Crash/cram For Gc Boards

Front 1

Max resolution of a high res karyotype?

Back 1

2-3Mb

Front 2

mtDNA - size, number of genes?

Back 2

16.5kb, 37 genes

Front 3

FISH resolution

Back 3

1-100 kb

Front 4

PWS - lacking ____ contribution of _____.

Back 4

paternal, 15q11-13

Front 5

Angelman - lacking _______ contribution of _________.

Back 5

maternal, 15q11-13

Front 6

PWS etiology by frequency

Back 6

pat 15q11-13 del (70%)
mat UPD (30%)
impriting center defect (5%)
unknown (<1%)
single-gene mutation

Front 7

Angelman etiology by frequency

Back 7

mat 15q11-13 del (70%)
single gene mutation - UBE3 (10%)
pat UPD (3-5%)
unknown case (10-15%)

Front 8

AR diseases with de novo mutations

Back 8

SMA
21-hydroxylase deficiency

Front 9

HD repeat ranges

Back 9

<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

Front 10

HD repeat: _ _ _ in the ___ region of the gene

Back 10

CAG in coding region (i.e. polyglutamine disorder)

Front 11

Fragile X repeat ranges

Back 11

<50 normal
50-58 intermediate
59-200 premutatoin
100-200 premutation with 100% of expanding to full mtn in oogenesis
>200 affected, hypermethylated

Front 12

Fragile X repeat: _ _ _ in the _____ region of the gene.

Back 12

CGG in the 5' UTR

Front 13

Myotonic dystrophy repeat ranges

Back 13

<30 normal
50-80 may be mildly affected
80-2000 affected

Front 14

Myotonic dystrophy: _ _ _ in the ________ region of the gene

Back 14

CTG in the 3' UTR

Front 15

Friedreich ataxia repeat ranges

Back 15

<34 normal
36-100 intermediate
>100 affected

Front 16

Friedreich ataxia repeat: _ _ _ in the ______ region.

Back 16

AAG in an intron

Front 17

example of pseudoautosomal inheritance

Back 17

dyschondrosteosis
mutations in SHOX or SHOXY (also cause short stature)
or deletions
in pseudoautosomal region
Ypter-p11.2, Xpter-p22.32

Front 18

what region of the X chromosome is critical for ovarian function?

Back 18

xq13-q26

Front 19

mutation rate

Back 19

• mutation rate:
• varies with disorder, gene, size of gene, mutability of gene
• avg: 10-6/locus/generation
• high rates: achon 1.4x10-5, 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

Front 20

XLR lethal numbers for bayes

Back 20

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 is a carrier 1/3

Front 21

definitions of
-coeff't of relationship (R)
-coeff't of inbreeding (F)
-probability child born to consanguineous parents will have an AR disorder

Back 21

• 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 is the likelihood of the child being homozygous at any one locus, because of decent; it is also the proportion of loci that are identical by decent.
• The probability that a child born to consanguineous parents will have an AR disorder = F/2
(this assumes that everyone carries 1 AR disorder (Young, Ch. 3))

Front 22

which mitochondrial diseases are homoplasmic?

Back 22

deafness induced by aminoglycoside antibiotics, caused by 12S rRNA mutations (1555A>G, 7335A>G)

LHON caused by ND4 and ND1 mutations (electron transport chain)

Front 23

which mitochondrial diseases are caused by the same mutation?

Back 23

MELAS, CPEO (chronic progressive external ophthalmoplegia) are both caused by tRNAleu(uur) 3242A>G

CPEO and KSS are both caused by the ~5kb large KSS deletion, which is usually sporadic

Front 24

which mitochondrial diseases are usually sporadic, caused by somatic mutation?

Back 24

Kearns-Sayre syndrome (KSS, ~5kb deletion)

CPEO (chronic progressive external ophthalmogplegia) due to the KSS del

Pearson syndrome, due to large deletions

Front 25

HB Kempsey

Back 25

GoF mutation
locks HB in high oxygen affinity state, thus reducing oxygen delivery to tissues

Front 26

Beta-thal trait -- which ethnicities is it prevalent in and what's the carrier rate?

Back 26

Mediteranean - 1/20-1/30
Hispanic - 1/30-1/50
SE asian - 1/30
Asian subcontinent (india, pakistan) - 1/30

(from ACMG)

Front 27

alpha-thal trait - which ethnicities? what carrier rate? cis or trans?

Back 27

mediteranean 1/30-1/50 trans
african-american 1/30 trans
carribean, west indean 1/30 trans
west african 1/30 trans

asian 1/20 cis
SE asian >1/20 cis

Front 28

sickle cell - which ethnicities? carrier frequencies?

Back 28

african-american 1/12
caribbean, west indean 1/12
west african 1/6

Front 29

Hb C - which ethnicities? what carrier rate?

Back 29

african-american 1/50
caribbean, west indian - 1/30
west african 1/20-1/30

Front 30

what is the time frame for amnio?

Back 30

beginning of 15th week to end of pregnancy

Front 31

what is the time frame for CVS?

Back 31

10-12weeks and 6 days

Front 32

What conditions are low uE3 associated with?

Back 32

SLO
x-linked ichthyosis
CAH
anencephaly

Front 33

what weeks of development are most susceptible to teratogens? i.e. teratogenic exposure most likely to cause birth defects?

Back 33

week 3-8, during organogenesis.

before week 3 any damage done would likely be lethal

after week 8, fetus is growing

Front 34

which birth defects are more common in males than females?

Back 34

most!

pyloric stenosis (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 hernia

Front 35

which birth defects are more common in female than males?

Back 35

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 hip (0.33:1)
absence of ribs

Front 36

Significance of poly T and TG tracts in CFTR.

Back 36

poly T in intron 8: 7T and 9T are normal, 5T is a variably penetrant mutation

poly TG tract is 5' to poly T tract

longer TG (13) & shorter T (5) - more problems with intron 8 splicing

5T alone - can be assocaited with CBAVD
R117H + 5T (cis) - CF mutation
5T in combination (cis) with 13TG - greater impact on intron 8 splicing (ex. deltaF508 with 5T/13TG - could develop non-classic CF or CBAVD)

only test T: 1) as reflux in carrier testing if R117H is found, 2) males with CBAVD, 3) non-classic CF (?)

Front 37

oncogenes and their diseases

Back 37

RET (MEN2a, b, familial medullary thyroid cancer)
MET (hereditary papillary renal carcinoma)

Front 38

tumor suppressors - gatekeepers

Back 38

RB1, TP53

Front 39

tumor suppressors - caretakers

Back 39

mismatch repair, TP53

Front 40

etiologies of congenital SNHL

Back 40

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% all other DFNB loci

Front 41

AD deafness syndromes

Back 41

Waardenburg - most common, pigmentary abnl of skin, hair, eyes
BOR - 2nd most common. all types of HL, external ear malformation, branchial cysts/fistulae, renal malform'n
Stickler - progressive SNHL, cleft palate, spondyloepiphyseal dysplasia
NF2 - HL secondary to vestibular schwannomas

Front 42

AR deafness syndromes

Back 42

Usher - most common. congenital SNHL, develop RP.
Pendred - 2nd most common, congenital SNHL, euthyroid goiter, Mondini malformation or dilated vestibular aqueduct on CT of temporal bone
JNL
Biotinidase deficiency
Refsum - progressive SNHL and RP. Treatable! metabolic.

Front 43

XL deafness syndromes

Back 43

Alport - postlingual progressive SNHL, kidney failure, ophtho findings. (85% XLR, 15% AR, also AD reported)
Mohr-Tranebjaerg

Front 44

FGFR3 disorders (GoF or LoF?)

Back 44

achondroplasia (GoF Gly280Arg)
hypochondroplasia (GoF N540K, others)
thanatophoric dysplasia (GoF, heterogeneous?)
SADDAN (GoF? Lys650Met)
Crouzon with acanthosis nigras (Ala391Glu)
nonsyndromic coronal synostosis
Muenke synd.

Front 45

FGFR2 disorders (GoF or LoF?)

Back 45

Crouzon syndrome (GoF)
Jackson-Weiss syndrome (GoF
Apert (GoF, P253R-syndactyly more common, S252W-cleft palate more common)
Pfeiffer (GoF
isolated coronal synostosis (GoF

Front 46

FGFR2 craniosynostosis synd and their distinguishing features

Back 46

Crouzon - normal hands, feet, greatest proptosis, parrot-beak nose, mandibular prognathism, allelic heterogeneity

apert - greatest risk for MR/DD (50%), syndactyly of hands and feet (mitten hand), P253R and S252W

Pfeiffer - type 1 also 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-Weiss - normal hands, broad medially deviated big toes, abnormal tarsals in feet,

Muenke - FGFR3 (not 2!) - Pro250ARg, need gt'ing to dx, broad great toes, carpal fusion, tarsal fusion

Front 47

which coronal craniosynostosis syndrome is NOT caused by an FGFR mutation?

Back 47

Saethre-chotzen syn - TWIST1 mtns, dels, dups
#

Low frontal hairline, ptosis, strabismus, facial asymmetry
Small ears with a prominent crus
Limb anomalies

Front 48

which skeletal dysplasia is AR?

Back 48

diastrophic dysplasia
mtns in SLC26A2 (DTDST) @ 5q32-q33.1

Front 49

what are the three stop codons?

Back 49

UGA -U Go Away
UAA-U Are Away
UAG-U Are Gone

Front 50

Which repeat disorders involve CAG repeats and polyglutamine expansion?

Back 50

Huntington -
SBMA
SCA 1,2,3,6,7,17
DRPLA (Dentatorubropallidoluysian atrophy)

Front 51

Which repeat disorders involve repeats in introns?

Back 51

Fredreich ataxia (only AR) (GAA in intron 1)

Front 52

Which repeat disorders involve repeats in UTRs?

Back 52

Fragile X (5' UTR) - CGG
Myotonic dystrophy (3' UTR) - CTG

Front 53

Which repeat disorders expand more frequently in spermatogenesis?

Back 53

HD (can occur in both, but big jumps happen in spermatogenesis)
SCAs with CAG repeats (except SCA8)

Front 54

Which repeat disorders expand more frequently in oogenesis?

Back 54

myotonic dystrophy (esp. congenital MD alleles (>1000))
fragile x
friedrech's ataxia
SCA8 (unlike other SCAs)

Front 55

F, R, and how to calculate them

Back 55

• F = coefficient of inbreeding - relates to a child of a consanguineous mating, probability that the child is homozygous for a gene derived from a common ancestor; i.e. chance to be identical by decent. When identical by decent – “autozygous”
• R = coefficient of r’ship – proportion of genes shared by individuals who are relatives
• If common ancestor is a carrier of a recessive disease (and we can generally assume that each person carries one autosomal recessive disease), then the chance for a child of a consanguineous r’ship to have that AR disease is F/2

i.e. F = chance to be homozygous by decent for either allele
F/2 is the chance to be homozygous by decent for the specific allele

Front 56

how do you calculate F?

what is it for sibs? first cousins?

Back 56

proportion of genes shared divided by 2.

sibs share 1/2 genes, therefore F=1/4
first cousins share (1/2*1/2*1/2=1/8) their genes, therefore F=1/16

Front 57

The coefficient of inbreeding (F) for a mating of first cousins once removed is:
(A) 1/4
(B) l/8
(C) l/16
(D) l/32
(E) l/64

Back 57

R - 1/16
F = 1/32

Front 58

Assume of 100,000 consecutive newborns all were examined for signs of an autosomal dominant disorder with 100% penetrance. Of
eight affected infants, five were born to unaffected parents. The new mutation rate is:

Back 58

new mutation rate = # of affected infants born to unaffected parents divided by total number of alleles. 5/(2x100,000) = 2.5 x 10^5

number of sporadic cases/ total number of alleles ascertained.

Front 59

gen pop risk for:
NTD
CHD
cleft lip/palate

Back 59

NTD: 1-2/1000 (caucasian)
CHD: 1/100
cleft lip/palate:
overall: 2-4%

Front 60

over the course of the pregnancy, what is the pattern for each of these serum markers:

hCG
estriol
AFP
inhibin
PAPP-A

Back 60

hCG - rises rapidly early on, peaks at 10 weeks, then declines

estriol - increases with gestational age

inhibin - rise during first trimester, decline after 10th week, stable 15th-20th week

AFP - increases and peaks at 32 weeks

PAPP-A - increases with gestation

Front 61

initially elevated AFP is repeated if...

Back 61

value is <3.0 MOM
gestational age is <18weeks

Front 62

PAPP-A
where made?
pattern over gestation?
what pattern ass'd with tri 13? 18? 21?

Back 62

made in embryo and placenta
increases over gestation
low levels ass'd with 13,18,21
detectable as early as 8 weeks

Front 63

hCG
where made?
pattern over gestation?
what pattern ass'd with tri 13? 18? 21? other findings?

Back 63

made by placenta
rise rapidly early on and then decline between 10th and 20th week
higher levels ass'd with tri 21 (H in it!)
lower levels ass'd with tri 18, SLOS
higher ass'd with triploidy, turner with hydrops

Front 64

AFP
where made?
pattern over gestation?
what pattern ass'd with tri 13? 18? 21? other findings?

Back 64

made by fetal liver
not measurable in maternal serum until end of first trimester
rise steadily through second trimester
high - NTD, abdominal wall defect
low - tri 21, tri 17, SLOS

Front 65

Inhibin A
where made?
pattern over gestation?
associations?

Back 65

made by ovaries and fetal placenta
rise during first trimester, decline after 10th week, stable 15th-20th week
twice as high in tri 21 pregnancies (has H in it, H=high in tri 21)
high (but not low) levels have been associated with pregnancy complications

Front 66

uE3
where made?
pattern over gestation?
associations?

Back 66

made by fetal adrenal glands, fetal liver, placenta
rise througout pregnancy
lower in tri 21, 18
very low in SLOS, antley-bixler, steroid sulfatase deficiency (x-linked ichthyosis)
only stable for 10 days, so if older sample than that will have no detectable uE3

Front 67

Hypoglycemia is commonly associated with the presence of abundant ketones in the urine. Which one of the following causes of
hypoketotic hypoglycemia (low blood glucose with low urine ketones) is the MOST common?

Back 67

(B) Fatty acid oxidation defects

Front 68

does tyrisonemia type 1 have MR?

Back 68

no

Front 69

what is the I1307K variant?

Back 69

in APC
6% of Ashkenazi Jews
susceptibility allele, 2-3x risk
not used clinically b/c of low PPV, NPV

Front 70

Which condition other than HNPCC can have MSI?

Back 70

Turcot! FAP variant with CNS tumors, can be caused by Lynch genes

Front 71

When immunohistochemical (IHC) staining is performed on a colon tumor looking for clues about Lynch syndrome, loss of staining for which gene is most likely to be representative of somatic mutation?

Back 71

Somatic mutations in MLH1 are more likely due to mutations in the BRAF gene. When BRAF is mutated, it leads to hypermethylation in MLH1, which explains why its not seen in IHC.

Front 72

What is hereditary colon cancer syndrome x?

Back 72

meets Amsterdam criteria for lynch but normal MSI and IHC.

Front 73

What are the Amsterdam and Amsterdam II criteria?

Back 73

Amsertdam (dx'c criteria for research in 1990):
3 or more family members, 1 FDR of the other 2, w confirmed dx of CRC**
2 successive affected generations
1 or more CRC** dx'd <50yo
-sensitivity 61% and specificity 67% for identifying MSH2 and MLH1 mtn

Amsterdam II (modified b/c original too strict):
3 or more family members, 1 FDR to other 2, w HNPCC-related cancers**
2 successive egnerations
1 or more with HNPCC-related** ca <50yo
-sensitivity 78%**, but lower specificity

-incorporation of MSI status or molecular diagnosis is necessary for specific diagnosis of HNPCC (criteria identify a diverse group of genetic etiogies) - i.e. if meet criteria but don't have MSI/IHC/mtn then probably a different sydnrome (X?)
-not perfect. if have Lynch gene mutation, make diagnosis, whether meet criteria or not.

Front 74

Homozygous PMS2 phenotype?

Back 74

high risk of developing colon CA at very early ages (<2nd decade), as well as brain tumors and other malignancies.

also hematologic cancer, cafe-au-lait macules

Front 75

what genes are associated with Turcot syndrome?

Back 75

2/3 APC
1/3 mismatch repair genes

Front 76

Sickle cell - phenotype, lab findings for:
MCV
MCH
Hgb (amount of Hb)
Hb electrophoresis

and for trait/het?

Back 76

HbSS - hemolytic anemia, aplastic crises, delayed growth, ischemia - acute pain, organ damage, first manifestation is dactylitis

Hb SS
MCV: nl or increased
MCH: nl
Hgb: moderately decreased (anemia)
Hb: HbA2 <3.5%
HbS 80-90%
HbF 2-20%


S-trait
MCV: nl
MCH: nl
Hgb: nl
Hb: HbA 60% (reduced)
HbS 34-42%
HbF <1%
HbA2 1-2%

Front 77

Sickle cell/Hb C disease - phenotype?

lab findings for:
MCV
MCH
Hgb (amount of Hb)
Hb eletrophoresis

and for trait/het?

Back 77

Hb SC - milder than Hb SS disease, but can be as severe

MCV: nl
MCH; nl
Hgb: mod decreased (anemia)
Hb: HbA2 <3.5%
HbS 45-55%
HbC 45-55%
HbF 1-8%

C-trait:
MCV: nl
MCH: nl
Hgb: nl
Hb: HbA 50-60% (reduced)
HbC 40-50%
HbF 1%

Front 78

Beta-thal major - brief pheno
labs:
MCV
MCH
Hgb (amount of Hb)
Hb eletrophoresis

Beta-thal minor (hets)
MCV
MCH
Hgb (amount of Hb)
Hb eletrophoresis

Back 78

beta-thal major -- microcystic hypochromic hemolytc anemia, pallor, growth retardation, skeletal changes, hepatosplenomegaly, etc.

MCV: 50-70 (decreased)
MCH: 12-20 (decreased)
Hgb (amount of Hb): <7 (decreased)
Hb eletrophoresis
beta-thal-0: HbF 95-98%
HbA2 2-5%
HbA 0
beta-thal-+: HbF 70-90%
HbA2 2-5%
HbA 10-30%

beta-thal-minor/hets:
MCV <79 (reduced)
MCH <27 (reduced)
Hgb (amount of Hb) 14-15
Hb eletrophoresis
HbA 92-95% (reduced)
HbF 0.5-4% (sometimes increased)
HbA2 >3.5%** (increased) indicative of beta-minor/het

Front 79

Normal Hb studies:
MCV
MCH
Hgb (amount of Hb)
Hb eletrophoresis

Back 79

MCV 89.1 (male), 87.6 (female)
MCH 30
Hgb Hb: 15.9 (male) 14(female)
HbA 96%-98%
HbF <1%
HbA2 2%-3%

Front 80

alpha thal lab values for
-minor (two -)
-silent (one -)
MCV
MCH
Hgb (amount of Hb)
Hb eletrophoresis

Back 80

alpha-thal minor (2 -)
MCV: 68-84 (low)
MCH: 21-24 (low)
Hgb (amount of Hb): slightly low (minor anemia)
Hb eletrophoresis
**normal! (vs. beta-thal)
HbA 96-98%
HbF <1%
HbA2 <3.5%

alpha thal silent (one -)
MCV slightly decreased
MCH slightly decreased
Hgb (amount of Hb) slightly decreased
Hb eletrophoresis
*** normal (vs. beta thal)
HbA 96-98%
HbF <1%
HbA2 <3.5%

Front 81

overall strategy for identifying thalassemia carriers by CBC?

Back 81

CBC to check for reduced MCV (alpha and beta), reduced MCH (alpha and beta), reduced Hgb (i.e. anemia) (alpha and beta)

then Hb eletrophoresis to identify Hb species:
-if normal -- could be alpha thal
-if abnormal -- which species determine what disease
-for beta thal carriers, HbA2 is increased >3.5%, HbA is decreased

Front 82

Lab values for Hb barts and HbH disease in alpha thalassemia?

Back 82

Hb Barts (fatal, diffiuse edema, hepatosplenomegaly in fetus):
MCV: >130 (very high)
MCH: 23-40 (normal?)
Hgb: 3-8 (very low)
Hb: Hb Bart only (no F, A, etc.)

Hb H (microcystic hypochromic hemolytic anemia, plenomegaly, mild jaundice, skeletal changes):
MCV 57 (kids), 61 (adults) (low)
MCH 16-20 (low)
Hgb: 8-12 (low)
Hb:
HbA 60-90%
HbF <1%
HbA2 <2%
HbBart 2-5%
HbH 1-40%

Front 83

what proportion (%) of spontaneous abortions result from aneupoidy?

Back 83

50% (online course)

Front 84

what is another name for 47,XYY?

Back 84

jacob's syndrome

Front 85

what proportion of conceptions are aneuploid?

Back 85

10-30% (Genzyme)

Front 86

What proportion of newborns are aneuploid?

Back 86

0.3% (1/333)

Front 87

Prenatally, which trisomies are most common?

Back 87

16 (31% of prenatal trisomies)
22 (10%)
21 (9%)
15 (8%)
18 (6%)
13 (5%)
(genzyme)

Front 88

Age-related risks? Tri 21 and all chromosome abnormalities?

Back 88

tri 21 all
33 0.16 0.29 (tri 21 ~1/2)
35 0.26 0.49
38 0.57 0.97
40 0.94 1.50 (tri 21 ~2/3)
42 1.56 2.56
45 3.33 5.26
(genzyme)

Front 89

how often does confined placental mosaicism occur with CVS? what outcomes is it associated with? how often is it true fetal mosaicism?

Back 89

1-2% rate of confined placental mosaicism

increased risk of IUGR or IUFD
risk of UPD

10% of CPM is true fetal mosaicism (more likely if in cultured prep (type II) and if chromosome is one of common trisomies)

Front 90

when seen as CPM on CVS, which chromosomes are more often due to *meiotic* nondisjunction and may be associated with UPD?

Back 90

9, 16, 22

Front 91

when seen as CPM on CVS, which chromosomes are more often due to *mitotic* nondisjunction and are *less* likely to be associated with UPD?

Back 91

2, 7, 8, 10, 12

Front 92

which ultrasound findings have a high risk of anueploidy and what are the risks?

Back 92

cystic higroma - 60%
holoprosencephaly - 47%
VSD - 38%
T-E fistula - 40%
hydrops - 32%
MCA - 29%
CHD - 17%
(Genzyme)

Front 93

what's the empiric risk for congenital anomoly with an apparently balanced de novo rearrangement?

Back 93

2-3x

(also: found 7x more frequently in people with MR vs. gen pop'n neonates)

(Genzyme)

Front 94

how do you assess risk of an abnormal liveborn from a carrier of a balanced reciprocal translocation?

Back 94

if there's a family history of someone with the unbalanced form then risk is highest - 20-25%

Risk is lower if no liveborns with unbalanced and couple has had multiple SABs - 2-4%

If incidentally ascertained (ex. amnio for age) - 2-5%

chromosome effect - is the unbalanced portion known to be tolerable (13, 18, 21, 8, 9 4p, 5p 18p)? then risk is higher.
(Genzyme)

Front 95

What is alternate segregation of a reciprocal translocation? what are the outcomes? how common is it?

Back 95

results in balanced and normal. no unbalanced outcome. most common segregation pattern.

Front 96

what is adjacent 1 segregation of a reciprocal transolcation? what are the outcomes? how common is it?

Back 96

results in unbalanced. centromeres segregate as expected. i.e. homologous centromeres separate.

Front 97

what is adjacent 2 segregation of a reciprocal translocation? what are the outcomes? how comon is it?

Back 97

results in unbalanced. most abnormal of the 2:2 segregation patterns. homologous centromeres segregate to the same pole/daughter cell. the resulting fertilized egg has three copies of one chromosome (2 normal and one derivative) and is monosomic for the other chromosome. rare.

Front 98

what are the risks of UPD in carriers of balanced a) homologous b) nonhomologous robertsonian translocations?

What about if the individual is phenotypically abnormal?

When should you test a balanced robertsonian translocaiton carrier for UPD?

Back 98

Risk of UPD in balanced carriers
0.4-0.6% with non-homologous rob
66-73% with homologous rob

Presence of UPD in phenotypically abnormal pts
4.7% with non-homologous rob
100% with homologous rob

test for UPD if it's 14 or 15 in either a carrier fetus or a patient with abnormal phenotype.

Front 99

what is the empiric risk of an unbalanced karyotype in offspring of carriers of

-a pericentric inversion with small distal segments?

-a paracentric inversion?

Back 99

pericentric inversion with small distal segments; 10-15% risk of unbalanced offspring.

paracentric inversion have 0.5% risk.

(Genzyme)

Front 100

what are the recurring terminal deletions?

Back 100

del(1)(p36.3) - monosomy 1p (1/10,000)
del(4)(p16) - Wolf-Hirschhorn (1/50,000)
del(5)(p15) - cri-du-chat (1/50,000)
del(16)(p13.3) - Rubinstein-Taybi (1/125,000)
del(17)(p13.3) - Miller-Dieker

Front 101

what conditions are seen in association with 22q11.2?

Back 101

22q11.2 deletion synd.

dup 22q11.2 - MR, autism

4x22q11.2 - cat-eye syndrome (usually dicentric bisatellited marker chromosome)

Front 102

which chromosome are 1/2 of all supernumary chromosomes from?

Back 102

15 -- test for UPD (in both familial and de novo cases)

Front 103

what is the most common mechanism that creates missense mutations?

Back 103

deamination. especially a 5-methylcytosine --> thymine

Front 104

heritability estimate from twin studies?

Back 104

twice the difference in concordance rates between monozygotic and dizygotic twins.

ex. monozygotic concordance = 0.40
dizygotic concordance = 0.25
heritability = 0.30
(online review course)

Front 105

during the 15-20wk window of second triemster serum screening, what are each of the analytes doing? i.e. stable, decreasing, increasing?

Back 105

inhibin A - stable

hCG - decreasing

uE3 - increasing
AFP - increasing

Front 106

what factors affect analyte levels in MSS and how?

Back 106

gestational age
maternal age
maternal weight (bigger, lower medians)

race: black (higher AFP medians); asian and Hispanic (higher uE3 medians)

number of fetuses

diabetic status - AFP lower if insulin dependent

smoking - affects inhibin and hCG

Front 107

what is the AFP cut-off?

Back 107

2.5MoM - for NTD, ab'l wall defect

Front 108

what are the risk cutoffs (in CA) for T21, T18, SLOS in MSS?

Back 108

T21 - 1/150
T18 - 1/100
SLOS - 1/250

Front 109

ethnicity-based screening in prenatal clinic (based on Luanne Hudgins' lecture)

Back 109

all women: screen for thalassemias
-MCV
-if MCV <80 - hemoglobin electrophoresis

African-american: sickle cell
-hemoglobin electrophoresis

northern european: CF
-25 most common mutations

AJ:
-tay-sachs serum screening
-canavan, CF, familial dysautonomia by molecular testing
-upon request - expanded panel - fancC, nieman-pick type A, bloom, MPS 4, Gaucher 1

french canadian:
-tay-sachs serum screening

SMA - controversial (ACMG endorses, ACOG doesn't)

Front 110

what is the false positive rate of PGD?

Back 110

5-10%

amnio or CVS recommended

Front 111

what is one situation that PUBs is useful for?

Back 111

u/s shows fetus has bilateral absence of radii

fetus may have thrombocytopenia absent radii (TAR). PUBS allows for study of fetal platelets.

Front 112

how is spina bifida diagnosed by ultrasound?

Back 112

not by detecting the lesion itself. by detecting the associated secondary findings in the fetal skull - 'lemon sign" and 'banana sign.'

dx can be made by u/s 80% of the time.

Front 113

which disorder is better tested by CVS than amnio?

Back 113

OI - b/c collagen studies need to be done on CVS sample.

Front 114

what fraction of trisomy 16 on CVS is CPM?

Back 114

all of it, essentially. so no risk for even mosaic trisomy 16.

but, there are assocaited negative outcomes: increased risk preeclampsia and IUGR

Front 115

what is the most common risk from 2nd trimester amniocentesis?

Back 115

rupture of fetal membranes. will often seal over.

this is more common than miscarriage.

Front 116

what is the recurrence risk for spina bifida when a couple had a previous child with spina bifida?

Back 116

2-3%

(vs. 0.1% gen pop)

Front 117

is there an association between maternal age and AFP levels?

Back 117

no!! AFP and the things it tests for are independent of maternal age and so AFP doesn't need to be adjusted based on maternal age.

Front 118

NTD risk factors?

Back 118

maternal valproic acid exposure in 1st trimester (1% risk)
spina bifida in parent (2-3% risk)

race (NTD more common among whites and Hispanics)
folic acid deficiency
maternal obesity
maternal increased body temperature in 1st trimester

Front 119

what should you do if a pregnant woman has a big NT >3.0 (? >4.0)?

Back 119

no need to do serum screen, b/c chance of chromosomal abnormality is so high.

offer 1) CVS, 2) fetal echo, 3) targeted u/s at 18 weeks

Front 120

what is an increased nuchal translucency assocaited with?

Back 120

trisomy 21, 18, 13
turner syndrome

cardiac abnormalities

noonan syndrome
skeletal dysplasias
congenital diaphragmatic hernia

many other rare genetic conditions

Front 121

which trisomy is better picked up by first trimester screening than by second trimester screening?

Back 121

trisomy 13 - b/c many have an increased NT

Front 122

a sequence is?

Back 122

single event, usuaslly of unknown etiology, that leads to multiple deformations and disruptions

Front 123

what is the notable feature of aicardi syndrome?

Back 123

retinal lacunae

Front 124

what are the empiric and theoretical risks for a first cousin mating to have a child with birth defects, genetic disorder, etc?

Back 124

theoretical: R=1/8, F=1/16, chance of rare AR disease =1/32 = ~3%

empiric risk for birth defects (T&T) = 3.6%

Front 125

what is the limit of consanguinity in terms of genetic significance?

Back 125

consanguinity among individuals that are 3rd cousins or more distantly relaed is not genetically significant.

Front 126

how does recombination distance (θ) compare to physical distance (base pairs)?

Back 126

θ = 0.01 = 1cM ~ 1 Mb (1x10^6 bp)

(average gene is 10-15kb or 0.015 Mb)

Front 127

how do you calculate new mutation rate given an incidence and fitness?

Back 127

The new mutation rate (u) is equal to the allele frequency * selection (s); and s = 1 – fitness (f)

ex. incidence = 1/45,000
fitness = 0.1

q = (1/2)(1/45,000) = 1/90,000
s = 0.9
u = (0.9) (1/90,000) = 1/100,000

Front 128

bayes, HW, other mat

Back 128

read the question!!
what are they asking for?!
after you're done, re-read the question. did you answer what they are asking for?

Front 129

what method of prenatal diagnosis must be used for OI ass'd with type I collagen abnormalites?

Back 129

CVS not amnio (b/c abnl type I collage runs on gel similar to normal from amniocytes)

Front 130

what method of prenatal diagnosis is used for biotinidase deficiency?

Back 130

amnio - look for metabolites in amniotic fluid or dx on maniocytes (by enzyme assay?)

Front 131

what type of prenatal diagnosis is needed for OTC deficiency?

Back 131

molecular testing. can't do enzyme or biochemical b/c OTC is expressed only in teh liver.

Front 132

what type of prenatal diagnosis is needed for GSD 1A?

Back 132

molecular testing. can't do enzyme or biochemical because expressed only in liver.

Front 133

genetic conditions ass'd with infertility

Back 133

-45,X (and mosaics)
-46,XXY
-fragile X premutation (20% risk POF, also ovarian insufficiency)
-CF, isolated CBAVD
-myotonic dystrophy - male infertility - oligoazoospermia due to sclerosis of seminiferous tubules
-kennedy disease/SBMA
-kartagener syndrome - male and female infertility

Front 134

ART ass' brith defects risk?

Back 134

-meta-analysis found 30-40% increase in brith defects with ART (i.e. OR=1.3)
-true for IVF w and w/o ICSI

Front 135

ass'n between ART and imprinting disorders?

Back 135

BWS - 6x increase in ART among children with BWS
-risk w ART is 1/4000 (9x gen pop)
-isolated omphalocele - 20% have BWS, 50% conceived by ART
-nearly all cases due to loss of meth'n (vs. 40-50% usually)

Front 136

when seen on 2nd tri ultrasound, what conditions is an isolated omphalocele suggestive of?

Back 136

BWS (20% chance)

Front 137

when seen on 2nd tri ultrasound, what conditions is a congenital diaphgragmatic hernia suggestive of?

Back 137

pallister killian (12p tetrasomy)
Fryns

Front 138

when seen on 2nd tri ultrasound, what conditions is an lissencephally suggestive of?

Back 138

miller deiker

Front 139

when seen on 2nd tri ultrasound, what conditions is an IUGR/ambiguous genitalia suggestive of?

Back 139

SLO

Front 140

trisomy 21 ultrasound findings?

Back 140

ventriculomegaly, brachycephaly
nuchal thickenng
cardiac defect (AV canal)
dudenal atresia, echogenic bowel
renal pyelectasis
shortened femur/humerus
clinodactyly of 5th finger
sandalfoot

Front 141

ultrasound findings in trisomy 18?

Back 141

CNS - agenesis of corpus callosum, meningomyelocele, ventriculomegaly
cystic hygroma
cardiac anomalies
*congenital diaphragmatic hernia
omphalocele
*clenched hands with overlaping digits
IUGR with polyhydramnios

Front 142

ultrasound findings in trisomy 13?

Back 142

CNS - holoprosencephaly, agenesis of corpus callosum, meningomyelocel, microcephaly
*cleft lip/palate, midface hypoplasia, cyclopia, microophthalmia
nuchal thickening
cardiac anomalies
omphalocele, echogenic bowel
echogenic kidneys
radial aplasia, polydactyly

Front 143

ultrasound findings ass'd with Turner?

Back 143

*cystic hygroma
cardiac defects (coarc)
*horseshoe kidneys
*hydrops

Front 144

ultrasound findings ass'd with triploidy?

Back 144

CNS - holoposencephaly, agenesis of corpus callosum, meningomyelocele, dandy walker malf'n
hypertelorism, micrognathia
*syndactyly 3rd/4th
cardiac defects
omphalocele
*early onset IUGR affected skeleton more than head
*placental abnormalities - enlarged, or small and calcified

Front 145

aneuploidy risk by major anomaly on u/s?
cystic hygroma
hydrops
holoprosencephaly
AV canal
omphalocele
duodenal atresia
bladder outlet obstruction

Back 145

cystic hygroma - >50%, 45,X
hydrops - >50% - 13,21,18,45,X
holoprosencephaly - 50% 13,18,18p-
AV canal - 40%, 21
omphalocele - 30%, 13,18
duodenal atresia - 30%, 21
bladder outlet obstruction - 20%, 13,18

Front 146

aneuploidy risk by major anomaly on u/s?
hydrocephaly/ventriculomegaly
cardiac defects
meningomyeloceles
anencephaly
encephalocele
limb reduction
clubfoot
facial clefts

Back 146

hydrocephaly/ventriculomegaly - 10% - 21,13,18,triploidy
cardiac defects - 10% - 21,18,13,22-,8,9
meningomyeloceles - 7% - 18
anencephaly - 2%
encephalocele - 10%
limb reduction - 8% - 18
clubfoot - 6% - 47,XXY,47,XXX,18,21
facial clefts - 1% - 13,18,22q-

Front 147

Cytogenetic abnormalities ass'd with infertility in males?

Back 147

47,XXY (most common; nonobstructive azoospermia)
DAZ microdeletion (frequent in oligospermia)
Yq microdeletions
46,r(X)Y
46,XY/45,X
46,XY/47,XXY
46,XX w SRY del'n
-balanced transloc'n more common with oligosp. (oligospermia)
-sex chromosome abnlts increase with decreasing sperm count

NOT 47,XYY

CBAVD - obstructive azoospermia

Front 148

loss rate for early amnio (<12wks)?

Back 148

2-3%
vs. CVS 1%
vs. standard amnio 0.5%

Front 149

risk of sex chromosome aneuploidy with ICSI?

Back 149

1% - may be due to underlying sex chromosome aneuploidy in father or due to ICSI itself.

Front 150

If a fetus has a nuchal translucency increased to 2 standard deviations at 11-14 weeks, the most
likely karyotype finding is

Back 150

normal karyotype

-risk of aneuploidy increased, but normal outcome still most likely

Front 151

Cytogenetic abnormalities ass'd with infertility in males?

Back 151

47,XXY (most common; nonobstructive azoospermia)
DAZ microdeletion (frequent in oligospermia)
Yq microdeletions
46,r(X)Y
46,XY/45,X
46,XY/47,XXY
46,XX w SRY del'n
-balanced transloc'n more common with oligosp. (oligospermia)
-sex chromosome abnlts increase with decreasing sperm count

NOT 47,XYY

CBAVD - obstructive azoospermia

Front 152

loss rate for early amnio (<12wks)?

Back 152

2-3%
vs. CVS 1%
vs. standard amnio 0.5%

Front 153

risk of sex chromosome aneuploidy with ICSI?

Back 153

1% - may be due to underlying sex chromosome aneuploidy in father or due to ICSI itself.

Front 154

If a fetus has a nuchal translucency increased to 2 standard deviations at 11-14 weeks, the most
likely karyotype finding is

Back 154

normal karyotype

-risk of aneuploidy increased, but normal outcome still most likely

Front 155

AR disorders of increased frequency for prenatal carrier screening?
-Mediterranean

Back 155

beta thal: 1/25
alpha thal: /140 (trans)
sickle cell: 1/40

Front 156

AR disorders of increased frequency for prenatal carrier screening?
-African American

Back 156

sickle cell: 1/12
alpha thal: 1/30 (trans)
Hb C: 1/50
beta thal: 1/65
G6PD-A: 1/10 males

Front 157

AR disorders of increased frequency for prenatal carrier screening?
-Non-Hispanic Caribbean, W. Indian

Back 157

sickle cell: 1/12
Hb C: 1/30
alpha thal: 1/30 (trans)

Front 158

AR disorders of increased frequency for prenatal carrier screening?
-West African

Back 158

sickle cell: 1/6
Hb C: 1/25
alpha thal: 1/30 (trans)

Front 159

AR disorders of increased frequency for prenatal carrier screening?
-Hispanic (Mexican; Central Amer'n)

Back 159

beta thal: 1/40

Front 160

AR disorders of increased frequency for prenatal carrier screening?
-Asian

Back 160

alpha-thal: 1/20 (*cis)
beta thal: 1/50

Front 161

AR disorders of increased frequency for prenatal carrier screening?
-Southeast Asian

Back 161

alpha-thal: >1/20 (*cis)
beta thal: 1/30

Front 162

AR disorders of increased frequency for prenatal carrier screening?
-Asian subcont (India, Pakistan)

Back 162

beta thal: 1/50

Front 163

AR disorders of increased frequency for prenatal carrier screening?
-midle eastern

Back 163

beta thal: 1/50

Front 164

Sickle cell disease

Back 164

-SS (60-70%); SC, S/beta-thal
-anemia (by 4-5 mo, normocytic, normochromic)
-infection (most common compl'n, prevent with penicillin prophylaxis early on)
-vaso-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, ocular dis., renal complic'ns
-dx: IEF (usually for NBS); HLPC; molecular for prenatal dx
-tx: penicllin prophylaxis, vaccination, oral hydration, folate supplements, avoid hypoxia/exhaustion/temp extremes
-hydroxurea to induce HbF
-chronic RBC transfusion to keep HbS <30%

Front 165

Hb Bart disease

Back 165

-non-immune fetal hydrops
-usually death in neonatal period
-all four alpha globin genes deleted
-really only occurs in asians (b/c cis)

Front 166

Hb H disease

Back 166

-2 alpha globin genes deleted
-mild to moderate microcytic hypochromic hemolytic anemia
-mild jaundice
-herpatosplenomegaly
-thalassemia-like bone changes
-live into adulthood
tx - avoid sulfonamides, antimalarias (to prevent hemolysis)
-monitor for hemolysis during fever
-folate suppl'n
-transfusion if needed during pregnancy

Front 167

alpha thal trait, silent carrier

Back 167

"trait"
-2 deleted
-microcytosis, hypocrhomia, normal % HbA2, Hb F (vs. beta thal trait)

"silent carrier"
-one deleted
-no phenotype

Front 168

beta-thal major

Back 168

dx: microcytic, hypochromic anemia; abnl peripheral blood smear w nucleated RBC; reduced HbA w increased HbA2 and Hb F
-severe anemia and hepatosplenomegaly by 6mo-2yo
-iron overload by 10yo
-FTT and reduced lifespan
tx - BMT is HLA-matched sib; if not - regular transfusions to maintain Hb at 100g/L
-chelation to reduce iron overload and prevent growth retard'n, failure of sexual matur'n

Front 169

beta-thal intermedia

Back 169

-milder and later symptoms
-rarely need transfusion
-at risk for iron overload due to increased intestinal absorption of excess iron from ineffective hematopoiesis

Front 170

beta-thal minor (carrier)

Back 170

-asymptomatic or mildly anemic
-MCV <79
-MCH<27
-Hb<7
-minor RBC morphological changes

Front 171

beta-thal causes

Back 171

beta-not: complete absence of beta globin genes; increased gamma globin chains

beta-plus: variable reduction in beta globin chains. pheno: mild to severe

HbE: thalassemic structural beta chain variant that activates a cryptic RNA splice site. Hb E/beta-thal compoiund het - often severe, but can be mild or even asymptoamtic. HbE/HbE - unaffected.

Front 172

what makes beta-thal milder?

Back 172

HPFH and alpha-thal trait

Front 173

cystic fibrosis

Back 173

-median survival: 35y. longer if pancreatic sufficient
dx: -NBS - increased immunoreactive trypsinogen in blood spot
-sweat chloride (positive in >90% of pt) - Cl >50mEq/L on 2 occasions
-transepithelial nasal potential difference
-molecular testing

Front 174

fragile x prevalence, carrier rates

Back 174

full mtn:
-1/1250 males
-1/200 females
pre-mtn:
-1/150 women
-1/755 men

Front 175

FXTAS phenotype and penetrance?

Back 175

-short-term memory loss, executive fxn deficits, cognitive decline
-late-onset, progressive cerebellar ataxia and intention tremor, parkinsonism, peripheral neuropathy, lower-lim proximal muscle weakness, autonomic dysfxn
-age-related penetrance:
---50-59 - 17%
---60-69 - 38%
---70-79 - 47%
--->80 - 75%

Front 176

empiric recurrence risks for deafness

Back 176

-sib of deaf child w hearing parents
----18%
----14% if GJB2(c26) ruled out
-offspring of deaf person and hearing person
---10% (b/c could be AD)
---test for GJB2
-offspring of deaf couple with no evident AD syndrome
---15%

Front 177

SAB chromosomal abnlts

Back 177

50-70% of SAB have chromosomal abnlts
-45,X, trisomy 16 most common; also other trisomies
-if previous SAB with chromosomale abnlt, greater risk future aneuploidy
-aneuplody *less* likely in POCs of couples with recurrent miscarriage (vs. sporadic SABs)

Front 178

thrombophilia and miscarriage

Back 178

-two meta-analyses found increased 1st trimester SAB and later pg loss ass'd with
-factor V Leiden and
-prothrombin G20210A
-(but C, S, antitrhombin II NOT ass'd)

Front 179

CF carrier frequency and detection rate
-northern european
-southern european
-AJ jews
-other pop'ns

Back 179

-northern european: 1/25, 85-90%
-southern european: 1/25, 70%
-AJ: 1/26, 97%
-others <=70%
---asians - 30%
---Hispanic 57%

Front 180

as the age of a subset of women undergoing aneuploidy screening increases, what happens to the detection rate and false positive rate?

Back 180

both increase.
example:
-overall 75% detec'n rate, 5% FPR
-20yo: 45% detec'n rate, 3% FPR
-40yo: 92% detec'n rate, 40% FPR

Front 181

aneuploidy screening detection rates and false positive rates (for down syndrome)

Back 181

-2nd tri quad: 82%, 7%
-1st tri NT + serum: 86%, 4%
-1st + 2nd tri: 93%, 2.6%

(cut off of 1/270)

Front 182

what is the 2nd tri analyte pattern if gestatinal age > dating?

Back 182

high AFP (b/c AFP goes up across GA)
low hCG (b/c hCF goes down across GA)
high uE3 (b/c uE3 goes up)
nl or slighlty hih inhibin (b/c flat)

Front 183

what is the 2nd tri analyte pattern if gestational age < dating

Back 183

low AFP (b/c AFP goes up across GA)
high hCG (b/c hCG goes down)
low uE3 (b/c uE3 goes up)
nl or slightly low inhibin (b/c flat)

Front 184

AR disorders - carrier screening should be offered to AJ individuals?

Back 184

Gaucher, type 1 - 1/18 - 4 mtns - 90% detection rate
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%
nieman pick A - 1/90 - 3 mtn - 97%
bloom - 1/107 - 1 mtn - 99%
mucolipidosis Iv - 1/127 - 1 mtn - 95%

Front 185

what is the risk of servere abnormality or mortality related to a genetic disorder in teh first child of first cousins?

Back 185

6%
3% background + and additional 3%

Front 186

what analytes are abnormal in 2nd tri screening with anencephaly

Back 186

AFP is up
uE3 may be down

Front 187

NSGC recommendations for genetic counseling and screening of consanguineous couples.

Back 187

consganguineous = 2nd cousins or closer
-recommend thorough fhx with follow-up of significant findings
-no additional screening or testing beyond 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 mortality 18%
---excess birth defects 9%
---overall risk for adverse outcome is 17-31%
-risk for adverse health outcome is greatest in 1st yr of life

Front 188

fetal alcohol syndrome

Back 188

-growth retardation
-microcephaly
-mental retardation
-short palpebral fissures
-short nose
-smooth philtrum
-thin upper lip
-small distal phalanges
-hypoplastic finger nails
-cardiac defects

Front 189

maternal PKU

Back 189

-growth retard'n
-mental retard'n
-microcephaly
-cardiac anomalies

Front 190

maternal diabetes

Back 190

-marosomia
-hypoglycemia, hypocalcemia
-CNS anomalies
-cardiac anomalies
-caudal regression

Front 191

retinoic acid embryopathy

Back 191

-anotia, microtia
-ipsilateral facial nerve paralysis
-CNS and cardiac anomalies

Front 192

hydantoin (anticonvulsant) embryopathy

Back 192

-growth retard'n
-mental retard'n
-large anterior fontanelle
-metopic ridge, hypertelorism
-short nose, falt bridge
-small nails, distal phalanges
-arch fingertip pattern

Front 193

potter sequence

Back 193

-primary anomaly: obstruction of urinary tract
->renal disease->oligohydramnios and compression
-potter's facies - flat nasal bridge, retrognathia

Front 194

pierre robin sequence

Back 194

-primary anomaly is micrognathia
-> superior displacement of tongue->failure of 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 Stickler, most have eye involvement (penetrant as newborn)
---22q11.2 is only half as common as Stickler

Front 195

what is a deformation?

Back 195

-compression or biomechanical distortion of an already normally formed body part
-usually occurs at 8-10 weeks
-developmental process is normal
-mechanical force alters structure
-ex. club foot, plagiocephaly, torticollis, contractures, dimples, joint dislocations

Front 196

what is a disruption?

Back 196

-compression/biomechanical distortion of an already formed (or to be formed) normal body part to such an extreme that the resulting defect looks like an anomaly
-vascular accident is most common
-ex. oligodactyly due to amniotic bands, cleft palate due to glossoptosis, web neck due to nuchal edema

Front 197

cleft lip w/wo palate and cleft palate alone

Back 197

-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% (higher for bilateral than unilateral)
-CLP varies in prevalence across populations (most common in asians)
-CLP and CPA can be ass'd with conductive hearing loss

Front 198

X-linked disorders with male lethality

Back 198

-aicardi syndrome
-goltz syndrome (focal dermal hypoplasia)
-incontinentia pigmenti
-rett syndrome
-chondrodysplasia punctata

Front 199

alpha-1-antitrypsin deficiency
chromosome 14

Back 199

-inhibitor of neutrophil elastase
-pulmonary emphysema (hets and homozygotes)
-hepatic cirrhosis (homozygotes)
-dx by electrophoresis
--M alllel - nl - 95% of whites
--Z allele (glu342lys) - 10-15% activity, impaired release from hepatocyts (liver toxicity)
-protein has multiple N-linked glycosylation sites (contribute to heterogeneity of bands on IEF)
-Z allele likely had a single origin
---null alleles - only lung disease, no liver disease
-tx: no smoking, antioxidant, transplantation, alpha-1-at augmentation

Front 200

polycystic kidney disease

Back 200

-AR - infantile, dilated collecting ducts, hepatic fibrosis, one locus
-AD - adult, two+ loci, liver and pancreatic cysts, hepatic fibrosis, diverticula, heart valve defects, aneurysms
----AD is most common (1-2/1000)

Front 201

components of human genome

Back 201

1.5-2% protein-coding genes
26% introns
12% miscellaneous unique sequences
8% miscellaneous
50% repeats
---20% LINEs
---13% SINEs

Front 202

AJ conditions for screening
-Tay-Sachs

Back 202

-GM2 gangliosidosis (hexosaminidase alpha-subunit deficiency), LSD
-AJ carrier rate: 1/28, 93% detection rate
-normal at birth
-onset <10mo, fatal <6yo
-hyperacusis/exagerated startle
-hypotonia
-herry red spot of macula
-seizures
-MR
-blindness
-AJ alleles: G269S, 1278insTATC, 1421+1G>C in IVS12

Front 203

AJ conditions for screening
-Canavan disease

Back 203

-LSD
-neurodegenerative
-dx depends on very high conc'n N-acetyl aspartic acid (NAA) in urine
-no cure, life expectancy typically <10y
-onset 3-5mo
-macrocephaly, head lag, dev. delay, hypotonia
-interact socially, not able to sit, stand, talk
-AJ carrier freq 1/40, 97% detection rate
-AJ mtn: Y231X, E285A

Front 204

AJ AR diseases for carrier testing
-familial dysautonomia

Back 204

-sensory autonomic neuropathy III
-decreased sensitivity to pain, temperature
-'cardiovascular instability'
-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% detection rate
-AJ mtn 2507+6T>C in IVS20
R696P

Front 205

AJ AR diseases for carrier testing
-Fanconi Anemia type C

Back 205

-most common of the rare inherited bone marrow failure syndromes
-progressive BM failure
-increased risk of malignances (AML, solid tumors)
-malformation of forearm and thumbs
-short stature
-skin pigmentation, hearing loss, developmental delay
-pancytopenia in first decade
-increased chromosome breakage
-AJ carrier freq 1/80, 99% detection rate
-AJ mtn: IVS4+4A>T

Front 206

AJ AR diseaes for carrier testing
-mucolipidosis IV

Back 206

-severe psychomotor delay by end of 1y
-progressive retinal degeneration and corneal clouding in first decade
-MR, most never speak, walk
-strabismus
-AJ carrier rate 1/127, 95% detection rate

Front 207

AJ AR diseases for carrier testing
-Niemann pick type A

Back 207

-LSD
-lack of acid phingomyelinase
-sphingomyelin accumulates in reticuloendothelial and other cell types throughout body; accumulation in ganglion cells of CNS leads to death
-FTT in infancy, jaundice, hepatosplenomegaly
-progressive neurodegeneration leading to death by 3yo
-AJ carrier freq: 1/180, 95% detection rate

Front 208

AJ AR diseases for carrier testing
-aka von Gierke disease; GSD1a

Back 208

-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 biochem profile
-primary symptoms improve w age
-after 20-30yo - liver tumors/cancer, chronic renal disease, gout, low nl IQ
-tx - dietary, maintain blood glucose levels
-AJ carrier freq 1/71, 94% detection rate

Front 209

AJ AR diseases for carrier testing
-Bloom syndrome

Back 209

-typical facial appearance and short stature
-increased chromosome breakage and sister chromatid exchange
-higher risk for multiple cancers
-AJ carrier freq 1/102, 97% detection rate
-tx: preventive - avoid sunlight and x-rays; BMT

Front 210

AJ AR diseases for carrier testing
-Gaucher disease type 1

Back 210

-LSD
-AJ carrier freq 1/18 (highest of all AJ conditions)
-type 1 - non-neuropathic glucocerebrosidase deficiency
-hepatosplenomegaly, fractures, cypoenia, pulmonary disease
-ERT, most effective is started in presymptoamtic stage
-variable age of onset (into adulthood)
-dx should be made by ezyme activity

Front 211

techniques for detecting specific small mutations (small deletions, missense, etc.)

Back 211

-dot blots (pt dna on blot, hybridize probes)
-reverse dot blots (used more) (mt and wt probes on blot, hybridize pt dna)
-OLA - oligo ligation assay (olgos matching mtn and wt, if anneals will be ligated and product produced)
-ARMS - allele-specific PCR - only runs if primers match (one primer for WT, one for mtn)
-sequencing! especially if don't need high throughput parallel tesitng (i.e. family mtn vs. carrier screening)

Front 212

techniqus for detecting deletions and duplications

Back 212

-MLPA - mutiplex ligation probe amplication; PCR in log phase to allow for quantificaiton (better for dups and carriers than southern and PCR) - may need to confirm or check if SNP at probe binding site is cause of apparent deletion

-array (better for dups and carriers than southern and PCR)

-PCR - multiplex (ex. DMD) - dups difficult ot detect, easier if done in log phase; need to confirm dups with another method
-rtPCR for quantitiy (better for heterozygotes than straight PCR)

-southern

Front 213

advantage of microsatellite repeats vs. restriction fragment length polymoprhisms?

Back 213

microsatellites are multi-allelic and are therefore often informative for linkage

Front 214

familial dysautonomia

Back 214

-feeding difficulties
-episodic vomiting
-autonomic neuropathy -- insensitivity to pain, temp
-absent tearing
-absent fungiform sweating
-IKBKAP gene
-splicing mtn in AJ
-AJ carrier rate - 1/32, 99% detection rate

Front 215

NF1 features by age

Back 215

-infancy/preschool
--plexiform neurofibromas
--tibial dysplasia
--development
-school age
--optic glioma
--lisch nodules
--short stature
--hypertension
--scoliosis
-adolescence
--dermal neurofibromas
-adulthood
--cosmetic
--malignancy
--osteopenia

Front 216

NF1 diagnostic criteria

Back 216

2 or more of...
-at least 6 CAL macules
---5mm pre-puberty
---15mm post-puberty
-skin-fold freckles
-two or more neurofribromas
-one plexiform neurofibroma
-optic glioma
-two or more iris lisch nodules
-characteristic skeletal dysplasia (tibia, orbit)
-affected FDR

Front 217

NF2 diagnostic criteria

Back 217

-bilateral vestibular schwannomas
OR
-FDR w NF2 and any two of:
---meninigioma
---glioma
---schwannoma
---juvenile posterior subcapsular cataract/cortical wedge opacity

Front 218

TSC diagnostic criteria

Back 218

Major
-facial angiofibrma
-forehead plaque
-periunual fibroma
-hypomelanotic macules (>3)
-shagreen patch
-multiple retinal hamartomas
-giant cell astrocytoma
-subependymal nodules
-cortical tumor
-cardiac rhabdomyoma (~50% of pt)
-renal angiomyolipoma
-lymphangiomyomatosis
Minor
-dental enamel pits
-hamartomatous rectal polyps
-bone cysts
-white matter migration lines
-gingival fibromas
-non-renal hamartomas
-retinal achromic patch
-confetti skin lesions
-renal cysts (histologic)
Definite TSC:
-two major
-one major, two minor
Probable TSC:
-one major, one minor
Possible TSC:
-one major or
-two or more minor

Front 219

VHL

Back 219

-hemangioblastoma (cerebellum, retina, spinal cord)
-pheo
-renal cell carcinoma
-endolympathic sac tumor

Front 220

Basal cell nevus (Gorlin) syndrome

Back 220

-macrocephaly
-basal cell nevi/carcinomas
-rib anomalies
-cysts in mandible
-medulloblastoma
-AD
-patched mutations, tumor supressor gene

Front 221

syndromes ass'd with holoprosencephaly

Back 221

-chromosomal (50% of cases)
-pallister-hall
-rubinstein-taybi
-kallman
-SLO
-meckel
-others

Front 222

friedreich ataxia

Back 222

-ataxia, impaired position and vibration sensation
-loss of DTR's, pes cavus, extensor plantars
-HCM, diabetes
-AR, GAA in intron, nl 5-33, premutation 34-65, mtn 66-1700
-5% compund het for point mtn
-impaired mito'l Fe metabolism

Front 223

CADASIL

Back 223

-cerebral arteriopathy w subcortical infarcts and leukoencephalopathy
-AD, notch3 gene (most are misssense mtns)
-small artery occlusions > ischemic episodes and strokes

Front 224

what disorder is caused by a deletion on 17p? duplication?

Back 224

deletion - heredtiary liability to pressure palsies.

duplication - CMT1A

Front 225

newborn with weakness, hypotonia, absent reflexes, tongue fasiculations. what's the diagnosis?

Back 225

SMA type 1
-almost all have tongue fasiculations
other features
-onset >6mo
-hypotonia and weakness
-lack of motor dev't
-tongue fasciculations
-postural termor of the fingers (occasional)
-mild contractures (often at knees)
-absence of tendon reflexes
-no sensory loss
-alert appearance
-NORMAL INTELLECT and cerebral function

Front 226

cause of CMT1A??

Back 226

duplication on 17p

Front 227

trisomy 13 etiology?

Back 227

47,XY,+13 (or XX) in 80% of cases
-20% of cases 46,XX,+13,der(13;14)(q10;q10)
---55% of time inherited from a carrier parent (i.e. 45,XY,der(13;14)(q10;q10) - this is the most common translocation in human pop (1/1100)
---a carrier parent has an empiric risk of ~1% of having a liveborn child with tri 13
---expect to see infertility, recurrent SAB, infant death, fhx of the same

Front 228

linkage vs. association

Back 228

-linkage is studied in families; associations can be studied in unrelated persons
-linkage is between loci; associations are between alleles
-associations may imply a causal (physiological) r'ship, linkage does not

Front 229

ataxia-telangectasia
-specific DNA damange deficiency

Back 229

-repair of double stand DNA breaks
-avoid ionizing radiation

Front 230

bloom
-specific DNA damage deficiency

Back 230

-chromatid/chromosome breaks on testing
-avoid UV light, x-ray

Front 231

XP
-specific DNA damage deficiency

Back 231

-impaired ability to sense, excise, repare UV-induced damage
-protect from UV light,

Front 232

what conditions have cataracts as a feature?

Back 232

-lowe syndrome
-stickler synd
-myotonic dystrophy
-galactosemia
-NF2 (juvenile posterior subcapsular lenticular opacity/juvenile cortical cataract)
-congenital rubella
-chondrodysplasia punctata
-hallermann-streiff

Front 233

what syndromes is polydactyly a feature of?

Back 233

-meckel-gruber
-trisomy 13
-pallister-hall
-chondroectodemial dysplasia (ellis-van creveld)
-Greig cephalopolysyndactyly syndrome
-BBS
-VACTERL

Front 234

Warburg syndrome

Back 234

-dies at 10 days of age
-agyria
-cerebellar hypoplasia
-dandy-walker cyst
-microphthalmia
-retinal detachment with retinal dysplasia

Front 235

Langer-Giedion syndrome

Back 235

-del(8)(q24.11-24.13)
-only 1/4 are cytogenetically visible
-true contiguous gene syndrome - TRPS1 gene and EXT1 gene
-MR, microcephaly, multiple exostoses, redundant skin, sparse hair

Front 236

campomelic dysplasia
SOX9

Back 236

-skeletal dysplasia with ambiguous genitalia or female genitalia with XY
-distinctive facies, pierre robin seq w cleft palate
-shortening and bowing of long bones
-club feet
-laryngotracheomalacia w respiratory compromise
-often neonatally lethal
-AD, most de novo
-seq'g (90%), deletion analysis (5%)

Front 237

incontinentia pigmenti
IKBKG (aka NEMO) @ Xq28

Back 237

-XLD, lethal in males, Xq28
-esoniphilia
-four stages of skin changes: erythema>blister>hyperpigmented streaks>atrophic skin patches
-hypo/andontia, small or malformed teeth, alopecia, woolly hair, nail ridgin or pitting
-reinal neovascularization causing retinal detachment
-MR is rare
-tests: free melanin granules if hyperpigmented streak biopsied
-molecular: southern blot for common exon 4-10 del (80%)

Front 238

meckel-gruber
17q22

Back 238

AR
3 major features:
-occipital encephalocele
-cystic kidneys
-postaxial polydactyly
also: potter-like facies; short webbed neck; dandy-walker malformation; arnold-chiar malformation; fibrotic liver
-perinatal death
-prenatal dx by ultrasound

Front 239

chondrodysplasia punctata

Back 239

-non-specific finding of punctate calcifications throughout the skeleton, seen in fetuses and young children
-etiologically heterogeneous
---genetic causes
-----arylsulfatase E on Xp22
-----zellweger syndrome
---non-genetic causes
-----warfarin exporuse

Front 240

lowe syndrome (oculo-cerebral-renal) synrome
OCLR @ Xq26

Back 240

XL
-defect in inositol metabolism
-DD, hypotonia, DTRs absent
-delayed motor milestones
-cataracts (all affected boys), infantile glaucoma (50%)
-generalized aminoaciduria
-renal tubular dysfunction (fanconi type)
-dx: enzyme activity <10% (on fibroblasts)
-sequencing (95%)

Front 241

NTD risks

Back 241

gen pop in US: 1/1000
one sib: 2%
two sibs: 10%
one parent: 4%
SDR: 1%
TDR: 0.5%

Front 242

Fryns syndrome

Back 242

-diaphragmatic defect (hernia, eventration, hypoplasia or agenesis)
-facies (coarse, ocular hypertelorism, broad and flat nasal bridge, thick nasal tip, long philtrum, low-set and poorly formed ears, tented upper lip, macrostomia, micrognathia)
-distal digital hypoplasia (nails, phalanges)
-pulmonary hypoplasia
-ass'd anomalies (polyhydramnios, cloudy corneas and/or micropthalmia, orofacial clefting, renal dysplasia/renal cortical cysts)
-neonatal lethal, usually (MR if not)
-no genes or testing; clinical diagnosis

Front 243

correct PCR primer orientation?

Back 243

3'----------------------------------------------
|||||||||||3' >

Front 244

what proportion of oocytes are aneuploid?

Back 244

20-25%

Front 245

triploidy

Back 245

-1-3% of all recognized pregnancies
-15-20% of all chromosomally abnl SAB
-6% of all SAB
-<1/20,000 liveborns
-85% diandric - 2 sperm most common
-diandric: **well-grown fetus, **large placenta with appearance of partial hydatidiform mole, **usually don't survive to term, 3/4 syndactyly
-dyginic: growth retarded fetus** w macrocephaly**, small and fibrotic placenta**, can survive to term**, 3/4 syndactyly

Front 246

greatest risk for choriocarcinoma?

Back 246

complete mole

Front 247

aneuploidy risk ass'd with u/s anomalies?
-cystic higroma
-holoprosencephaly
-VSD
-T-e fistula
-hydrops
-multiple anomalies
-CHD

Back 247

cystic higroma - 60%
holoprosencephaly - 47%
VSD - 38%
TE fistula - 40%
hydrops - 32%
multiple anomalies - 29%
CHD - 17%

Front 248

chromosome abnormalities ass'd with increased risk of cancer

Back 248

trisomy 8 - myeloid neoplasia
down syndrome - acute leukemia
47,xxy - breast cancer
45,x/46,xy - gonadoblastoma
5q21-22 - colon ca
11p13, 11p15 - wilms tumor
13q14.2 - retinoblastoma

Front 249

what proportion of birth defects are due to teratogens?

Back 249

2-3% of birth defets are due to drug treatment (more defects are due to other exposures - infection, maternal disease state, etc.)

Front 250

what happens if there is exposure to a teratogen before implantation? (up to 7 days post-fertilization)

Back 250

all or none period

Front 251

what happens if there is exposure to a teratogen during the embryonic period?

18-60 days after conception
3-8 weeks

Back 251

-this is the period of organogenesis
-maximum sensitivity to teratogeneicity b/c tissues developing rapidly and b/c damage becomes irreparable
-greatest likelihood of structural anomaly

Front 252

what happens if there is exposure to a teratogen during the fetal phase?

after 8 weeks

Back 252

-growth and functional maturation of organs and systems
-teratogen exposure affect fetal growth (eg. IUGR), size of organ, function organ
-structural anomalies less likely
-called 'fetal toxicity'
-psychoactive agents (antidepressants, antiepileptics, alcohol, other drugs of abuse) can have an affect on the CNS --> behavioral teratology

Front 253

can the affect of a teratogenic exposure manifest after birth?

Back 253

yes! for example, most adenocarcinomas ass'd wit 1st trimester exposure to synthetic estrogen (diethylstilbestrol), occur many years after exposure

Front 254

what evidence is suggestive of human teratogenicity?

Back 254

-recognizable pattern of anomalies
-statistically higher prevalence of particular anomaly in patients exposed to an agent than in appropriate controls
-presence of agent in teh stage or organogenesis of the affected organ system
-decreased incidence of the anomaly in the population prior to the introduction of the agent
-production of the anomaly in experimental animals by administering the agent in the critical period of organogenesis

Front 255

FDA categories for teratogens
A
B
C
D
X

Back 255

-A - controlled studies show no risk. eg. thyroxine
B - no evidence of risk in humans. -either animal studies show risk, but human studies don't; or no human data but animal data is negative (eg prednisone)

C - risk cannot be ruled out.
--human studies are lacking, animal studies are either lacking or positive (eg. lorazepam)

D - positive evidence of risk
-human data show risk to fetus. (eg. warfarin, valproic acid, lithium)

B, C, D - benefits may still outweigh risks

X - contraindicated in pregnancy
-data shows fetal risk that clearly outweighs benefits (eg. thalidomide, isotretinoin (retinoic acid/accutane)

Front 256

teratogenic counseling

Back 256

-get details of exposure - length, dosage, timing
-other exposures?
-collect relevant current data - assess risk
-counsel:
---background risk
---whether risk is increased
---any specific anoaly ass'd
---methods of prenatal detection and their limitations
---limitations in our knowledge
---risks ass'd with maternal condition itself (ex. diabetes, epilepsy)
-ideally done preconeptually

Front 257

teratogens - alcohol

Back 257

-FAS
-IUGR, growth retard'n continues postnatally
-microcephaly
-developmental delay
-dysmorphic facies: low nasal bridge, midface hypoplasia, long featureless philtrum, small palpebral fissures, thin upper lip
-also - cleft palate and cardiac anomalies may occur

Front 258

teratogens - ACE inhibitors

Back 258

-use in late pregnancy ass'd with fetal toxicity
-neonatal hypotension, oliguria w renal failure, hyperkalemia
-complications of oligohydramnios (limb contractures, lung hypoplasia, craniofacial anomalies)
-prematurity
-IUGR
-fetal death

Front 259

teratogens - DES (diethylstilbestrol)

Back 259

-used in 1950s-1960s for recurrent miscarriage
-1st tri exposure
-clear cell adenocarcinoma of the vagina in adulthood
-benign adenosis of the vagina
-increased miscarriage rate
-males - genetial lesions

Front 260

teratogens - warfarin/coumadin

Back 260

-1st tri exposure, critical period: 6-9 weeks
-'fetal warfarin syndrome'
-nasal hypoplasia
-calcific stippling of the epiphyses
-IUGR, DD (CNS damange)
-eye defects, hearing loss
-increased miscarriage risk

**heparin is not teratogenic!

Front 261

teratogens - antiepileptics

Back 261

-carbamazepine/tegratol - 1% risk of NTD (RR=10)

-hydantoins (phenytoin/dilantin, trimethadione/tridione)
--"fetal hydantoin syndrome"
--dysmoprh - wide anterior frontanelle, oular hypertelorism, metopic ridge, broad depressed nasal bridge, short antevereted nose, bowed upper lip, cleft lip, cleft palate
--hypoplasia of distal phalanges, nail hypoplasia, low arch dermal drige patterning
-MR, growth retard'n, cardiac defects

-valproate (depacon)
--1st tri exposure -- 1-2% risk of meningomyelocele
-'fetal valproate syndrome'
--narrow bifrontal diamtere, high forehead, epicanthal folds, infra-orbital creases, telecanthus, low nasal bridge, short nose w anteverted nares, midfacial hypoplasia, long philtrum, thin vermilion border, small mouth
-cleft lip
-cardiac defects
-long fingers and toes, hyperconvex fingernails

Front 262

teratogens - folic acid antagonists - aminopterin and methotrexate

Back 262

-severe embryopathy, leading to fetal death
-many anomalies
-aminopterin now used for abortions

Front 263

teratogens - isotretinoin (accutane, 13-cis-retinoic acid)

Back 263

-potent teratogen - behavioral and structural
-'retinoic acide embryopathy'
-craniofacial anomalies - microtia or anotia, accessory parietal sutures, narrow sloping forehead, micrognathia, flat nasal bridge, cleft lip and palate, ocular hypertelorism)
-cardiac defects (primarily conotruncal)
-abnormalities in thymic development
-alterations in CNS development
-40% risk of miscarriage

Front 264

teratogens - thalidomide

Back 264

-malformations of tissues of mesodermal origin
-primarily limbs, ears, cardiac, gut muscluature

Front 265

FMRI prenatal testing

Back 265

-amniocytes are ideal specimen
-CVS:
---FMRI methylation status not yet established
---folow-up CVS may be required if male fetus with 100-250 CGG repeats, not methylated
-PGD
---by detection of normal parental alleles, therefore parents must have different numbers
---POF issues in premutation females

Front 266

which neuro condition responds to l-DOPA?

Back 266

dystonia due to GTP cyclyohydrolase I mutation

important to identify since it's treatable

Front 267

Features of DMD carriers

Back 267

-2/3 have CK levels >95th %le
-15-20% have left ventricular dilatation, 7% have DCM
-15% have muscle weakness
-5% have cramps and myalgia
-calf pseudohypertrophy is rare

Front 268

hypertension, preeclampsia, which is assocaited with premature rupture of membranes, IUGR, abruptio placentae,
perinatal death, '50% risk of complications?
a. MSAFP ' 2.5 MoM
b. hCG ' 2.0 MoM
c. MSAFP ' 2.5 MoM and hCG ' 2.0 MoM
d. uE3 < 0.15 MoM

Back 268

Elevated MSAFP AND hCG can be associated with any of these findings.

PROM and IUGR are not usually seen with hCG elevation alone. An elevation in either marker can be
associated with hypertension, pre-eclampsia, or fetal and perinatal demise. What is noteworthy
when both markers are elevated is the very high risk of a poor outcome

Front 269

VWD
von willebrand disase
VWF

Back 269

-AD (rare AR types)
-congenital bleeding disorder
-may only become apparent on hemostatic challenge

Front 270

thrombophelias and pregnancy compications risks

Back 270

-pre-eclampsia - highest risk with protein C and S, but also antithrombin II, factor V, MTHFR homozygosity

-stillbrith - highest risk iwht protein S and factor V Leiden

-VTE - highest risk with factor V leiden and prothrombin G20210A, much higher for double hets for these two

Front 271

what disease can be tested by CVS but not by amnio?

Back 271

osteogenesis imperfecta

b/c collagen studies can be done on CVS but not on amnio

Front 272

prenatal dx scenarios

30yo undergoe amnio b/c of abnl screening w tri 21 risk of 1/125

result: 45,XX,rob(14)(q10;q10)

interpretation? next steps?

Back 272

-parental chromosome studies to determine if de novo or inherited

-if inherited and parent normal - no increased risk

-if de novo, risk not increased above background of 3%

Front 273

prenatal dx scenarios

30yo undergoe amnio b/c of abnl screening w tri 21 risk of 1/125

result: 45,XY, t6;8

interpretation? next steps?

Back 273

-parental chromosome studies

-if de novo, risk of abnl phenotype is 6%

-if inherited, risk for abnl phenotype is low

Front 274

prenatal dx scenarios

30yo undergoe amnio b/c of abnl screening w tri 21 risk of 1/125

result: inversion

interpretation? next steps?

Back 274

-parental chromosome studies

-if de novo, risk of abnl phenotype is 9%

Front 275

prenatal scenaorios

36yo has amnio for AMA. results: marker chromosome

Back 275

-parental chromosome studies - inherited or de novo?

-lab characterize the marker:
---unable to characterize - 13%
---i(18)p, idic(22) or i(12)p - 100% risk
---der (X) without XIST - 100% risk
---no coding material (small, bisatellited) - no increasaed risk

Front 276

prenatal scenario

trisomy 20 mosaicism on amniocentesis - 47,XY +20/46, XY

Back 276

-trisomy 20 is a fairly common finding on amnio
-more likely to e found in baldder, kdineys, intestine
-most cases are phenotypically normal, low risk of abnormal outcome

Front 277

prenatal scenarios

CVS - 100% trisomy 16

Back 277

-not trisomy 16 in the fetus
-trisomy 16 fetus wouldn't make it to 10-13 weeks gestational age

-BUT ass'd with IUGR and pre-eclampsia!!

Front 278

very general rules of thumb - empiric recurrence risks for birth defects

Back 278

1 FDR affected: 3-5%
2 sibs: 8-12%
Both parents: 30-40%
>3 FDR: 45-50%

Front 279

what's on the core AJ panel and the expanded?

Back 279

core (ACOG 04) - CF, TS, canavan, familial dysautonomia

expanded (ACOG 04) - MPSIV, nieman-pick A, fanconi anemia c, bloom, gaucher

(ACMG 08 too)

Front 280

ACOG 2007 HB-opathies guidelines

Back 280

-offer carrier screening to individuals of african, southeast asian, mediterannean decent
-by CBC and HB eletrophoresis
-solubility test inadequate
-offer carrier couples GC'ing, PNDx by DNA analysis

Front 281

CFTR and CBAVD?

Back 281

-in CBAVD pop'n most common CFTR mtn is delftaF508, often trans with 5T
-85% are either a het or double het for CFTR mutations

Front 282

pancreatic cancer risk w BRCA2 mutations?

Back 282

10%

Front 283

possible (and likely) explanation for normal NF1 sequencing in first person in the family with NF1 (or NF2 sequencing in NF2)?

Back 283

mosaicism! very often the first person is mosaic.

better to test younger generation.

Front 284

which genetic conditions can cause azoospermia?

Back 284

10-15% of men with azoospermia have a karyotype abnormality

-Yq deletions, DAZ is most common microdeletion in azoospermia (10%)
-CF or CBAVD -- isolated CBAVD causes obstructive azoospermia and cocurs in 1-2% of infertile men; 85% of men with CBAVD have at least one CFTR mutation
-47,xxy - nonobstructive oligo or azoo

Front 285

which genetic conditions can cause oligospermia?

Back 285

5% of men with oligospermia have a karyotype abnormality.

-unbalanced translocations are more common in men w oligospermia
-47,xxy - non-obstructive oligo or azoo

Front 286

fasting plasma ammonia levels in normal, UCD, transient hyperammonemia of newborn

Back 286

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 - slightly high (54) vs. nl 6-20

arginine:
-CPS, OTC, AS, AL - low
-THAN - normal (30-84)

Front 287

risk for abnormal outcome in 1st cousin mating?

Back 287

3-5%, double the overall background risk of 2-3% (for stillbirth, neonatal death, congenital malformations)

-increased risk for 3rd cousins or more distantly related is negligible

(T&T)

Front 288

Leigh syndrome, NARP
Leigh - many mitochondrial genes
NARP - MT-ATP6 only gene

Back 288

-Leigh and NARP (neurogenic uscle weakness, ataxia, RP) are part of a continuum of progressive neurodegenerative disorders
-Leigh:
--onset 3-12mo, often after viral infection
--decompensation (w lactic acidosis) in incurrent illness - ass'd w psychomoto retardation or regression
-hypotonia, spasticity, movement disorders (chorea), cerbellar ataxia, peripheral neuropathy, cranial nerve abnormalities)
--HCM
--75% die by 2-3yo (usualy respiratory or cardiac failure)
-NARP
--proximal neurogenic muscle weakness w sensory neuropathy, ataxia, pigmentary retionopathy

Front 289

relationship between mutation rate and fitness for calculations?

Back 289

Mutation rate = s*q(allele frequency)
= (1-f)*(allele frequency)

Front 290

calculation of mtn rate from fitness of x-linked recessive

Back 290

Selection Against X-Linked Recessive Mutations – If an X-linked phenotype is benign and if affected males have normal fetuses, 1/3 of mutant alleles are in males and 2/3 are in females. When selective disadvantage against males occurs, µ = s * q/3 When s = 1, 1/3 of all copies a mutant gene are lost in each generation and the disease is a genetic lethal condition.

Front 291

biochemical lab finding ass'd with Lesch-Nyhan syndrome?

Back 291

high uric acid

Front 292

biochemical lab finding ass'd with acute itnermittent porphyria?

Back 292

high delta-aminolevulinic acid

Front 293

biochemical lab finding ass'd with x-linked ardrenoleukodystrophy?

Back 293

high very long chain fatty acids

Front 294

galactosemia

Back 294

-jaundice, abnormal liver function tests (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
-tx: stop breastfeeding, dairy; soy feeds; consdier septic risk; treat liver disease and jaundice

Front 295

at what week in the pregnancy to physiologic omphaloceles resolve by?

Back 295

15 weeks. if seen prior to that an omphalocele may be completely normal and doesn't warrant further testing.

Front 296

is maternal diabetes ass'd with an increased risk for NTD?

Back 296

yes

Front 297

MSAFP at 2.5MoM detection rate for open neural tube defects?

Back 297

80%

Front 298

what percentage of balanced translocations are inherited?

Back 298

70%

(online review course)

Front 299

what phenotype is seen with 46,XY,del(9)(p24) ?

Back 299

sex reversal

Front 300

Which of the following parental karyotypes is associated with the lowest risk for having a liveborn child 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

Back 300

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%

Front 301

ASAFP + ultrasound
-detection rates for NTD and anencephaly?

Back 301

-NTD - 98-99%
-anenceaphaly - virtually all

Front 302

reasons for elevated AFAFP

Back 302

-NTD
-underestimated gestational age
-fetal death
-twins
-blood contamination
-abdominal wall defects (omphalocele, gastroschesis)

Front 303

when is acetylcholinesterase present (AChE)?

Back 303

within open NTD only (not closed, not abdominal wall defect)

Front 304

what is the recommended dosage of folic acid
-general population?
-previous child with NTD?

Back 304

-gen pop: 0.4 mg/day
-previous child: 4mg/day

Front 305

CVS details

Back 305

10-12 wks 6 days
-0.5-1.5% miscarriage risk (some studies say comparable to amnio)
-biochemical testing possible (on chorionic vili, not on amniocytes, ex. collagen studies for OI)
-CVS <10 weeks - increased risk transverse limb abnormality

Front 306

PUBS details

Back 306

->16 weeks
-1-3% fetal loss rate
-rapid karyotyping (48 hrs, tho less of an advantage with interphase FISH on amnio or cvs)
-indications: mgmt of Rh compatibility, featal blood profile for genetic conditons, detection of infection, diagnosis of hemoglobinopathies, confirmation of CVS/amnio results

Front 307

2nd tri screening - time window?

Back 307

15-20 weeks

Front 308

which markers have the strongest ass'n with down syndrome?

Back 308

hCG and Inhibin A

Front 309

MSAFP cutoff and detection rates

Back 309

2.5MoM
-90% of anencephaly
-80% of NTD

Front 310

when do you repeat MSAFP?

Back 310

if it's 2-3MoM (depends on the center)

Front 311

uE3 associations

Back 311

-low in down syndrome
-low in trisomy 18
-very low (0-0.15 MoM) with:
----x-linked ichthyiosis (scaling skin, corneal opacities, hyperkeratosis)
----SLOS (MR, microcephaly, 2-3 toe syndactyly, males w hypogonadism or ambiguous genitalia)
----CAH
----maternal antibiotic or corticosteroid therapy
---anencaphly

Front 312

time window for first trimester screen?

Back 312

10-14 weeks

Front 313

NT>3mm ass'd with?

Back 313

-tri 21, 18, 13
-turner
-triploidy
-CHD
-diaphragmatic hernia
-skeletal dysplasia
-arthrogryposis
-noonan syndrome

-- if karyotype normal offer details ultrasound and fetal echo

Front 314

what maternal serum analyte patterns are ass'd with increased risks of IUGR, fetal demise, preeclampsia, placental dysfunction?

Back 314

-high AFP
-high hCG (>2-3 MoM)
-high Inhibin (>2-2.5 MoM)
-low PAPP-A (<0.35-38 MoM)

Front 315

integrated vs sequential screening?

Back 315

false positive rate is higher in sequential (9% vs. 5%), detection rates are similar

contingent achieves a detection and FPR similar to integrated, but few women come back for the second draw

Front 316

twin pregnancy screening detection rates?

Back 316

-NT 75% with 7% false positive
-integrated screening 45% with 5% false positive

Front 317

interpretation of serum screening results
GA: 15 weeks
Maternal weight: 132 lbs
Race: Caucasian
IDDM: No
Multiple gestation: No
Maternal age at EDD: 34 yo
AFP MoM: 4.75
uE3 MoM: 1.47
hCG MoM: 2.64

Back 317

increased risk for NTD (b/c high AFP)
increased risk for obstetric complications - IUGR, fetal demise, preeclampsia (b/c high AFP)

Front 318

ultrasound sensitivity for defects
-ventral wall defects
-urinary tract
-NTD
-cardiac defects
-cleft lip/palate
-microephaly
-limbs

Back 318

-ventral wall defects - 92%
-urinary tract - 91%
-NTD - 80-90%
-cardiac defects - 13-35% (67% in targeted 2nd tri u/s)
-cleft lip/palate - 30%
-microephaly - 27%
-limbs - 25%

Front 319

down syndrome soft markers on ultrasoudn? which has the biggest effect size/RR?

Back 319

-NT thickening (1st tri)
-nuchal thickening (2nd tri) - biggest effect size/RR
-cardiac defects
-intracardiac echogenic focus
-CPC (more ass'd w tri 18)
-echogenic bowel
-shortened femur and humerus
-dudenal atresia
-pyelectasis
-5th finger clinodactyly

Front 320

cleft lip +/- palate
-ethnicity ass'n?
-ass'n with other congenital defects?
-recurrence risk for sib, child?

Back 320

-native americans > asians > caucasians > hispanics > african americans
-cleft lip - 7-13% ass'd with other anomalies
-cleft lip w palate - 11-14% ass'd with other anomalies
-sib recur. risk 3-7%
-child recur risk 2-4%

Front 321

syndromes ass'd with cleft lip/palate

Back 321

-pierre robin sequence (CP)
-22q del (CP)
-stickler (CP)
-treacher collins (CP)
-van der worude (CL +/- CP, or CP)
-trisomy 13/18 (CL +/- CP)
-apert/crouzon (CP)
-waardenburg (CP or CL)

Front 322

what is cystic hygroma ass'd with?

Back 322

-turner
-trisomies
-triploidy
-noonan
-FAS

"an area of sonolucency in teh soft tissue of the posterior aspects of the neck, consisting of 2 symmetrical cavities completely separated by a midline septum"

Front 323

congenital toxoplasmosis

Back 323

-chorioretinitis (most common finding - eye infection)
-pneumonia
-anemia
-jaundice
-nephritis
-rash

long term: MR, seizures, spasticity, deafnes, blindness

tosoplasosis gondii is a parasite found in undercooked meat, cat feces, soil

-prevention is key, tx w antiobiotics decreases severity but doesn't decrease transmission

Front 324

CMV

Back 324

-congenital CMV: hepatosplenomegaly, chorioretinitis, optic atrophy, microcephaly, hearing loss, MR

-antibody screening, amnio. PUBS as screening tools

-only 5% have abnormal ultrasound (IUGR, echogenic bowel, intracranial calcification, ventriculomegaly)

Front 325

maternal diabetes and birth defects

Back 325

-in 6-10% of poorly controlled patients, up to 20% of very poorly controlled
-NTD
-heart defects
-skeletal defects
-defects in urinary, reproductive, digestive systems
-increased risk of breathing difficulties, hypoglycemia, jaundice

Front 326

teratogens - radiation

Back 326

CNS defects, MR, microcephaly, growth retardation

>5 rads

Front 327

carrier screening for spehardic jewish population - mediteranean

Back 327

-beta thal
-familial mediteranean fever
-glucose-6-phosphate dehydrogenase deficiency
-glycogen storage disease type III

Front 328

which asian countries do not have an increased frequency of hemoglopinopathies?

Back 328

japan and korea

Front 329

what AR conditions are increased in indivdiuals of chinese ancestry (for carrier screening)?

Back 329

beta thal -- 3% (1/33)
alpha thal cis -- 1/20
southern china - hemoglobin e

Front 330

how to test in Tay-Sachs carrier screening?

Back 330

NSGC publication recommends biochemical not molecular testing b/c "simple, inexpensive, and highly accurate"

-hexomindase a and total hoxosaminidase measured in serum -- males, non-pregnant females

-leukocyte hexosaminidase for pregnnat women, women taking OCP, anyone whose seum assy is incocnlusive

-perform molecular analysis when enzyme analysis is abnormal to rule out presence of pseudodeficiency allele (35% of non-AJ heterozygotes are actually carriers of a pseudodeficiency allele)

Front 331

what carrier screening should be offered to individuals of french canadian or cajun ancestry?

Back 331

-tay sachs by enzyme studies
-CF panel

Front 332

prenatal diagnosis for Tay-Sachs?

Back 332

-enzyme analysis on either CVS or amnio sample

-molecular testing if mutation is known in both parents

Front 333

Hispanics - what conditions for carrier screening?

Back 333

-incidence of hemoglobinopathies varies a lot within Hispanic populations dependent on African-origin admixture

-Carribean ancestry is highest: 1/9 for Hb S, 1/30 for Hb C - offer screening

-mexico - low (highest is Hb S at 1/67-1/104) - screening probably not indicated

Front 334

conditions for carrier screening for sephardic jews?

Back 334

-Tay-Sachs - 1/45 in Moroccan Jews; low and same as non-Jewish in other Sephardic Jews
-FMF - 1/3-1/7 in North African jews and Iraqi Jews
-beta-thal - 1/5 in Kurdish and Iranian jews
-alpha-thal - yemenite and iraque jews
-G6PD -

-screen for thalassemias
-screen for tay sachs if Morrocan jewish ancestry
-G6PD screening prior to offering sulpha or related drugs

Front 335

conditions for carrier screening for mediterranean ancestry?

Back 335

mediterranean ancestry: italy, greece, cyprus, portugal, souther spain

-beta-thal - 1/25
-alpha thal (trans) - 1/40
-structural Hb variants - S, D, G, Lepore

-G6PD

Front 336

conditions for carrier screening for middle eastern populations?

Back 336

-beta-thal
-Hb S in some countries (eastern saudi arabia, central india, bepal, turkey, syria)
-Hb E - India, Nepal, Srik Lanka, Bhutan, Bangladesh
-other structural Hb variants
-alpha thal - trans

-offer Hb studies,
-G6PD before sulphas and related drugs
-FMF if family mtn is known

Front 337

which peroxisome disorder has normal VLCFA?

Back 337

-rhizomelic condrodysplasia punctata - VLCFA are normal

-VLCFA are elevated in other disorders (zellweger, refsum, adrenoleukodystrophy)
-VLCFA are the most common and informative initial screen

Front 338

what is elevated MSAFP associated with?

Back 338

-NTD
-ventral wall defect
-intrauterine fetal demise
-premature or low birth-weight baby
-gestational dates underestimated
-congenital skin defects, pilonidal cysts, GI defects, cloacal exstrophy, cystic hygroma, sacrococcygeal teratoma, renal anomalies (polycystic kidney, absent kidney, congenital nephrosis)
-OI
-low birth-weight, oligohydroamnios, multiple gestations, decreased maternal weight
-obstruction, liver necrosis, urinary obstruciton