Genetic Screening - Part 1 Flashcards
What is prenatal diagnosis?
- Prenatal diagnosis is the diagnosis of normality / abnormality in a child before birth.
What sort of samples are referred for prenatal diagnosis?
1) . Screening programmes:
- Advanced maternal age - April 2010 (replaced by serum screening only access).
- Biochemical screening - maternal serum analytes.
- Abnormalities seen on ultrasound scan:
- Second trimester detailed anomaly scan where main organ formation is complete
- First trimester nuchal translucency screening - in isolation or as part of an integrated serum screening programme.
2) . Previous history:
- Previous child / family history of (numerical) chromosome abnormality. With previous history the risk is about 1% about the age related risk for autosomal trisomy.
- Family history of structural chromosome abnormality - risk of conceiving unbalanced offspring.
e. g. der(14:21) 10% risk to female balanced carrier, 5% if male carrier.
Gene translocations 5-30% if previous live born unbalanced individual.
3) . Miscellaneous:
- Monogenic molecular tests / metabolic disorder tests (maternal anxiety).
Describe maternal age related aneuploidy and screening.
- Everyone has a risk - 1 in 250 to 1 in 50 for ages 35 to 45.
- Less than 30% of Down syndrome children are born to older mothers = detections rate for screening programmes based on age only.
- Large number of Down syndrome births attributed to younger age group.
- Purpose of screening programme is to improve the efficiency of detection of at risk groups by modifying the prior risk of the individual.
Describe the principles of antenatal screening.
DEFINITION:
Segregation out from a whole population (or defined sub population) those individuals having an increased risk of abnormality.
OBJECTIVE:
To reduce the birth incidence of serious abnormality. Creation of informed choice for at risk individuals.
BENEFITS:
Benefits to both parents and community. Reduce trauma and tragedy of unexpected abnormal child to parents. Reduce cost of health and caring professions for community.
REQUIREMENTS:
Cost effective / Simple / Practical.
Reliable and timely.
Psychosocial impact acceptable.
What is meant by the terms ‘high specificity’ and ‘high sensitivity’?
High Specificity:
- Specific to the abnormality not detecting normal cases.
- Low false positive rate.
- Reduce any unnecessary anxiety by false alarms.
High Sensitivity:
- Sensitive enough to detect the abnormal cases.
- Low false negative rate.
- Reduce the risk of unanticipated live-born abnormal individuals.
Outline the difference between a screening test and a diagnostic test.
SCREENING TEST:
- Screening tests will point towards individuals at high or low risk but they will give false positive and false negative results.
- Relative risk estimation by modifying pre existing (prior) risk.
- Targets a specific group of abnormalities.
DIAGNOSTIC TEST:
- Prenatal diagnosis sampling (definitive test).
- High degree of accuracy of result.
- All abnormalities detected.
Wha key abnormalities are we looking for in an ultrasound scan?
USS as a screening test for chromosomal abnormalities:
- Mainly looking for trisomy 21, 18, 13 and monosomy X.
- Some USS features such as cardiac abnormalities are common in all chromosomal abnormalities.
- Some features are specific to certain conditions such as: 1). polydactyly and holoprosencephaly in trisomy 13,
2) . duodenal atresia in trisomy 21,
3) . micrognathia and fisted hand in trisomy 18.
Discuss nuchal thickening / translucency.
- First trimester screen - early detection of a potential problem - other foetal tests are looking in the second trimester.
- Vascular sensitive measurement.
- Type VI collagen is coded for on chromosome 21.
- Increased in DS and other chromosome abnormalities.
- Increased in vascular abnormalities.
- As a measurement on its own nuchal translucency is not a great indicator - possibly have a detection rate of 74-82% for a 5% false positive rate. This is why we need to include biochemistry tests also.
- 30 karyotypic investigations for each case of Down syndrome detected.
- 1 in 100 (0.5-1.0%) pregnancy loss rate for invasive karyotype test.
- Babies with normal karyotypes and increased nuchal translucency have decreased neonatal survival which is proportional to the nuchal translucency measurement.
- For example with a nuchal translucency >6.5mm there is only a 15% chance of that child being normal.
- NT is broader than just chromosomal abnormalities.
Discuss Echogenic Bowel on USS.
- White speckling.
- Increased likelihood of DS or CF.
Discuss duodenal atresia.
- Possible indicator of trisomy 21.
- The stomach and duodenum is usually a continuous tube.
- In duodenal atresia there is a restriction or a closure such that the the two tubes will suddenly appear almost aligned together.
- If you do a transverse cross section you can see two tubes.
What might a clenched fist on USS indicate?
- Trisomy 18 (Edward’s syndrome) indicator.
- Have a flexion defect in the hand
- Soft marker.
What might talipes (club foot) on USS indicate?
- Trisomy 18 (Edward’s syndrome) indicator.
- Soft marker.
What might micgrognathia on USS indicate?
- Trisomy 18 (Edward’s syndrome) indicator.
- Small chin.
- Soft marker.
What might post axial polydactyly on USS indicate?
- Trisomy 13 (Patau syndrome).
- Extra on little finger side of the hand.
What might unilateral cleft lip on USS indicate?
- Unilateral cleft lip indicates trisomy 18.
- This is only an indicator and unilateral cleft lip is actually quite common. When the face is formed it is very sensitive to disruption.
- 1 in 1000 - environmental, multifactorial, maternal exposure to drugs (anticonvulsants, alcohol).
- 70% of cleft lip are associated with a cleft palate.
- 7-13% isolated cleft lip are syndromic (risk may be as low as 1 in 200).
