nc e r i s k f o r s i b , c h i l d ?
nativeamericans>asians>caucasians>hispanics>africanamericans-cleft lip- 7 - 1 3 % a s s ‘ d w i t h o t h e r a no ma l i e s - c l e f t l i p w p a l a t e - 1 1 - 1 4 % a s s ‘ d w i t h o t h e r anomal i es -si b recur. ri sk 3-7% -chi l d recur ri sk 2-4%
mutation rate
• mutation rate: • varies with disorder, gene, size of gene, mutability of gene • avg:
10-6/locus/generati on• high rates: achon1.4x10-5, DMD 3.5x10-5 • 10-
6/locus/generation x 25,000 genes = 2.6% risk of new mutation at one
locus/generation, i .e. 1/40 ppl received a new mutation
s y nd r o me s a s s ‘ d w i t h c l e f t l i p / p a l a t e
pierrerobinsequence(CP)-22q del (CP)-stickler(CP)-treachercollins(CP)-vand e r w o r u d e ( C L + / - C P , o r C P ) - t r i s o my 1 3 / 1 8 ( C L + / - C P ) - a p e r t / c r o u z o n ( C P ) -
waardenburg (CP or CL)
XLR lethal numbers for bayes
chance any woman is a carrier 4u chance mother of isolated male case is a carrier
2/3 chance mat’l GM of isolated male case i s a carrier 1/3
definitions of -coeff’t of relationship (R) -coeff’t of inbreeding (F ) -probability
child born to consanguineous parents will have an AR disorder
• Coeff of Relationship ( R) = proportion of shared genes between two people =
1/2^degree of r’ship • Coeff of inbreeding for this couple’s child (F ) = R/2; F i s
the likelihood of the child being homozygous at any one locus, because of
decent; it is al so the proportion of loci that are identical by decent. • The
probability that a child born to consanguineous parents wi l l have anAR disorder =
F /2 (this assumes that everyone carries 1 AR disorder (Young, Ch. 3))
what is cystic hygroma ass’d with?
t u r ne r - t r i s o mi e s - t r i p l o i d y - no o na n - F A S “ a n a r e a o f s o no l u c e nc y i n t e h s o f t t i s s u e of theposterioraspectsof theneck,consistingof 2symmetrical cavities compl etel y separated by a mi dl i ne septum”
congenital toxoplasmosis
chorioretinitis (most commonfinding - eye infection) -pneumonia -anemia - jaundice -nephritis -rash long term: MR, seizures, spasticity, deafnes, blindness tosoplasosis gondii is a parasite found inundercooked meat, cat feces, soil - p r e v e nt i o n i s k e y , t x w a nt i o b i o t i c s d e c r e a s e s s e v e r i t y b u t d o e s n’ t d e c r e a s e transmi ssi on
which mitochondrial diseases are homoplasmic?
deafness induced by aminoglycoside antibiotics, caused by 12S rRNA mutations
(1555A>G, 7335A>G) LHON caused by ND4 and ND1 mutations (electron transport chain)
CMV
congenital CMV: hepatosplenomegaly, chorioretinitis, optic atrophy,
mi c r o c e p h a l y , h e a r i ng l o s s , M R - a nt i b o d y s c r e e ni ng , a mni o . P U B S a s s c r e e ni ng tools -only 5% have abnormal ultrasound (IUGR, echogenic bowel, intracranial calcification, ventriculomegaly)
which mitochondrial diseases are caused by the same mutation?
MELAS, CPEO (chronic progressive external ophthalmoplegia) are both caused by tRNAl eu(uur) 3242A>G CPEO and KSS are both caused by the ~5kb large KSS
deletion, which i s usually sporadic
maternal diabetes and birth defects
in6-10% of poorly controlled patients, up to 20% of very poorly controlled -NTD -heart defects -skeletal defects -defects inurinary, reproductive, digestive systems -increased risk of breathing difficulties, hypoglycemia, jaundice
teratogens- radiation
CNS defects, MR, microcephaly, growth retardation>5 rads
which mitochondrial diseases are usually sporadic, caused by somatic mutation?
Kearns-Sayre syndrome (KSS, ~5kb deletion) CPEO (chronic progressive external
ophthalmogplegia) due to the KSS del Pearson syndrome, due to large deletions
HB Kempsey
GoF mutation locks HB in high oxygen affinity state, thus reducing oxygen delivery
to tissues
c a r r i e r s c r e e ni ng f o r s p e h a r d i c j e w is h population - mediteranean
-beta thal -familial mediteraneanfever-glucose-6-phosphate dehydrogenase deficiency -glycogenstorage disease type III
Beta-thal trait – which ethnicities i s it prevalent in and what’s the carrier rate?
Mediteranean- 1/20-1/30 Hi spani c - 1/30-1/50 SE asi an- 1/30 Asi an
subcontinent (i ndi a, paki stan) - 1/30 (fromACMG)
which asiancountries do not have anincreased frequency of hemoglopinopathies?
Japan and Korea
alpha-thal trait - which ethnicities? what carrier rate? cis or trans?
mediteranean 1/30-1/50 trans african-american1/30 trans carribean, west indean
1/30 trans west afri can1/30 trans asi an1/20 ci s SE asi an>1/20 ci s
sickle cel l - which ethnicities? carrier frequencies?
african-american1/12 caribbean, west indean1/12 west african1/6
Hb C - which ethnicities? what carrier rate?
african-amerian 1/50 caribbean, west indian- 1/30 west african1/20-1/30
what is the time frame for amnio?
beginning of 15th week to end of pregnancy
w h a t A R c o nd i t i o ns a r e i nc r e a s e d i n i nd i v d i u a l s o f c h i ne s e a nc e s t r y ( f o r c a r r i e r screeni ng)?
betathal –3%(1/33)alphathal cis–1/20southernchina-hemoglobine
what is the time frame for CVS?
10-12 weeks and 6 days
howtotest inTay-Sachscarrierscreening?
NSGCpublicationrecommendsbiochemical notmoleculartestingb/c”simple,
i nexpensi ve, and hi ghl y accurate” -hexomi ndase a and total hoxosami ni dase measured inserum– males, non-pregnant females -leukocyte hexosaminidase for pregnnat women, womentaking OCP, anyone whose seumassy is incocnlusive - performmolecularanalysiswhenenzymeanalysisisabnormal toruleout presence of pseudodeficiency allele (35% of non-AJ heterozygotes are actually carriers of a pseudodeficiency allele)
what carrierscreeningshould beoffered toindividualsof frenchcanadianor cajunancestry?
taysachsbyenzymestudies-CF panel
what weeks of development are most susceptible to teratogens? i .e. teratogenic
exposure most likely to cause birth defects?
week 3-8, during organogenesis. before week 3 any damage done would likely be
lethal after week 8, fetus is growing
prenatal diagnosisforTay-Sachs?
enzymeanalysisoneitherCVSoramniosample-moleculartestingif mutationis knowninboth parents
which birth defects are more common in males than females?
most! pyloric stenosi s (4.43:1) hirschsprung disease (2.79:1) clubfoot (1.43:1)
cleft lip with/without palate (1.41:1) polydactyly syndactyly cranyosynostosis
congenital diphragmatic herni a
Hispanics- what conditionsforcarrierscreening?
incidence of hemoglobinopathies varies a lot withinHispanic populations dependent onAfrican-originadmixture-Carribeanancestryishighest:1/9forHb S , 1 / 3 0 f o r H b C - o f f e r s c r e e ni ng - me x i c o - l o w ( h i g h e s t i s H b S a t 1 / 6 7 - 1 / 1 0 4 ) - s c r e e ni ng p r o b a b l y no t i nd i c a t e d
which birth defects are more common in female than males?
most are more common in males than females. male:female ratio: anencephaly
(0.48:1) holoprosencephaly (0.5:1) spina bifida (0.77:1) microcephaly (0.67:1)
congenital dislocation of hi p (0.33:1) absence of ribs
Significance of poly T and TG tracts in CFTR.
poly T in intron8: 7T and 9T are normal , 5T i s a vari abl y penetrant mutation poly
TG tract i s 5’ to pol y T tract longer TG (13) &shorter T (5) - more probl ems with
intron8 splicing 5T al one - can be assocaited with CBAVD R117H + 5T (ci s) - CF
mutation 5T incombination(ci s) with 13TG - greater impacton intron8 splicing
(ex. deltaF508 with 5T/13TG - could develop non-classic CF or CBAVD) only test
T: 1) as reflux in carrier testing i f R117H i s found, 2) males with CBAVD, 3) non-
cl assi c CF (?)
c o nd i t i o ns f o r c a r r i e r s c r e e ni ng f o r s e p h a r d i c j e w s ?
Tay-Sachs - 1/45 inMoroccanJews; low and same as non-Jewish inother
S e p h a r d i c J e w s - F M F - 1 / 3 - 1 / 7 i n N o r t h A f r i c a n j e w s a nd I r a q i J e w s - b e t a - t h a l - 1/5 inKurdish and Iranianjews -alpha-thal - yemenite and iraque jews -G6PD - - screenforthalassemias-screenfortaysachsif Morrocanjewishancestry-G6PD
s c r e e ni ng p r i o r t o o f f e r i ng s u l p h a o r r e l a t e d d r u g s
oncogenes and their diseases
RET (MEN2a, b, familial medullary thyroid cancer) MET (hereditary papillary
renal carcinoma)
tumor suppressors - gatekeepers
RB1, TP53
tumor suppressors - caretakers
mismatch repair, TP53
etiologies of congenital SNHL
25% idiopathic 25% non-genetic 50% genetic 30% syndromic 70% nonsyndromic 1-
2% XL 15-24% AD 75-85% AR 50% DFNB1 (GJB2/6) 50% al l other DFNB loci
AD deafness syndromes
Waardenburg - most common, pigmentary abnl of ski n, hair, eyes BOR - 2nd most
common. all types of HL, external ear malformation, branchial cysts/fistulae, renal
mal form’nStickler - progressi ve SNHL, cl eft pal ate, spondyloepiphyseal dysplasia
NF2 - HL secondary to vestibular schwannomas
AR deafness syndromes
Usher - most common. congenital SNHL, devel op RP. Pendred - 2nd most common,
congenital SNHL, euthyroid goiter, Mondi ni mal formati onor dilated vestibular
aqueduct onCT of temporal bone JNL Biotinidase deficiency Ref sum-
progressi ve SNHL and RP. Treatable! metabol i c.
XL deafness syndromes
Al port - postlingual progressi ve SNHL, kidney fai l ure, ophtho findings. (85% XLR,
15% AR, al so AD reported) Mohr-Tranebjaerg
FGFR3 disorders (GoF or LoF ?)
achondroplasia (GoF Gl y280Arg) hypochondroplasa (GoF N540K, others)
thanatophoric dysplasia (GoF , heterogeneous?) SADDAN (GoF ? Lys650Met)
Crouzonwith acanthosis nigras (Al a391Gl u) nonsyndromic coronal synostosis
Muenke synd.
FGFR2 disorders (GoF or LoF ?)
Crouzonsyndrome (GoF ) Jackson-Wei ss syndrome (GoF Apert (GoF , P253R-
syndactyly more common, S252W-cleft pal ate more common) Pfeiffer (GoF isolated
coronal synostosis (GoF
FGFR2 craniosynostosis and their distinguishing features
Crouzon- normal hands, feet, greatest proptosis, parrot-beak nose, mandibuar
prognathism, al l el i c heterogeneity apert - greatest risk for MR/DD (50%),
syndactyly of hands and feet (mittenhand), P253R and S252W Pfeiffer - type 1
al so caused by FGFR3 mtn(5%), broad, short, medially deviated thumbs and big
toes, type 2 and 3 more severe beare-stevenson- normal hands and feet, all have
MR, abnl ears, GU and skin abnlts Jacson-Wei ss - normal hands, broad medially
deviated big toes, abnormal tarsals in feet, Muenke - FGFR3 (not 2!) -
which coronal craniosynostosis syndrome i s NOT caused by anFGFR mutation?
Saethre-chotzensyn- TWIST1 mtns, del s, dups # Low frontal hairline, ptosis,
strabismus, facial asymmetry Small ears with a prominent crus Li mb anomalies
which skeletal dysplasia is AR?
diastrophic dysplasia mtns in SLC26A2 (DTDST) @ 5q32-q33.1
what are the three stop codons?
UGA -U Go Away UAA-U Are Away UAG-U Are Gone
Which repeat disorders involve CAG repeats and polyglutamine expansion?
Huntington- SBMA SCA 1,2,3,6,7,17 DRPLA (Dentatorubropal lidoluysi anatrophy)
Which repeat disorders involve repeats in introns?
Fredreich ataxia (only AR) (GAA in intron1)
Which repeat disorders involve repeats in UTRs?
Fragile X (5’ UTR) - CGG Myotonic dystrophy (3’ UTR) - CTG
Which repeat disorders expand more frequently in spermatogenesis?
HD (can occur in both, but big jumps happen in spermatogenesis) SCAs with CAG
repeats (except SCA8)
