Abnormals Flashcards
What’s the incidence of aneuploidy in stillbirths
4%
+13, +18, +21
What’s the incidence of aneuploidy in livebirths
0.3%
+13, +21, +18, XXX, XXY, XYY
What’s the incidence of aneuploidy in spontaneous abortions
35%
XO, +16, +21, +22
What’s Polyhydromnios a symptom of
Maternal diabetes.
Impeded fetal swallowing.
Neural tubes defects. Severe abns of CNS. BWS.
Detailed ultra sound required
What’s oligohydromnios a symptom of
Premature membrane rupture.
Urinary tract abns. Renal agenesis (lack of fetal urine).
Cause deformities of the foetus: amniotic bands, IUGR, pulmonary hypoplasia.
Why carry out an AF/CVS
Manages remaining weeks of pregnancy.
Determine outcome of pregnancy.
Plan for problems that might occur as a neonate.
Decide whether to continue with pregnancy.
Diagnose conditions that could affect future pregnancies.
What’s the maternal age risk figure for T21 for a 30yr old
1/890
What’s the maternal age risk figure for T21 for a 35yr old
1/355
What’s the maternal age risk figure for T21 for a 37yr old
1/220
What’s the maternal age risk figure for T21 for a 40yr old
1/90
What chromosomal abnormalities of seen in 1st trimester spontaneous pregnancy losses
50%: Trisomies (3rd are trisomy 16).
25%: 45,X.
18%: triploid.
Tetraploid are seen
10%: mosaic
What chromosomal abnormalities of seen in 2nd trimester spontaneous pregnancy losses
40% Trisomies (majority T13 (13%), T18 (23%), T21 (63%))
20% 45,X.
10% triploid.
What chromosomal abnormalities of seen in 3rd trimester spontaneous pregnancy losses
Over 50% : Trisomies (50%: T18. Only 13 (17%),18, 21(32%) seen).
Less than 5%: 45,X.
15% other sex chromosome abnormalities.
20% structural abnormalities.
15%: mosaic.
What chromosomal abnormalities of seen in livebirths
1/3: other sex chromosome abnormal.
1/3: structural.
1/3: trisomy (80-90%: T21)
What percentage of T16 conceptuses are lost
100% lethal
What percentage of T21 conceptuses are lost
80%
What percentage of T13, 18 conceptuses are lost
90%
What percentage of Triploid and tetraploid conceptuses are lost
Almost 100%
What percentage of 45,X conceptuses are lost
95-99%
What percentage of Unbalanced structural conceptuses are lost
Up to 95%: depends on imbalance
What’s the pregnancy loss rate with a normal karyotype
8%
What’s the loss rate of a 1st trimester pregnancy and what percentage of the losses are chromosomally abnormal
20% loss
50% abn
What’s the loss rate of a 2nd trimester pregnancy and what percentage of the losses are chromosomally abnormal
2-5% loss
20% abn
What’s the loss rate of a 3rd trimester pregnancy and what percentage of the losses are chromosomally abnormal
Less than 1% loss
5% abn
Describe level 1 mosaicism
A single abnormal cell -? Cultural artefact
Occurs in 2.5-7% AF
Describe level 2 mosaicism
2 or more cells with the same abnormality I a single culture or colony (some instances: multiple colonies from 1 culture)
Pseudomosaicism
Occurs in 0.7-1.1% AF
Describe level 3 mosaicism
2 or more cells/colonies with the same abnormality distributed over 2 or more independent cultures.
?true mosaicism
0.2% AF
Describe a basic work up
In situ: all single cell abnormalities
Work up: examination of at least 15 colonies from 2 separate cultures.
Suspension: a single cell with: 45,X, unbalanced rearr, balanced rearr, break at the centromere with loss of 1 arm.
Work up: 20 cells over 2 separate cultures.
Describe a moderate work up
1) extra sex chromosome (SC, MC, SCo,MCo).
2) 45,X (MC, SCo,MCo).
3) monosomy (MC, SCo,MCo).
4) marker (SC, SCo).
5) balanced structural rearr (MC, MCo).
6) unbalanced structural rearr (SCo).
7) Trisomies: 1,3,4,6,7,10,11,17,19 (SC, MC, SCo,MCo)
Work up: in situ: 12 colonies (2 further separate cultures).
Suspension: 20 cells (1 additional culture).
Describe the extensive work up
1) trisomy: 2,5,8,9,12,13,14,15,16,18,20,21,22 (SC, MC, SCo,MCo).
2) unbalanced structural rearr (MC, MCo).
3) marker (MC, MCo).
Work up: in situ: 24 colonies (at least 2 further cultures).
Suspension: 40 cells (2 independent cultures)
What percentage of cvs show mosaicism at diagnosis
2% (common)
True mosaicism: 10%
CPM (trisomic placenta, normal foetus) : 90%
Discuss T20 mosaicism in prenatals
7% abn outcomes.
Correlation between abn% and outcome:
Over 50%: 20% Rick of abn.
Less then 50%: less risk of abn outcome.
Cells may exist in kidney/ urinary tract but rarely seen in blood
What abns is AVSD antrioventricular septal defect associated with
50% anueploidy.
60% T21
25% T18
What abns is myelomeningocele associated with
T13 and T18
What’s ventriculomegaly associated with
Abn K 7%
50% T21
What do you think when find a balanced rearrangement in foetus
Inherited: unlikely to cause phenotype (?UPD). Reproductive risks for future preg (parent and foetus: risk: 10-100%!). Genetic counselling.
De novo: risk of abn: 5-10%. Depends on disruption, position effect, etc
What’s the risk of an abn phenotype when find a marker in a foetus.
Overall risk of abn: 13%.
If inherited: risk is reduced. If de novo:
Small meta centric i(12p), i(18p): 100%. Satellited with euchromatin: 80%. Not further characterised:13%. Dots/ small C band +ve: lees then 5%. Small bisatellited no euchromatin: less than 2%.
Reporting markers
Parental bloods, refer to Gen counselling, detailed scan, provide risk.
40% markers are familial.
50% markers are acrocentric (80% are chr15)
What percentage of genetically abnormal pregnancies would be detected by rapid testing
75%.
T13, T18, T21, Triploidy, sex chromosome abns.
Other 25%: structural, mar, other aneuploidies.
What percentage of high serum risk pregnancies would be detected by rapid testing
About 95%
Of the abnormal scan cohort: What percentage of clinically significant abns are NOT detected by the rapid test
66%
How do you detect mosaicism of QF PCR
Extra peaks: larger than stutter peaks. Skewed ratios. Present in a single chromosome. Detect to about 15%
What does MCC look like on QF PCR
Mixture of two related genotypes so maximum of 3 peaks. One peak will be shared between mum and foetus so:
1 taller peak. 2 smaller peaks= taller peak.
All chromosomes will be involved
If low level and hasn’t given inconclusive results: report.
What does a diploid/triploid mosaic look like on QF PCR
All marker involved.
2 main alleles have a 1:1 ratio, and a smaller 3rd allele.
What are the 3 complex situations affecting 1 marker in QF PCR
Primer site polymorphism.
Submicroscopic microsatellite duplication. (1:1:1. Marker- get parents)
Somatic microsatellite mutation. (1:1:2 two small markers will equal larger marker)
What percentage of AF are mosaic
0.1-0.3%
What the incidence of triploidy
1-3% recognised pregnancies.
99.9% abort in 1st try or lost in 2nd as fetal death in utero.
Livebirths: extremely poor prognosis (survival less than 1 month)
What is the sperm origin of complete hydatidiform mole
20% dispermic and an empty egg (UHPD)
80% monosoermic and an empty egg (UIPD)
What are the histological and genetic features of a partial mole
Triploid: 69, XXX, XXY, XYY (rare).
2mpopulations of villi (small normal and large hydropic).
Enlarged villi.
Irregular villi.
Trophoblast hypoplasia.
What causes familial recurrent hydatidiform mole
Failure to maintain maternal imprint within the ovum.
What’s the breakdown of Trisomies in 1st trimester loss
T16: 30%. T22: 20%. T21: 9%. T15: 7%. T13: 6% T2: 2%. T18: 5%
What percentage of ooctyes and sperm are genetically abnormal
Sperm: 10%
Ooctyes: 20-25%
What are the stats (non-genetic) about RM
30%: fail to implant.
30%: lost following implantation.
What are the incidence of markers
Prenatal: 0.075%.
Livebirths: 0.44%.
Pts with MR: 0.288%.
Sub fertile pts: 0.125%
What’s the likely behaviour of a marker at meiosis
Probably forms a univalent.
If very small- prone to loss (mosaicism).
Familial ESACs are often maternally derived.
What mechanisms likely cause markers
1) numerical error with subsequent partial T rescue/ M rescue/ gamete comp.
2) unbalanced structural rearr.
3) U-shaped exchange produces inv dups.
4) break within centromeric DNA causes non-acro inv dup.
5) ring formation: interstitial deletion or complex rearr resulting in an inv dup prior to ring formation.
What chromosomes make up markers
70% all markers: acrocentrics.
70-80% all acrocentric mar: Chr 15 derived: 50%: abn, 50%: normal
30% all markers: non-acro: 50%: i(12p) or i(18p)
What’s the inheritance patterns of markers
77% de novo (75% abnormal phenotype).
23% inherited (76% normal phenotype).
What’s the current BPG for characterising markers.
C-banding. Establicpsh number of centromeres. Silver stain for number of satellites.
Concurrently:
Parental bloods (inheritance/extract DNA for UPD studies). FISH (chr 15, 14/22, 13/21, X and Y if appropriate). Maintain remaining cultures for further FISH/DNA extraction.
What phenotype is a PWASCR+ mar associated with
MR, epilepsy, autism.
What are the limitations to investigating a mar by aCGH
No/poor coverage in pericentromeric HC/satellites.
No positional info.
Poor low-level mosaicism detection.
What must be taken into account when considering the clinical significance of a marker prenatally
Size. Origin. Content. Tissue distribution. Inheritance.
What markers are considered high risk of an abnormal phenotype
Chr15 PWASCR+.
Chr22 (cat-eye).
I(12p), i(18p/q).
Rings
What markers are considered low risk of an abnormal phenotype
Chr 14.
Chr13/21.
Chr1, 9, 16
What features are associated with mosT2
Absent gall bladder.
Talipes.
Renal cysts
What features are associated with mosT9
IUGR. Microphthalmia. CHD. Cerebellar vermis hypoplasia. Enlarged renal cysts.
What features are associated with mosT7
Talipes/rocker bottom feet.
Clitoromegaly.
Renal agenesis.
Low set ears.
What features are associated with mosT8
Skeletal anomalies.
CHD.
renal anomalies
What features are associated with 22q11.2 deletion
CHD (outflow- ToF). Renal anomalies. IUGR. Clefting. Polyhydromnios. Thy mic hypoplasia.
What features are associated with Williams syndrome
Supravalvular aortic stenosis.
IUGR.
Nasal bone hypoplasia.
What features are associated with Roberts syndrome
Symmetrical limb shortening. Clefting. Cystic kidneys. Oligodactyly. Thumb aplasia.
What features are associated with pallister Killian
Diaphragmatic hernia.
Polyhydromnios.
Short limbs.
Abn feet and hands
What features are associated with wolf hirshorn
IUGR.
Clefting lip
CHD.
Cri du chat
CHD.
Clefting lip and palate
What features are associated with upd14
Pat: severe IUGR. Polyhydromnios.small thorax.
Mat: IUGR.
What features are associated with T21
Nuchal translucency/ cystic hygroma. Ascites. CHD (AVSD). Duodenal atresia. Pleural effusion. Ventriculomegaly. Hydrops. IUGR. Renal anomalies.
Soft markers: echogenic bowel. Sandal gap. Short femur. NT. clinodactyly. Nasal bridge hypoplasia.
What features are associated with T13
Club foot/rocker bottom feet. Talipes. Postaxial polydactyly. Holoprosencephaly/central cleft. Neural tube defects. Cystic kidneys. CHD. IUGR. Mega cysterna magna.
What features are associated with T18
Choroid plexus cysts. Absent corpus callosum. Enlarged cisterna magna. Micrognathia. Rocker bottom feet. Overlapping fingers. Clenched hands. Single umbilical artery. Omphalocele. Diaphragmatic hernia. IUGR. Renal anomalies. CHD.
What features are associated with turners
Renal anomalies (horseshoe kidney). CHD (left side). Lymphatic anomalies (cystic hygroma, ascites, pleural effusion, lymphangiectasia) hydrops.
Discuss fish vs QF PCR for rapid anueploidy
FISH: low throughout, time consuming, requires expertise, expensive, only detect MCC if male fetus, limited to 1 loci/chr. Can detect mosaicism, esp X,XX,XXX better than QF PCR.
QF PCR: high throughput, simple to perform, can be automated, cheap if batched, detected MCC and zygosity, multiple loci/chr, if has TAF9 can quantify number of X’s. Difficulties determining X,XX,XXX mosaicism in any combination.
