• 1.
  

  a) F b) T c) F d) T e) T

Genetic counselling involves a full description of testing modalities, their advantages and disadvantages, their risks and benefits and the meaning and consequences of testing results. Non-directive genetic counselling has been a fundamental principle of genetic counselling since its first inception as a responsibility and duty to prospective parents. Support after reproductive decision-making is a necessary component of healthcare, as long as such support does not violate established standards of care. Reproductive decision-making represents a culmination and integration of individual personal values, pressure from others, including partner and healthcare provider, understanding and confidence in the medical system, partner’s support, and socioeconomic status.

• 2.
  

  a) F b) T c) F d) T e) F

Over 1700 different mutations exist in the cystic fibrosis gene, and each one requires a separate test. Different panels have been constructed whose test number range from 23 to over 100 mutations, and the frequency of each mutation varies according to ethnicity. The frequency of mutations common to the Ashkenazi population is not zero, merely much lower, so it is even possible for two non-Ashkenazi parents to have a child with a disease commonly present in the Ashkenazi population. It is not unusual to attend a meeting of parents with children with Tay-Sachs disease to find that only one member of a couple is of Ashkenazi parentage. Carrier screening is designed to identify the most common mutation(s) in a disease-causing gene, but not all of the mutations; therefore, carrier screening if negative provides a reduction in reproductive risk but not elimination of that risk. Carrier screening for cystic fibrosis has become an internationally recognised standard, although not practised in certain European countries and in the Far East. Spinal muscular atrophy screening is a standard test as recommended by the American College of Medical Genetics but not the American College of Obstetrics and Gynecology. Screening for pre-mutations in the case of fragile X syndrome is based on the recommendation of individual care-givers.

• 3.
  

  a) T b) T c) F d) F e) T

These parameters have been shown to be true, although ultrasound evaluation of nuchal translucency can be measured accurately from 11 weeks and 3 days to 13 weeks and 6 days, and maternal serum proteins from 9 weeks to 13 weeks and 6 days. Three separate risk assessments are usually provided for Down’s syndrome, which includes maternal age-related risk, risk to a 35-year-old and the first-trimester risk, which includes combined risk assessment based upon maternal age, ultrasound measurement of fluid in the neck, and protein levels of pregnancy-associated plasma protein and human chorionic gonadotropin (free or total). The detection rate for first-trimester screening for Down’s syndrome ranges from 78–92% and somewhat lower for trisomies 13 and 18, depending on the actual experiences of different centres. In the case of pregnancies that are screen positive, either for Down’s syndrome or trisomies 13 and 18, if diagnostic testing identifies a chromosome abnormality, at least 40% of the time, a chromosome abnormality other than trisomies 13, 18, 21 (Down’s) is present.

• 4.
  

  a) F b) F c) F d) F e) T

Although reasons underlying the choice of undergoing invasive testing has been the subject of numerous publications, formal studies that critique the reasons women refuse chorionic villus sampling or amniocentesis have not been carried out. No international obstetric risks have been established for either chorionic villus sampling or amniocentesis; in fact, a large disparity exists within the USA and between the USA and Europe. Early in the history of amniocentesis, a requirement to terminate was part of the genetic counselling, but in the past 30 years, no such requirement is made. Diagnostic testing by chorionic villus sampling and amniocentesis does not guarantee a normal child because non-chromosome and non-genetic disorders potentially affect all children (e.g. autism).

• 5.
  

  a) T b) T c) T d) F e) F

Free fetal DNA and genetic material are all sourced from maternal blood, fetal blood and fetal trophoblast. There is no DNA available per se with AFP and the technology does not support sampling form the upper cervix at this stage.

• 6.
  

  a) T b) T c) T d) T e) F

Though the fetus and father have no legal rights there is still the duty of beneficence to them to do the best possible, though it is ultimately the mother’s life first. TOP should be offered in these circumstances but again it is the woman’s choice whether to terminate.

• 7.
  

  a) F b) T c) T d) F e) T

Protection of health and life, respect for patient autonomy and best interest decisions are core duties of a doctor.

• 8.
  

  a) T b) T c) T d) T e) T

These are all important and should be discussed prior to any testing as they all have influences on choices and decision making.

• 9.
  

  a) T b) T c) T d) T e) T

All of the above are important ethical considerations but paternal consent is not actually required legally.

• 10.
  

  a) T b) T c) F d) F e) F

Offspring will be affected by the disease only through inheriting both mutant alleles from the parent, which is a probability of 25%. The risk of being a carrier is indeed 50% and there is therefore a 75% risk the offspring will be affected or carriers. The risk is the same for each child – previous outcomes are irrelevant to any subsequent pregnancy.

• 11.
  

  a) T b) T c) T d) T e) F

Aneuploid rate increases with maternal age and contributes to infertility of women with advanced maternal age. It is believed that embryo aneuploidy is one of the major causes for adverse in-vitro fertilisation outcomes, such as implantation failure and miscarriage. Infertile men, such as men with azoospermia, are at risk to have 10–15% chromosome abnormalities compared with about less than 1 % in the fertile male population. Sporadic miscarriage is common and needs no investigation whereas genetic screening is important for repeated pregnancy loss.

• 12.
  

  a) F b) T c) F d) F e) F

The corpus callosum, cerebellum, palate and cardiac outflow tracts cannot reliably be seen at this gestation and fetal sexing is not reliable either.

• 13.
  

  a) F b) F c) F d) T e) F

Only bilateral renal agenesis cannot be reliably detected by the end of the first trimester.

• 14.
  

  a) F b) F c) T d) F e) F

The association is 20% of cases of megacystis overall; the severity does not increase the risk.

• 15.
  

  a) F b) F c) F d) T e) F

Fetal sexing can be performed before 14 weeks but it is not reliable enough as the male external genitalia are still developing. The genital tubercle cannot be seen at 6 weeks gestation. Assigning the gender as male if the angle of the genital tubercle to the lumbosacral skin surface was greater than 30° and classifying as female a genital tubercle angle of less than 10° have shown very good but not perfect correlation.

• 16.
  

  a) T b) F c) F d) F e) T

Since the systematic administration of anti-D immunoglobulin to mothers who are RhD negative, the incidence of RhD has decreased from 1% to 0.1%. Fetal RhD genotype can be assessed on fetal DNA in the maternal circulation. This is a non-invasive procedure that can be carried out as early as the first trimester of pregnancy. Fetal RhD status can also be diagnosed by amniocentesis, chorion villus biopsy or fetal blood sampling. Fetal hydrops is a late sign of fetal anaemia. Doppler ultrasound allows measurement of the peak systolic velocity in the fetal middle cerebral artery. The latter is a good indicator of the severity of fetal anaemia. Transfusion before hydrops is present leads to higher survival rates and better neurologic outcomes. Intrauterine transfusion is more challenging in early pregnancy owing to the small size of the cord. As such, early procedures are more likely to be unsuccessful or to be complicated. In experienced hands, intrauterine transfusions are highly successful and complication rates are low.

• 17.
  

  a) F b) T c) F d) T e) F

In contrast to the postnatal circulation where left and right heart circulation are serial circuits, the fetal left and right heart circulation are arranged in parallel. Obstructive lesions on one side do, therefore, not lead to cardiac decompensation and intrauterine fetal demise. Spontaneous fetal mortality in severe fetal aortic stenosis is low. The aim of antenatal valvuloplasty is to allow further left ventricular growth in utero and to preserve the left ventricle for an eventual postnatal biventricular repair. The Eurofetus trial comparing repetitive amniodrainage to fetoscopic laser for severe midtrimester twin-to-twin transfusion syndrome has shown that fetoscopic laser is associated with higher fetal survival rates and lower rates of neurologic impairment. In contrast to macrocystic congenital cystic adenomatoid malformation of the lung (CCAM), microcystic CCAM lesions do not contain large cysts that can be drained by shunting. Eventual prenatal therapy consists of either/and maternal administration of corticoids or open fetal surgery. As with many invasive procedures, preterm premature rupture of membranes (PPROM) and preterm delivery are the Achilles heels of fetoscopic tracheal occlusion. In a study of more than 200 cases, PPROM rate was 47% and mean gestational age at delivery 35 weeks. Mild and moderate stable effusions have excellent outcomes when managed expectantly. Only severe effusions leading to cardiac decompensation or severe pulmonary compression and ensuing pulmonary hypoplasia should be drained antenatally.

• 18.
  

  a) F b) F c) F d) T e) F

The aim is deliver a normal gene to cells to replace the aberrant protein. The genotype cannot be corrected per se.

• 19.
  

  a) F b) F c) F d) F e) T

Timing of immune recognition of foreign antigens is important and 14 weeks is the critical time in immune development.

• 20.
  

  a) T b) T c) T d) F e) T

  
  
• 21.
  

  a) F b) F c) F d) T e) T

  
  
• 22.
  

  a) T b) T c) T d) T e) F

All of the first three issues are significant barriers to IUSCT. It is the necessary to overcome the host immune system and create a tolerant microenvironment to facilitate engraftment. The removal of host stem cells allows the empty bone marrow niches to act as ‘docking stations’ for the engraftment of donor cells, and suppression of the host immune system facilitates donor cell proliferation (in the absence of competition from host cells) and eventual reconstitution of the bone marrow. Fetal stem cells are more susceptible to vector transduction and show a higher proliferative, self-renewal and differentiation capacity than postnatal and adult stem cells

• 23.
  

  a) T b) T c) T d) T e) T

Tolerance toward the transplanted cells may be induced in the pre-immune fetus before antigen-recognition develops at the end of the first trimester, facilitating engraftment in an immature bone-marrow compartment where there is little competition from host cells. Because of the physical limitation on the quantity of donor stem cells that can be harvested and transplanted, fetal size offers a distinct advantage allowing a greater concentration of stem cells to be achieved in the target organ compared with postnatal recipient several log-fold larger. Fetal tissue in the absence of extensive cellular damage has a greater capacity for healing and responsiveness to therapy compared with scarred adult tissue setting the stage for more complete recovery.

• 24.
  

  a) F b) F c) F d) T e) F

A loss rate of 1 in 200 was once universally offered, but actually no such statistical difference was ever proved. CVS requires considerable experience before safe performance, more so than amniocentesis. In experienced hands, loss rates are similar for both procedures. From 10 weeks onwards, there is seemingly no increased risk of LRDs, but this is not true earlier. Chorionic villus sampling should not be used at gestation for traditional indications before 9 weeks. Early amniocentesis is not safe and is associated with increased pregnancy loss and equino-varus deformity.

• 25.
  

  a) F b) F c) F d) F e) T

Sensitivity rates for any screening test directly relate to incidence. This sensitivity is greater in older women. Sensitivity is 10–15% lower. Not all pregnancies will exclude trisomy 21 by non-invasive methods. Unexpectedly, the frequency of trisomy 21 increased in Colorado, mostly because of lower detection in women over age 35 years. The difference is small (5–7%) but consistent in favour of first trimester being more sensitive. On the basis of modelled data, first plus second trimester should detect 90–95% cases, compared with 5–10% less for first- or second-trimester screening alone.

• 26.
  

  a) F b) T c) F d) F e) F

In every pregnancy cell-free fetal DNA is found. Some variation exists, but 5% in euploid pregnancies is accepted as typical. Although not available clinically, testing for Marfans should be robust if the father were affected. The mother’s DNA would show the Marfan mutation irrespective of fetal status. Although many companies are preparing to launch, the number of vendors remains few and whether large volumes could be handled in the near future is unclear. Intact fetal cells are devoid of contaminating maternal DNA, thus diagnostic opportunities would be expanded compared with cell-free fetal DNA.

• 27.
  

  a) T b) F c) T d) F e) F

Trophoblast cells entering the maternal circulation is a common biological phenomenon, but trophoblasts may not be detectable in all pregnancies consistently, and rapid clearing by the pulmonary circulation makes it difficult to enrich from maternal blood. Cells also possess about a 1% incidence of chromosomal mosaicism. Nevertheless, if these cells were readily accessible more consistently, they could be suitable cells for non-invasive prenatal diagnosis.

Fetal nucleated red blood cells have a limited life span in the maternal circulation of about 90 days, bear complete complement of nuclear genes and carry developmentally specific markers (e.g. embryonic globin), which can be used for identify the cells. If readily isolated, these would be the most suitable fetal cells for use in non-invasive prenatal diagnosis. Cells that enter the maternal circulation are able to engraft in maternal tissue or organs. Cells from previous pregnancies could confound the prenatal diagnosis for the current pregnancy. Use of CD34+ leukocytes would require prior human leukocyte antigen testing of both parents before cell enrichment. Amniocytes are obtained from amniocentesis, an invasive procedure.

• 28.
  

  a) F b) T c) F d) F e) F

As ζ-globin continues to be expressed in adults with alpha-thalassaemia trait, and is not completely down-regulated in one-half of the definitive erythrocytes between 15 and 22 weeks gestation and one-third of the erythrocytes at term, it has only limited use as a fetal-cell identifier. Epsilon-globin has been shown to be fetal specific and gender independent by having demonstrated the presence of epsilon-globin positive male fetal cells in post- chorionic villus sampling (CVS) and post-termination of pregnancy maternal blood samples. Epsilon-globin has never been described in the red blood cells of adults. Furthermore, comparing its specificity between the two embryonic globins (Ɛ and ζ) in the detection of FNRBCs in CVS supernatant fluid, epsilon-globin was found to be more reliable and specific in detecting FNRBCs. There is limited use for γ-globin, as a minority of maternal nucleated red blood cells express γ-globin, especially in an acute erythroid expansion, such as in pregnancy, recovery from iron-deficiency anaemia and women with beta-thalassaemia. (d) and (e) are expressed in adult red blood cells, and cannot be used to identify fetal cells.

• 29.
  

  a) T b) F c) T d) T e) F

The technique described is for laser micro-dissection and pressure catapulting and not the classical micro-manipulation technique. Cell loss can indeed occur during transfer because it is not carried out under direct vision. This technique has been successfully used to determine the described conditions and gender in FNRBCs enriched and micro-manipulated from maternal blood.

• 30.
  

  a) T b) T c) F d) T e) F

Transferrin receptor (CD71) is expressed on the entire erythroid lineage, activated lymphocytes, monocytes, trophoblasts and any cell incorporating iron. There is loss of CD71 expression beyond the reticulocyte stage. GPA is expressed on all erythroid lineage cells and definitive FNRBCs in maternal blood. EPO-r is a receptor for erythropoietin and present on all red blood cells, which is crucial for erythroid survival, proliferation and differentiation. CD45 and CD14 are present on maternal nucleated lymphocytes but absent on FNRBCs; therefore, they have been used to deplete maternal nucleated lymphocytes from maternal blood.