• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off

Card Range To Study



Play button


Play button




Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

338 Cards in this Set

  • Front
  • Back
Max resolution of a high res karyotype?
mtDNA - size, number of genes?
16.5kb, 37 genes
FISH resolution
1-100 kb
PWS - lacking ____ contribution of _____.
paternal, 15q11-13
Angelman - lacking _______ contribution of _________.
maternal, 15q11-13
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%)
unknown case (10-15%)
AR diseases with de novo mutations
21-hydroxylase deficiency
HD repeat ranges
<35 normal
35-39 intermediate
<40 affected

<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 in coding region (i.e. polyglutamine disorder)
Fragile X repeat ranges
<50 normal
50-58 intermediate
59-200 premutatoin
100-200 premutation with 100% of expanding to full mtn in oogenesis
>200 affected, hypermethylated
Fragile X repeat: _ _ _ in the _____ region of the gene.
CGG in the 5' UTR
Myotonic dystrophy repeat ranges
<30 normal
50-80 may be mildly affected
80-2000 affected
Myotonic dystrophy: _ _ _ in the ________ region of the gene
CTG in the 3' UTR
Friedreich ataxia repeat ranges
<34 normal
36-100 intermediate
>100 affected
Friedreich ataxia repeat: _ _ _ in the ______ region.
AAG in an intron
example of pseudoautosomal inheritance
mutations in SHOX or SHOXY (also cause short stature)
or deletions
in pseudoautosomal region
Ypter-p11.2, Xpter-p22.32
what region of the X chromosome is critical for ovarian function?
mutation rate
• 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
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 is 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 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))
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)
which mitochondrial diseases are caused by the same mutation?
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
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
Beta-thal trait -- which ethnicities is it prevalent in and what's the carrier rate?
Mediteranean - 1/20-1/30
Hispanic - 1/30-1/50
SE asian - 1/30
Asian subcontinent (india, pakistan) - 1/30

(from ACMG)
alpha-thal trait - which ethnicities? what carrier rate? cis or trans?
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
sickle cell - which ethnicities? carrier frequencies?
african-american 1/12
caribbean, west indean 1/12
west african 1/6
Hb C - which ethnicities? what carrier rate?
african-american 1/50
caribbean, west indian - 1/30
west african 1/20-1/30
what is the time frame for amnio?
beginning of 15th week to end of pregnancy
what is the time frame for CVS?
10-12weeks and 6 days
What conditions are low uE3 associated with?
x-linked ichthyosis
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
which birth defects are more common in males than females?

pyloric stenosis (4.43:1)
hirschsprung disease (2.79:1)
clubfoot (1.43:1)
cleft lip with/without palate (1.41:1)
congenital diphragmatic hernia
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 hip (0.33:1)
absence of ribs
Significance of poly T and TG tracts in CFTR.
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 (?)
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% all other DFNB loci
AD deafness syndromes
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
AR deafness syndromes
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
Biotinidase deficiency
Refsum - progressive SNHL and RP. Treatable! metabolic.
XL deafness syndromes
Alport - postlingual progressive SNHL, kidney failure, ophtho findings. (85% XLR, 15% AR, also AD reported)
FGFR3 disorders (GoF or LoF?)
achondroplasia (GoF Gly280Arg)
hypochondroplasia (GoF N540K, others)
thanatophoric dysplasia (GoF, heterogeneous?)
SADDAN (GoF? Lys650Met)
Crouzon with acanthosis nigras (Ala391Glu)
nonsyndromic coronal synostosis
Muenke synd.
FGFR2 disorders (GoF or LoF?)
Crouzon syndrome (GoF)
Jackson-Weiss syndrome (GoF
Apert (GoF, P253R-syndactyly more common, S252W-cleft palate more common)
Pfeiffer (GoF
isolated coronal synostosis (GoF
FGFR2 craniosynostosis synd and their distinguishing features
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
which coronal craniosynostosis syndrome is NOT caused by an FGFR mutation?
Saethre-chotzen syn - TWIST1 mtns, dels, dups

Low frontal hairline, ptosis, strabismus, facial asymmetry
Small ears with a prominent crus
Limb 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 -
SCA 1,2,3,6,7,17
DRPLA (Dentatorubropallidoluysian atrophy)
Which repeat disorders involve repeats in introns?
Fredreich ataxia (only AR) (GAA in intron 1)
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)
Which repeat disorders expand more frequently in oogenesis?
myotonic dystrophy (esp. congenital MD alleles (>1000))
fragile x
friedrech's ataxia
SCA8 (unlike other SCAs)
F, R, and how to calculate them
• 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
how do you calculate F?

what is it for sibs? first cousins?
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
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
R - 1/16
F = 1/32
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:
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.
gen pop risk for:
cleft lip/palate
NTD: 1-2/1000 (caucasian)
CHD: 1/100
cleft lip/palate:
overall: 2-4%
over the course of the pregnancy, what is the pattern for each of these serum markers:

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
initially elevated AFP is repeated if...
value is <3.0 MOM
gestational age is <18weeks
where made?
pattern over gestation?
what pattern ass'd with tri 13? 18? 21?
made in embryo and placenta
increases over gestation
low levels ass'd with 13,18,21
detectable as early as 8 weeks
where made?
pattern over gestation?
what pattern ass'd with tri 13? 18? 21? other findings?
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
where made?
pattern over gestation?
what pattern ass'd with tri 13? 18? 21? other findings?
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
Inhibin A
where made?
pattern over gestation?
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
where made?
pattern over gestation?
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
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?
(B) Fatty acid oxidation defects
does tyrisonemia type 1 have MR?
what is the I1307K variant?
in APC
6% of Ashkenazi Jews
susceptibility allele, 2-3x risk
not used clinically b/c of low PPV, NPV
Which condition other than HNPCC can have MSI?
Turcot! FAP variant with CNS tumors, can be caused by Lynch genes
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?
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.
What is hereditary colon cancer syndrome x?
meets Amsterdam criteria for lynch but normal MSI and IHC.
What are the Amsterdam and Amsterdam II criteria?
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.
Homozygous PMS2 phenotype?
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
what genes are associated with Turcot syndrome?
2/3 APC
1/3 mismatch repair genes
Sickle cell - phenotype, lab findings for:
Hgb (amount of Hb)
Hb electrophoresis

and for trait/het?
HbSS - hemolytic anemia, aplastic crises, delayed growth, ischemia - acute pain, organ damage, first manifestation is dactylitis

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

MCV: nl
MCH: nl
Hgb: nl
Hb: HbA 60% (reduced)
HbS 34-42%
HbF <1%
HbA2 1-2%
Sickle cell/Hb C disease - phenotype?

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

and for trait/het?
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%

MCV: nl
MCH: nl
Hgb: nl
Hb: HbA 50-60% (reduced)
HbC 40-50%
HbF 1%
Beta-thal major - brief pheno
Hgb (amount of Hb)
Hb eletrophoresis

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

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
Normal Hb studies:
Hgb (amount of Hb)
Hb eletrophoresis
MCV 89.1 (male), 87.6 (female)
MCH 30
Hgb Hb: 15.9 (male) 14(female)
HbA 96%-98%
HbF <1%
HbA2 2%-3%
alpha thal lab values for
-minor (two -)
-silent (one -)
Hgb (amount of Hb)
Hb eletrophoresis
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%
overall strategy for identifying thalassemia carriers by CBC?
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
Lab values for Hb barts and HbH disease in alpha thalassemia?
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)
HbA 60-90%
HbF <1%
HbA2 <2%
HbBart 2-5%
HbH 1-40%
what proportion (%) of spontaneous abortions result from aneupoidy?
50% (online course)
what is another name for 47,XYY?
jacob's syndrome
what proportion of conceptions are aneuploid?
10-30% (Genzyme)
What proportion of newborns are aneuploid?
0.3% (1/333)
Prenatally, which trisomies are most common?
16 (31% of prenatal trisomies)
22 (10%)
21 (9%)
15 (8%)
18 (6%)
13 (5%)
Age-related risks? Tri 21 and all chromosome abnormalities?
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
how often does confined placental mosaicism occur with CVS? what outcomes is it associated with? how often is it true fetal mosaicism?
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)
when seen as CPM on CVS, which chromosomes are more often due to *meiotic* nondisjunction and may be associated with UPD?
9, 16, 22
when seen as CPM on CVS, which chromosomes are more often due to *mitotic* nondisjunction and are *less* likely to be associated with UPD?
2, 7, 8, 10, 12
which ultrasound findings have a high risk of anueploidy and what are the risks?
cystic higroma - 60%
holoprosencephaly - 47%
VSD - 38%
T-E fistula - 40%
hydrops - 32%
MCA - 29%
CHD - 17%
what's the empiric risk for congenital anomoly with an apparently balanced de novo rearrangement?

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

how do you assess risk of an abnormal liveborn from a carrier of a balanced reciprocal translocation?
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.
What is alternate segregation of a reciprocal translocation? what are the outcomes? how common is it?
results in balanced and normal. no unbalanced outcome. most common segregation pattern.
what is adjacent 1 segregation of a reciprocal transolcation? what are the outcomes? how common is it?
results in unbalanced. centromeres segregate as expected. i.e. homologous centromeres separate.
what is adjacent 2 segregation of a reciprocal translocation? what are the outcomes? how comon is it?
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.
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?
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.
what is the empiric risk of an unbalanced karyotype in offspring of carriers of

-a pericentric inversion with small distal segments?

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

paracentric inversion have 0.5% risk.

what are the recurring terminal deletions?
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
what conditions are seen in association with 22q11.2?
22q11.2 deletion synd.

dup 22q11.2 - MR, autism

4x22q11.2 - cat-eye syndrome (usually dicentric bisatellited marker chromosome)
which chromosome are 1/2 of all supernumary chromosomes from?
15 -- test for UPD (in both familial and de novo cases)
what is the most common mechanism that creates missense mutations?
deamination. especially a 5-methylcytosine --> thymine
heritability estimate from twin studies?
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)
during the 15-20wk window of second triemster serum screening, what are each of the analytes doing? i.e. stable, decreasing, increasing?
inhibin A - stable

hCG - decreasing

uE3 - increasing
AFP - increasing
what factors affect analyte levels in MSS and how?
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
what is the AFP cut-off?
2.5MoM - for NTD, ab'l wall defect
what are the risk cutoffs (in CA) for T21, T18, SLOS in MSS?
T21 - 1/150
T18 - 1/100
SLOS - 1/250
ethnicity-based screening in prenatal clinic (based on Luanne Hudgins' lecture)
all women: screen for thalassemias
-if MCV <80 - hemoglobin electrophoresis

African-american: sickle cell
-hemoglobin electrophoresis

northern european: CF
-25 most common mutations

-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)
what is the false positive rate of PGD?

amnio or CVS recommended
what is one situation that PUBs is useful for?
u/s shows fetus has bilateral absence of radii

fetus may have thrombocytopenia absent radii (TAR). PUBS allows for study of fetal platelets.
how is spina bifida diagnosed by ultrasound?
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.
which disorder is better tested by CVS than amnio?
OI - b/c collagen studies need to be done on CVS sample.
what fraction of trisomy 16 on CVS is CPM?
all of it, essentially. so no risk for even mosaic trisomy 16.

but, there are assocaited negative outcomes: increased risk preeclampsia and IUGR
what is the most common risk from 2nd trimester amniocentesis?
rupture of fetal membranes. will often seal over.

this is more common than miscarriage.
what is the recurrence risk for spina bifida when a couple had a previous child with spina bifida?

(vs. 0.1% gen pop)
is there an association between maternal age and AFP levels?
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.
NTD risk factors?
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
what should you do if a pregnant woman has a big NT >3.0 (? >4.0)?
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
what is an increased nuchal translucency assocaited with?
trisomy 21, 18, 13
turner syndrome

cardiac abnormalities

noonan syndrome
skeletal dysplasias
congenital diaphragmatic hernia

many other rare genetic conditions
which trisomy is better picked up by first trimester screening than by second trimester screening?
trisomy 13 - b/c many have an increased NT
a sequence is?
single event, usuaslly of unknown etiology, that leads to multiple deformations and disruptions
what is the notable feature of aicardi syndrome?
retinal lacunae
what are the empiric and theoretical risks for a first cousin mating to have a child with birth defects, genetic disorder, etc?
theoretical: R=1/8, F=1/16, chance of rare AR disease =1/32 = ~3%

empiric risk for birth defects (T&T) = 3.6%
what is the limit of consanguinity in terms of genetic significance?
consanguinity among individuals that are 3rd cousins or more distantly relaed is not genetically significant.
how does recombination distance (θ) compare to physical distance (base pairs)?
θ = 0.01 = 1cM ~ 1 Mb (1x10^6 bp)

(average gene is 10-15kb or 0.015 Mb)
how do you calculate new mutation rate given an incidence and fitness?
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
bayes, HW, other mat
read the question!!
what are they asking for?!
after you're done, re-read the question. did you answer what they are asking for?
what method of prenatal diagnosis must be used for OI ass'd with type I collagen abnormalites?
CVS not amnio (b/c abnl type I collage runs on gel similar to normal from amniocytes)
what method of prenatal diagnosis is used for biotinidase deficiency?
amnio - look for metabolites in amniotic fluid or dx on maniocytes (by enzyme assay?)
what type of prenatal diagnosis is needed for OTC deficiency?
molecular testing. can't do enzyme or biochemical b/c OTC is expressed only in teh liver.
what type of prenatal diagnosis is needed for GSD 1A?
molecular testing. can't do enzyme or biochemical because expressed only in liver.
genetic conditions ass'd with infertility
-45,X (and mosaics)
-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
ART ass' brith defects risk?
-meta-analysis found 30-40% increase in brith defects with ART (i.e. OR=1.3)
-true for IVF w and w/o ICSI
ass'n between ART and imprinting disorders?
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)
when seen on 2nd tri ultrasound, what conditions is an isolated omphalocele suggestive of?
BWS (20% chance)
when seen on 2nd tri ultrasound, what conditions is a congenital diaphgragmatic hernia suggestive of?
pallister killian (12p tetrasomy)
when seen on 2nd tri ultrasound, what conditions is an lissencephally suggestive of?
miller deiker
when seen on 2nd tri ultrasound, what conditions is an IUGR/ambiguous genitalia suggestive of?
trisomy 21 ultrasound findings?
ventriculomegaly, brachycephaly
nuchal thickenng
cardiac defect (AV canal)
dudenal atresia, echogenic bowel
renal pyelectasis
shortened femur/humerus
clinodactyly of 5th finger
ultrasound findings in trisomy 18?
CNS - agenesis of corpus callosum, meningomyelocele, ventriculomegaly
cystic hygroma
cardiac anomalies
*congenital diaphragmatic hernia
*clenched hands with overlaping digits
IUGR with polyhydramnios
ultrasound findings in trisomy 13?
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
ultrasound findings ass'd with Turner?
*cystic hygroma
cardiac defects (coarc)
*horseshoe kidneys
ultrasound findings ass'd with triploidy?
CNS - holoposencephaly, agenesis of corpus callosum, meningomyelocele, dandy walker malf'n
hypertelorism, micrognathia
*syndactyly 3rd/4th
cardiac defects
*early onset IUGR affected skeleton more than head
*placental abnormalities - enlarged, or small and calcified
aneuploidy risk by major anomaly on u/s?
cystic hygroma
AV canal
duodenal atresia
bladder outlet obstruction
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
aneuploidy risk by major anomaly on u/s?
cardiac defects
limb reduction
facial clefts
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-
Cytogenetic abnormalities ass'd with infertility in males?
47,XXY (most common; nonobstructive azoospermia)
DAZ microdeletion (frequent in oligospermia)
Yq microdeletions
46,XX w SRY del'n
-balanced transloc'n more common with oligosp. (oligospermia)
-sex chromosome abnlts increase with decreasing sperm count


CBAVD - obstructive azoospermia
loss rate for early amnio (<12wks)?
vs. CVS 1%
vs. standard amnio 0.5%
risk of sex chromosome aneuploidy with ICSI?
1% - may be due to underlying sex chromosome aneuploidy in father or due to ICSI itself.
If a fetus has a nuchal translucency increased to 2 standard deviations at 11-14 weeks, the most
likely karyotype finding is
normal karyotype

-risk of aneuploidy increased, but normal outcome still most likely
Cytogenetic abnormalities ass'd with infertility in males?
47,XXY (most common; nonobstructive azoospermia)
DAZ microdeletion (frequent in oligospermia)
Yq microdeletions
46,XX w SRY del'n
-balanced transloc'n more common with oligosp. (oligospermia)
-sex chromosome abnlts increase with decreasing sperm count


CBAVD - obstructive azoospermia
loss rate for early amnio (<12wks)?
vs. CVS 1%
vs. standard amnio 0.5%
risk of sex chromosome aneuploidy with ICSI?
1% - may be due to underlying sex chromosome aneuploidy in father or due to ICSI itself.
If a fetus has a nuchal translucency increased to 2 standard deviations at 11-14 weeks, the most
likely karyotype finding is
normal karyotype

-risk of aneuploidy increased, but normal outcome still most likely
AR disorders of increased frequency for prenatal carrier screening?
beta thal: 1/25
alpha thal: /140 (trans)
sickle cell: 1/40
AR disorders of increased frequency for prenatal carrier screening?
-African American
sickle cell: 1/12
alpha thal: 1/30 (trans)
Hb C: 1/50
beta thal: 1/65
G6PD-A: 1/10 males
AR disorders of increased frequency for prenatal carrier screening?
-Non-Hispanic Caribbean, W. Indian
sickle cell: 1/12
Hb C: 1/30
alpha thal: 1/30 (trans)
AR disorders of increased frequency for prenatal carrier screening?
-West African
sickle cell: 1/6
Hb C: 1/25
alpha thal: 1/30 (trans)
AR disorders of increased frequency for prenatal carrier screening?
-Hispanic (Mexican; Central Amer'n)
beta thal: 1/40
AR disorders of increased frequency for prenatal carrier screening?
alpha-thal: 1/20 (*cis)
beta thal: 1/50
AR disorders of increased frequency for prenatal carrier screening?
-Southeast Asian
alpha-thal: >1/20 (*cis)
beta thal: 1/30
AR disorders of increased frequency for prenatal carrier screening?
-Asian subcont (India, Pakistan)
beta thal: 1/50
AR disorders of increased frequency for prenatal carrier screening?
-midle eastern
beta thal: 1/50
Sickle cell disease
-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%
Hb Bart disease
-non-immune fetal hydrops
-usually death in neonatal period
-all four alpha globin genes deleted
-really only occurs in asians (b/c cis)
Hb H disease
-2 alpha globin genes deleted
-mild to moderate microcytic hypochromic hemolytic anemia
-mild jaundice
-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
alpha thal trait, silent carrier
-2 deleted
-microcytosis, hypocrhomia, normal % HbA2, Hb F (vs. beta thal trait)

"silent carrier"
-one deleted
-no phenotype
beta-thal major
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
beta-thal intermedia
-milder and later symptoms
-rarely need transfusion
-at risk for iron overload due to increased intestinal absorption of excess iron from ineffective hematopoiesis
beta-thal minor (carrier)
-asymptomatic or mildly anemic
-MCV <79
-minor RBC morphological changes
beta-thal causes
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.
what makes beta-thal milder?
HPFH and alpha-thal trait
cystic fibrosis
-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
fragile x prevalence, carrier rates
full mtn:
-1/1250 males
-1/200 females
-1/150 women
-1/755 men
FXTAS phenotype and penetrance?
-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%
empiric recurrence risks for deafness
-sib of deaf child w hearing parents
----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
SAB chromosomal abnlts
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)
thrombophilia and miscarriage
-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)
CF carrier frequency and detection rate
-northern european
-southern european
-AJ jews
-other pop'ns
-northern european: 1/25, 85-90%
-southern european: 1/25, 70%
-AJ: 1/26, 97%
-others <=70%
---asians - 30%
---Hispanic 57%
as the age of a subset of women undergoing aneuploidy screening increases, what happens to the detection rate and false positive rate?
both increase.
-overall 75% detec'n rate, 5% FPR
-20yo: 45% detec'n rate, 3% FPR
-40yo: 92% detec'n rate, 40% FPR
aneuploidy screening detection rates and false positive rates (for down syndrome)
-2nd tri quad: 82%, 7%
-1st tri NT + serum: 86%, 4%
-1st + 2nd tri: 93%, 2.6%

(cut off of 1/270)
what is the 2nd tri analyte pattern if gestatinal age > dating?
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)
what is the 2nd tri analyte pattern if gestational age < dating
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)
AR disorders - carrier screening should be offered to AJ individuals?
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%
what is the risk of servere abnormality or mortality related to a genetic disorder in teh first child of first cousins?
3% background + and additional 3%
what analytes are abnormal in 2nd tri screening with anencephaly
AFP is up
uE3 may be down
NSGC recommendations for genetic counseling and screening of consanguineous couples.
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
fetal alcohol syndrome
-growth retardation
-mental retardation
-short palpebral fissures
-short nose
-smooth philtrum
-thin upper lip
-small distal phalanges
-hypoplastic finger nails
-cardiac defects
maternal PKU
-growth retard'n
-mental retard'n
-cardiac anomalies
maternal diabetes
-hypoglycemia, hypocalcemia
-CNS anomalies
-cardiac anomalies
-caudal regression
retinoic acid embryopathy
-anotia, microtia
-ipsilateral facial nerve paralysis
-CNS and cardiac anomalies
hydantoin (anticonvulsant) embryopathy
-growth retard'n
-mental retard'n
-large anterior fontanelle
-metopic ridge, hypertelorism
-short nose, falt bridge
-small nails, distal phalanges
-arch fingertip pattern
potter sequence
-primary anomaly: obstruction of urinary tract
->renal disease->oligohydramnios and compression
-potter's facies - flat nasal bridge, retrognathia
pierre robin sequence
-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
what is a deformation?
-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
what is a disruption?
-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
cleft lip w/wo palate and cleft palate alone
-CP alone is twice as likely to be part of a genetic syndrome (25-40% vs. 10-25%)
-CL/P: M:F=2:1; CP: M:F=1:2
-recurrence risk:
---sporadic CP: 1%
---sporadic CLP: 1-5% (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
X-linked disorders with male lethality
-aicardi syndrome
-goltz syndrome (focal dermal hypoplasia)
-incontinentia pigmenti
-rett syndrome
-chondrodysplasia punctata
alpha-1-antitrypsin deficiency
chromosome 14
-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
polycystic kidney disease
-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)
components of human genome
1.5-2% protein-coding genes
26% introns
12% miscellaneous unique sequences
8% miscellaneous
50% repeats
---20% LINEs
---13% SINEs
AJ conditions for screening
-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
-herry red spot of macula
-AJ alleles: G269S, 1278insTATC, 1421+1G>C in IVS12
AJ conditions for screening
-Canavan disease
-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
AJ AR diseases for carrier testing
-familial dysautonomia
-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
AJ AR diseases for carrier testing
-Fanconi Anemia type C
-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
AJ AR diseaes for carrier testing
-mucolipidosis IV
-severe psychomotor delay by end of 1y
-progressive retinal degeneration and corneal clouding in first decade
-MR, most never speak, walk
-AJ carrier rate 1/127, 95% detection rate
AJ AR diseases for carrier testing
-Niemann pick type A
-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
AJ AR diseases for carrier testing
-aka von Gierke disease; GSD1a
-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
AJ AR diseases for carrier testing
-Bloom syndrome
-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
AJ AR diseases for carrier testing
-Gaucher disease type 1
-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
techniques for detecting specific small mutations (small deletions, missense, etc.)
-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)
techniqus for detecting deletions and duplications
-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)

advantage of microsatellite repeats vs. restriction fragment length polymoprhisms?
microsatellites are multi-allelic and are therefore often informative for linkage
familial dysautonomia
-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
NF1 features by age
--plexiform neurofibromas
--tibial dysplasia
-school age
--optic glioma
--lisch nodules
--short stature
--dermal neurofibromas
NF1 diagnostic criteria
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
NF2 diagnostic criteria
-bilateral vestibular schwannomas
-FDR w NF2 and any two of:
---juvenile posterior subcapsular cataract/cortical wedge opacity
TSC diagnostic criteria
-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
-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
-hemangioblastoma (cerebellum, retina, spinal cord)
-renal cell carcinoma
-endolympathic sac tumor
Basal cell nevus (Gorlin) syndrome
-basal cell nevi/carcinomas
-rib anomalies
-cysts in mandible
-patched mutations, tumor supressor gene
syndromes ass'd with holoprosencephaly
-chromosomal (50% of cases)
friedreich ataxia
-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
-cerebral arteriopathy w subcortical infarcts and leukoencephalopathy
-AD, notch3 gene (most are misssense mtns)
-small artery occlusions > ischemic episodes and strokes
what disorder is caused by a deletion on 17p? duplication?
deletion - heredtiary liability to pressure palsies.

duplication - CMT1A
newborn with weakness, hypotonia, absent reflexes, tongue fasiculations. what's the diagnosis?
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
cause of CMT1A??
duplication on 17p
trisomy 13 etiology?
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
linkage vs. association
-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
-specific DNA damange deficiency
-repair of double stand DNA breaks
-avoid ionizing radiation
-specific DNA damage deficiency
-chromatid/chromosome breaks on testing
-avoid UV light, x-ray
-specific DNA damage deficiency
-impaired ability to sense, excise, repare UV-induced damage
-protect from UV light,
what conditions have cataracts as a feature?
-lowe syndrome
-stickler synd
-myotonic dystrophy
-NF2 (juvenile posterior subcapsular lenticular opacity/juvenile cortical cataract)
-congenital rubella
-chondrodysplasia punctata
what syndromes is polydactyly a feature of?
-trisomy 13
-chondroectodemial dysplasia (ellis-van creveld)
-Greig cephalopolysyndactyly syndrome
Warburg syndrome
-dies at 10 days of age
-cerebellar hypoplasia
-dandy-walker cyst
-retinal detachment with retinal dysplasia
Langer-Giedion syndrome
-only 1/4 are cytogenetically visible
-true contiguous gene syndrome - TRPS1 gene and EXT1 gene
-MR, microcephaly, multiple exostoses, redundant skin, sparse hair
campomelic dysplasia
-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%)
incontinentia pigmenti
IKBKG (aka NEMO) @ Xq28
-XLD, lethal in males, Xq28
-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%)
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
chondrodysplasia punctata
-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
lowe syndrome (oculo-cerebral-renal) synrome
OCLR @ Xq26
-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%)
NTD risks
gen pop in US: 1/1000
one sib: 2%
two sibs: 10%
one parent: 4%
SDR: 1%
TDR: 0.5%
Fryns syndrome
-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
correct PCR primer orientation?
|||||||||||3' >
what proportion of oocytes are aneuploid?
-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
greatest risk for choriocarcinoma?
complete mole
aneuploidy risk ass'd with u/s anomalies?
-cystic higroma
-T-e fistula
-multiple anomalies
cystic higroma - 60%
holoprosencephaly - 47%
VSD - 38%
TE fistula - 40%
hydrops - 32%
multiple anomalies - 29%
CHD - 17%
chromosome abnormalities ass'd with increased risk of cancer
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
what proportion of birth defects are due to teratogens?
2-3% of birth defets are due to drug treatment (more defects are due to other exposures - infection, maternal disease state, etc.)
what happens if there is exposure to a teratogen before implantation? (up to 7 days post-fertilization)
all or none period
what happens if there is exposure to a teratogen during the embryonic period?

18-60 days after conception
3-8 weeks
-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
what happens if there is exposure to a teratogen during the fetal phase?

after 8 weeks
-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
can the affect of a teratogenic exposure manifest after birth?
yes! for example, most adenocarcinomas ass'd wit 1st trimester exposure to synthetic estrogen (diethylstilbestrol), occur many years after exposure
what evidence is suggestive of human teratogenicity?
-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
FDA categories for teratogens
-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)
teratogenic counseling
-get details of exposure - length, dosage, timing
-other exposures?
-collect relevant current data - assess risk
---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
teratogens - alcohol
-IUGR, growth retard'n continues postnatally
-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
teratogens - ACE inhibitors
-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)
-fetal death
teratogens - DES (diethylstilbestrol)
-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
teratogens - warfarin/coumadin
-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!
teratogens - antiepileptics
-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
teratogens - folic acid antagonists - aminopterin and methotrexate
-severe embryopathy, leading to fetal death
-many anomalies
-aminopterin now used for abortions
teratogens - isotretinoin (accutane, 13-cis-retinoic acid)
-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
teratogens - thalidomide
-malformations of tissues of mesodermal origin
-primarily limbs, ears, cardiac, gut muscluature
FMRI prenatal testing
-amniocytes are ideal specimen
---FMRI methylation status not yet established
---folow-up CVS may be required if male fetus with 100-250 CGG repeats, not methylated
---by detection of normal parental alleles, therefore parents must have different numbers
---POF issues in premutation females
which neuro condition responds to l-DOPA?
dystonia due to GTP cyclyohydrolase I mutation

important to identify since it's treatable
Features of DMD carriers
-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
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
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
von willebrand disase
-AD (rare AR types)
-congenital bleeding disorder
-may only become apparent on hemostatic challenge
thrombophelias and pregnancy compications risks
-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
what disease can be tested by CVS but not by amnio?
osteogenesis imperfecta

b/c collagen studies can be done on CVS but not on amnio
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?
-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%
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?
-parental chromosome studies

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

-if inherited, risk for abnl phenotype is low
prenatal dx scenarios

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

result: inversion

interpretation? next steps?
-parental chromosome studies

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

36yo has amnio for AMA. results: marker chromosome
-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
prenatal scenario

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

CVS - 100% trisomy 16
-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!!
very general rules of thumb - empiric recurrence risks for birth defects
1 FDR affected: 3-5%
2 sibs: 8-12%
Both parents: 30-40%
>3 FDR: 45-50%
what's on the core AJ panel and the expanded?
core (ACOG 04) - CF, TS, canavan, familial dysautonomia

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

(ACMG 08 too)
ACOG 2007 HB-opathies guidelines
-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
-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
pancreatic cancer risk w BRCA2 mutations?
possible (and likely) explanation for normal NF1 sequencing in first person in the family with NF1 (or NF2 sequencing in NF2)?
mosaicism! very often the first person is mosaic.

better to test younger generation.
which genetic conditions can cause azoospermia?
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
which genetic conditions can cause oligospermia?
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
fasting plasma ammonia levels in normal, UCD, transient hyperammonemia of newborn
normal - 15-35uM
THAN - 4,750uM
CPS - 1,000uM
OTC - 1,100uM
AS - 892
AL - 807

use citrulline and arginine to differentiate:

-CPS & OTC - no/v. low citrulline
-AS - vs. high (2656) citulline
-AL - high citrulline (176)
-THAN - slightly high (54) vs. nl 6-20

-CPS, OTC, AS, AL - low
-THAN - normal (30-84)
risk for abnormal outcome in 1st cousin mating?
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

Leigh syndrome, NARP
Leigh - many mitochondrial genes
NARP - MT-ATP6 only gene
-Leigh and NARP (neurogenic uscle weakness, ataxia, RP) are part of a continuum of progressive neurodegenerative disorders
--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)
--75% die by 2-3yo (usualy respiratory or cardiac failure)
--proximal neurogenic muscle weakness w sensory neuropathy, ataxia, pigmentary retionopathy
relationship between mutation rate and fitness for calculations?
Mutation rate = s*q(allele frequency)
= (1-f)*(allele frequency)
calculation of mtn rate from fitness of x-linked recessive
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.
biochemical lab finding ass'd with Lesch-Nyhan syndrome?
high uric acid
biochemical lab finding ass'd with acute itnermittent porphyria?
high delta-aminolevulinic acid
biochemical lab finding ass'd with x-linked ardrenoleukodystrophy?
high very long chain fatty acids
-jaundice, abnormal liver function tests (LFTs), hyperbilirubinemia
-bleeding diatheses, burising, coagulopathy
-feeding problems
-irritability, lethargy
-elevated amino acids
-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
at what week in the pregnancy to physiologic omphaloceles resolve by?
15 weeks. if seen prior to that an omphalocele may be completely normal and doesn't warrant further testing.
is maternal diabetes ass'd with an increased risk for NTD?
MSAFP at 2.5MoM detection rate for open neural tube defects?
what percentage of balanced translocations are inherited?

(online review course)
what phenotype is seen with 46,XY,del(9)(p24) ?
sex reversal
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
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
-detection rates for NTD and anencephaly?
-NTD - 98-99%
-anenceaphaly - virtually all
reasons for elevated AFAFP
-underestimated gestational age
-fetal death
-blood contamination
-abdominal wall defects (omphalocele, gastroschesis)
when is acetylcholinesterase present (AChE)?
within open NTD only (not closed, not abdominal wall defect)
what is the recommended dosage of folic acid
-general population?
-previous child with NTD?
-gen pop: 0.4 mg/day
-previous child: 4mg/day
CVS details
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
PUBS details
->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
2nd tri screening - time window?
15-20 weeks
which markers have the strongest ass'n with down syndrome?
hCG and Inhibin A
MSAFP cutoff and detection rates
-90% of anencephaly
-80% of NTD
when do you repeat MSAFP?
if it's 2-3MoM (depends on the center)
uE3 associations
-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)
----maternal antibiotic or corticosteroid therapy
time window for first trimester screen?
10-14 weeks
NT>3mm ass'd with?
-tri 21, 18, 13
-diaphragmatic hernia
-skeletal dysplasia
-noonan syndrome

-- if karyotype normal offer details ultrasound and fetal echo
what maternal serum analyte 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)
integrated vs sequential screening?
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
twin pregnancy screening detection rates?
-NT 75% with 7% false positive
-integrated screening 45% with 5% false positive
interpretation of serum screening results
GA: 15 weeks
Maternal weight: 132 lbs
Race: Caucasian
Multiple gestation: No
Maternal age at EDD: 34 yo
AFP MoM: 4.75
uE3 MoM: 1.47
hCG MoM: 2.64
increased risk for NTD (b/c high AFP)
increased risk for obstetric complications - IUGR, fetal demise, preeclampsia (b/c high AFP)
ultrasound sensitivity for defects
-ventral wall defects
-urinary tract
-cardiac defects
-cleft lip/palate
-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%
down syndrome soft markers on ultrasoudn? 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)
-echogenic bowel
-shortened femur and humerus
-dudenal atresia
-5th finger clinodactyly
cleft lip +/- palate
-ethnicity ass'n?
-ass'n with other congenital defects?
-recurrence risk for sib, child?
-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%
syndromes ass'd with cleft lip/palate
-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)
what is cystic hygroma ass'd with?

"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"
congenital toxoplasmosis
-chorioretinitis (most common finding - eye infection)

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
-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)
maternal diabetes and birth defects
-in 6-10% of poorly controlled patients, up to 20% of very poorly controlled
-heart defects
-skeletal defects
-defects in urinary, reproductive, digestive systems
-increased risk of breathing difficulties, hypoglycemia, jaundice
teratogens - radiation
CNS defects, MR, microcephaly, growth retardation

>5 rads
carrier screening for spehardic jewish population - mediteranean
-beta thal
-familial mediteranean fever
-glucose-6-phosphate dehydrogenase deficiency
-glycogen storage disease type III
which asian countries do not have an increased frequency of hemoglopinopathies?
japan and korea
what AR conditions are increased in indivdiuals of chinese ancestry (for carrier screening)?
beta thal -- 3% (1/33)
alpha thal cis -- 1/20
southern china - hemoglobin e
how to test in Tay-Sachs carrier screening?
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)
what carrier screening should be offered to individuals of french canadian or cajun ancestry?
-tay sachs by enzyme studies
-CF panel
prenatal diagnosis for Tay-Sachs?
-enzyme analysis on either CVS or amnio sample

-molecular testing if mutation is known in both parents
Hispanics - what conditions for carrier screening?
-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
conditions for carrier screening for sephardic jews?
-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
conditions for carrier screening for mediterranean ancestry?
mediterranean ancestry: italy, greece, cyprus, portugal, souther spain

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

conditions for carrier screening for middle eastern populations?
-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
which peroxisome disorder has normal VLCFA?
-rhizomelic condrodysplasia punctata - VLCFA are normal

-VLCFA are elevated in other disorders (zellweger, refsum, adrenoleukodystrophy)
-VLCFA are the most common and informative initial screen
what is elevated MSAFP associated with?
-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)
-low birth-weight, oligohydroamnios, multiple gestations, decreased maternal weight
-obstruction, liver necrosis, urinary obstruciton