• 1.
  

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

This question refers to the DICER1 -cancer predisposition syndrome. Cervical cancer is predisposed to, however this is embryonal rhabdomyosarcoma and not adenoma malignum, which is seen in Fanconi Anaemia. Wilm’s tumour is part of the DICER1 -cancer predisposition syndrome. Pleuropulmonary blastoma is also part of the DICER1 -cancer predisposition syndrome. Multinodular goitre is associated with DICER1 germline mutation and may present with features of hyper- or hypothyroidism. Soft tissue Ewing sarcoma is a form of primitive neuroectodermal tumour which is part of the DICER1 -cancer predisposition syndrome.

• 2.
  

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

Germline BRCA1 and BRCA2 mutations are associated with an increased risk of breast cancer, ovarian cancer and to a lesser extent pancreatic cancer. The family history is not suggestive of Lynch syndrome and so assessing for microsatellite instability in the tumour is not indicated. Similarly surveillance for bowel cancer is not required. The most recent evidence has concluded that bilateral salpingo-oopherectomy should not be recommended for the purpose of breast-cancer risk reduction; further studies are necessary to investigate this. There is currently no evidence to suggest that surveillance by way of CA125 or transvaginal ultrasound improve mortality from ovarian cancer in individuals with a family history of ovarian cancer; this should not be offered in the clinical setting but may be considered as part of a clinical trial.

• 3.
  

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

Fetal chromosomal error is the most common known cause of early miscarriage before 10 weeks of gestation. The majority of miscarriages occur in chromosomally-normal parents. Two to 4 percent of couples with RM have a major chromosomal rearrangement; usually a balanced translocation (60% reciprocal, 40% Robertsonian) or, less commonly, an inversion. One or both partners may harbor lethal genes in a heterozygous or balanced combination that does not affect them, but causes pregnancy loss when inherited by the embryo in a homozygous or unbalanced state. There is no consensus for systematic karyotyping of patients with RM, because it is expensive and does not always yield information. Couples with a major chromosomal rearrangement have a low risk of viable offspring with unbalanced chromosomal abnormalities, and their chances of having a healthy child seem to be as high as non-carrier couples, despite a higher risk of miscarriage. Some studies showed that the most frequent trisomy related to first trimester miscarriage is in chromosome 16, and is more frequent in the first trimester. Most chromosomal abnormalities in the embryo arise de novo. The abnormality is rarely inherited from a parent who may have a balanced chromosomal translocation. Advancing maternal age is associated with a higher rate of miscarriage of normal and abnormal conceptuses, and this probably reflects poor oocyte quality in these patients. The increased risk of miscarriage with advancing age was illustrated in a review of over 1 million pregnancies with known outcome and with admission to a hospital. The approximate rates of clinically-recognized miscarriage according to maternal age were: age 20 to 30 years (9–17%), age 35 + (20%), age 40 + (40%), and age > 45 (80%).

• 4.
  

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

Miscarriage is the most common complication of pregnancy, with approximately 15% of all clinically-recognized pregnancies resulting in pregnancy failure, and is a distressing matter for both clinicians and patients. Some risk factors are widely known in recurrent miscarriage: endocrine disorders, infectious diseases, environmental factors, uterine diseases, thrombophilic disorders or genetic abnormalities, with the latter being one of the most recognized causes of recurrent miscarriage. All these diseases have one thing in common: their ability to disrupt the homeostatic balance in the pregnancy, thereby increasing fetal wastage. The cause of the miscarriage in these cases is not clear, but it may be related to disordered uterine function, implantation defects and anomalies in placental angiogenesis promoted by placental-bed microinfarcts (especially in sickle cell anemia). Genetic and epigenetic polymorphisms are the highlight of research on recurrent miscarriage. The main studies and meta-analysis on genetic polymorphisms have been conducted since the 2000s, identifying a large number of genes that are expressed aberrantly in pregnancy wastage; however, studies on the association between genetic variant and recurrent miscarriage can be traced back to the 1990s to 2000s and mainly started with thrombophilia-related genes. In a normal pregnancy, Th-1 immune response switches to a Th-2/Th17 interleukin driven action for correct embryo implantation and induction of maternal immune tolerance to the allogenic fetus. If the immune response of Th-1 prevails beyond Th-2, the risk of RM is increased. New research lines suggest that the unknown miscarriage causes (40–50%) could be explained by this immune imbalance; however, more evidence is needed to confirm these hypothesis.

• 5.
  

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

Specifically, HLA-G rs66554220, IL-6 rs1800795 and TNF 1800629 are the most investigated genetic polymorphisms in immune response, showing significant differences with recurrent miscarriage in some meta-analyses. It is exactly the other way around: significant results have been observed between RM and genetic polymorphisms of IL-4, IL-10 and TGF-β (anti-inflammatory cytokines), and their reduced serum levels. VEGF, directly and indirectly acting as a mediator of nitric oxide formation, stimulates correct placental angiogenesis and implantation and development of the embryo. Thus, insufficient levels of both molecules could impair placental perfusion and endometrial receptivity, which may be associated with an increased risk of recurrent miscarriage. It has been suggested that epigenetic changes in miRNA, which are expressed in a large number in the placenta, could be involved in the pathogenesis of recurrent miscarriage. Specifically, miRNA-16 seems to regulate placental angiogenesis by targeting VEGF expression and suppressing its formation; so, higher rates in serum of miRNA-16 are traduced in diminished VEGF expression, finally raising the risk of miscarriage. Annexin A5 is also termed the placental anticoagulant protein because of its importance on the maintenance of placental strength and irrigation. The presence of polymorphisms that involve abnormalities in that molecule could increase the risk of RM especially in European and Asian women.

• 6.
  

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

The gold standard test for the diagnosis of fetal chromosomal alterations is G-banding conventional karyotyping. Molecular techniques have been proposed as an alternative to conventional karyotyping diagnosis because of their ability to deal with a part of the limitations of the gold standard technique:

able to detect undersized deletions and duplications, is not hampered by maternal contamination, culture failure or errors in chromosomal samples. The screening of embryos performed in in vitro fertilization forms part of some protocols for parents affected by RM, especially for translocation carriers. However, available data are controversial and conflicting regarding the improvement in live births rate in these couples. The majority of miscarriages occur in chromosomally-normal parents and no consensus has been reached for systematic karyotyping of patients with RM, since it is expensive and does not always yield information. Until the 1990s, many genetic polymorphisms were thought to be involved in RM pathogenesis, mainly related to immune imbalance, thrombophilia and hyper-coagulative state and placentation abnormalities. The current literature suggests that further research would cast light on its importance in the diagnosis and management of RM; however, further functional studies are needed to establish their role as blood biomarkers and their introduction into routine clinical practice.

• 7.
  

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

The distribution of the mosaic abnormal cell line in the fetus and the placenta depends on the timing and localization of the mitotic event generating the mosaicism: if it occurs before the separation of placental and fetus compartments, the mosaicism will be generalized to both ones; if it occurs after this separation, it will be confined to one compartment only. Due to the unpredictable distribution of the abnormal cell line, when a chromosomal mosaicism is detected in CV it is not necessarily true that it is also extended to the fetus. For this reason, it is always recommended to perform a confirmatory amniocentesis. In TFM conditions the abnormal cell line can be present either in a mosaic or in a homogeneous form in the fetus. Due to the limitations of US examinations, the uncompleted fetal development and the lack of knowledge of the entire phenotypic spectrum of most conditions, abnormal fetal karyotypes are not necessarily associated with abnormal U/S findings in the first trimester or at later gestation. So, a negative U/S finding does not necessarily exclude with certainty the presence of a TFM. A cytogenetic prenatal diagnosis on CV is performed following compulsory laboratory guidelines that minimize the risk of technical contamination and artifacts. The laboratories are also subjected to control quality audits monitoring the level of contamination that must be always under a controlled threshold (usually 2%). CfDNA testing is a screening test for common aneuploidies and not a diagnostic one. For this reason, it cannot be considered a valid alternative to a confirmatory amniocentesis, which is a diagnostic test for all cytogenetically visible chromosome abnormalities.

• 8.
  

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

600 cases of mosaic autosomal trisomies in CV were detected, but only 45 cases (7.5%) were confirmed as TFM. Hence autosomal trisomies show the highest rate of involvement as mosaic in CV with the lowest risk of confirmation compared with other groups of chromosome abnormalities. Sex chromosome aneuploidies are the most confirmed chromosome abnormality in the fetus with an overall risk of TFM of 33.3%. However, separating monosomy X from the other SCAs, the TFM risk of MX is 26.8% while that of the other SCAs is 53.5%. The sSMC are the second most confirmed group of chromosome abnormalities after SCAs with a TFM risk of 30.6%. Triploidies were always confirmed in the fetus; on the contrary tetraploidies were always CPM. Unbalanced structural rearrangements (derivative chromosomes from unbalanced translocations, deletions, duplications, and additional material of unknown origin), although frequently detected as mosaic in CV, are confirmed as TFM in 11.6% of the cases; while balanced rearrangement (reciprocal and Robertsonian translocations and inversions), although more rarely seen as mosaic in CV compared with unbalanced ones, they show a similar risk of confirmation (12.8%).

• 9.
  

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

cfDNA testing is a screening tool because, although rare, they can provide false positive and negative results. Because cytotrophoblast is the source of the cfDNA fragments circulating in the maternal plasma targeted by the cfDNA testing technologies and it can be involved in feto-placental chromosomal mosaicisms, false positive and negative results by cfDNA testing can arise when the genetic constitution of the cytotrophoblast is discordant with that of the fetus. False negative results can rarely occur and could be due to the presence of a TFM5 in the conceptus. As a low risk cfDNA is not followed by invasive tests, a FN case is detectable only at later weeks of gestation or at birth. For this reason risk of false negative result, although remote, should be disclosed to the patient. QF-PCR is aimed at detecting homogeneous T21, 18, 13 as well as SCAs on invasively obtained prenatal samples. It is a molecular method that dosages short DNA segments located on the chromosomes of interest. In case of CVS, this dosage analysis is performed on the DNA extracted from the entire placental biopsy, including a mix of DNAs coming either from the cytotrophoblast and/or from the mesenchyme. If there is a mosaic condition in one or both placental tissues there is a risk that the abnormal cell line will not be detected by QF-PCR or, although detected, the trisomic cell line cannot be assigned to a specific placental tissue, thus preventing any accurate fetal involvement prediction. So, if QF-PCR provides a normal result the residual risk for mosaic trisomies is still consistent. If QF-PCR provides a positive result, the clinical utility of the positive result is low because the risk of fetal involvement cannot be predicted. In addition, QF-PCR is not informative for the detection of mosaic monosomy X. Because MX is the most common single aneuploidy involved in mosaic in CV and because the risk of finding a mosaic in CV after a high risk cfDNA testing result is about 60%, CVS is discouraged as diagnostic confirmatory invasive procedure. However, in case the woman opts for CVS, QF-PCR is not the elective test because of the limits in detecting mosaicism in CV. Because cfDNA testing results reflect the chromosome constitution of the outer placental cellular layer it could be roughly assimilated to the cytogenetic analysis of the cytotrophoblast. Consequently, any high risk result should be assumed to be derived from a mosaic cytotrophoblast. Hence, the confirmatory amniocentesis after a high risk cfDNA testing result should be analysed following the same criteria of analysis of a confirmatory amniocentesis performed after the detection of a mosaic in the CV by conventional cytogenetic analysis. Current cytogenetic guidelines recommend an extended analysis and/or cell count on amniocytes to exclude the presence of a mosaic condition also in the fetus. Due to the limits in mosaicisms detection of QF-PCR, its application is discouraged. Each chromosome has its own typical behaviour in tissue distribution during the feto-placental development. In table 4 in the article it is reported the chromosome-specific risk of finding a mosaic in CV if after a high risk cfDNA testing result a confirmatory CVS is performed. This chromosome-specific ‘personalized’ risk score should be provided to the patient during counselling before any invasive procedure.

• 10.
  

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

SNP arrays have a higher resolution for VOUS than BAC arrays, but the finding of a VOUS is usually not helpful in the prenatal setting and therefore cannot be considered an advantage. SNP arrays usually have a higher resolution than BAC arrays which is an advantage for detection of pathogenic CNVs. SNP arrays can detect regions of homozygosity, which may indicate a pathogenic finding of uniparental disomy. Triploidies do not show a relative deviation of copy number, since all chromosomes are present in 3 copies. Therefore only SNP arrays, but not BAC arrays can detect this common prenatal pathology. There is no difference for the application of SNP and BAC arrays in respect to fetal number; both can be applied in singleton and twin pregnancies on invasive material.

• 11.
  

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

NIPT is not recommended in cases of ultrasound abnormalities. Conventional karyotyping is correct but if results are negative, molecular karyotyping should follow. CMA increases the detection rate of pathological chromosomal imbalances considerably in fetuses with multiple ultrasound anomalies. MLPA can detect only deletions or duplications for specifically addressed loci, it is not genome wide. Therefore, it would be a good choice only in the presence of a strong phenotypic suspicion, which prenatally is very rare. QF-PCR is recommended to first exclude the most common aneuploidies (e.g. trisomy 21, 13, 18) and, if normal, proceed with molecular karyotyping.

• 12.
  

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

It is true that CMA has a higher resolution in comparison to conventional karyotyping, but this is clearly an advantage. CMA works on uncultured material, which is another advantage.

• 13.
  

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

The recurrent CNVs in 15q11.2 are found more commonly in a variety of neurodevelopmental and psychiatric disorders but show incomplete penetrance. Therefore they are considered as variants in susceptibility loci (VISL).

• 14.
  

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

CfDNA is comprised of small fragments of extracellular DNA that circulate freely in the bloodstream. The majority of cfDNA in plasma is derived from haematopoietic cells that release fragments of DNA during cell turnover, but a large variety of solid organs also contribute to the circulating plasma pool. During pregnancy, cfDNA from the placenta is also released into the maternal plasma. These DNA fragments originate from the outer cytotrophoblast, and are released into the maternal circulation during apoptosis. CfDNA arising from the placenta – so-called “cell-free fetal DNA” (cffDNA) – is detectable in maternal plasma from as early as 5 weeks gestation and comprises on average only 10–20% of the total plasma cfDNA. CffDNA levels rise gradually with increasing gestation and are cleared quickly from the maternal circulation after delivery.

• 15.
  

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

There are a number of different NIPT platforms for aneuploidy detection, including random whole genome or massively parallel sequencing (MPS), targeted or chromosome-selective sequencing (CSS) and single nucleotide polymorphism (SNP)-based sequencing. In whole genome MPS approach, short stretches, or “reads”, of randomly selected plasma DNA fragments are performed simultaneously (“massively parallel”), enabling millions of DNA molecules to be sequenced quickly at single nucleotide resolution. The CSS approach improves the efficiency of the sequencing step. In this method, the plasma DNA fragments undergo an ‘enrichment’ process, so that only preselected fragments from chromosomes 13, 18 and 21 and the sex chromosomes are read and sequenced, rather than the entire plasma mixture which contains DNA from all chromosomes. A SNP is a variation in a single base pair in a given stretch of DNA that occurs in >1% of the population. In SNP-based NIPT, DNA is extracted separately from the maternal plasma and maternal leucocytes. Targeted amplification and analysis of ∼20,000 SNPs on chromosomes 21, 18, 13, X and Y is performed on these samples and the variations at each SNP locus measured. The fetal genotype is then deduced by comparing the sequencing results from maternal leucocytes with plasma. Each NIPT approach has particular features that may affect the clinician’s choice of assay. The random MPS method is able to provide dosage information on any chromosome. These “off-target” abnormalities can be maternal or fetal in origin, and involve whole chromosome or subchromosomal abnormalities depending on the depth of sequencing and bioinformatics used. However, the targeted approaches (CSS or SNP-based NIPT) will not detect off-target abnormalities, limiting the potential for incidental findings. SNP-based NIPT is the only assay able to detect triploidy and can also be used for parent of origin analysis of aneuploidy. It is unsuitable however for situations where there are more than two possible genotypes represented in plasma – such as twin pregnancy, egg donor pregnancy, or past maternal organ transplant. Test failure rates are highest in targeted SNP-based assays and lowest in whole genome/MPS methods assays.

• 16.
  

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

The pooled sensitivity of NIPT for trisomy 21 was 99.3%, for trisomy 18, 97.4% and for trisomy 13, 97.4% in the most recent meta-analysis. The American College of Medical Genetics and Genomics accordingly recommends informing all pregnant women that NIPT is the most sensitive screening option for trisomies 13, 18 and 21. The specificity of NIPT is also very high at 99.9% for trisomy 21. A highly specific test means fewer false positive results, which is desirable given the anxiety and additional testing that occurs when women receive a “high risk” screen result. When looking at the performance of NIPT panels as a whole, false positive rates however are cumulative with each additional chromosome assessed. The X chromosome in particular, contributes the most to the false positive rate due to maternal age-related loss and undiagnosed maternal mosaicism. The overall false positive rate for tests assessing chromosomes 21, 18, 13 and the sex chromosomes is therefore higher at 0.72% or approximately 1 in 140. Although sensitivity and specificity are inherent to the test itself, the positive and negative predictive values depend on the population being tested and the pre-test probability of disease. The PPV correlates with the background prevalence of disease and will therefore be lower in low risk women. Although the clinical validity of NIPT was initially established in high risk populations, in which the PPV would be expected to be high, NIPT far outperforms traditional aneuploidy screening approaches in the general all risk population as well. Although a low risk result after NIPT is very reassuring, it does not completely exclude an affected fetus. False negatives for trisomy 21 would be expected to occur at a rate of approximately 1 in 10,000 in a high risk population with a 1 in 100 prevalence.

• 17.
  

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

All these statements are true. Aneuploidy screening should be offered to all couples but is voluntary. Although NIPT for chromosomal aneuploidies is an excellent screening test for common chromosome conditions, it does not provide the detail and range of genomic information gained by invasive testing so, if diagnostic information is desired, this can only be gained with an amniocentesis or CVS. An early ultrasound must be performed prior to considering NIPT as up to 16% of high risk women will have an ultrasound finding at 10–14 weeks that alters the prenatal counselling, such as correction of gestational age, detection of multiple pregnancy, fetal demise or structural abnormalities. Women with an increased risk of an atypical abnormality should be counselled about the risk of missing a clinically significant diagnosis if NIPT is chosen over genome-wide diagnostic testing with chromosome microarray. These include women with a fetus with a structural abnormality on ultrasound, a nuchal translucency ≥3.5 mm, or extreme values in the individual cFTS serum analytes (if cFTS was performed).

• 18.
  

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

Vertebral column abnormalities and dural ectasia are both features that may be observed in Marfan syndrome but do not require MRI surveillance. Use of a beta blocker is recommended in Marfan syndrome as it can reduce hemodynamic stress on the aortic wall. The dose should be titrated to keep the heart rate lower than 100 beats per minute in adults. Vaginal delivery is not contraindicated in women with a stable aortic root diameter less than 40 mm and for those without significant valvular disease. There has been an increased risk for preterm delivery in select studies in women with Marfan syndrome, however the mechanism is unknown and is not thought to be due primarily to cervical insufficiency, therefore cervical cerclage placement should be reserved for usual indications.

• 19.
  

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

Aortic dissection in pregnancy is a recognized risk in women with TS, and has been reported in the setting of a normal aortic root therefore contraindications to pregnancy include previous aortic coarctation or dissection, and aortic size >25 mm/m ² . The incidence of cardiac disease in women with Turner syndrome ranges from 25–50%. The most common cardiac conditions include bicuspid aortic valve, dilated ascending aorta and coarctation of the aorta. Hypertension is a complication seen in many women with Turner syndrome.

• 20.
  

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

The ventricles of the brain are cavities filled with CSF fluid. These ventricles become enlarged when there is an obstruction to the flow of the CSF fluid. Non obstructive causes include congenital CNS malformation, where there is failure of normal development of the brain. Brain destruction by congenital infection (CMV, toxoplasmosis), vascular malformation or mechanical insults are other aetiologies. Overproduction of the CSF in conditions such as choroid plexus papilloma is another non obstructive cause of ventriculomegaly. Unilateral ventriculomegaly is typically physiological. Pathological cases occur from brain destruction due to congenital infections, vascular or mechanical insult. CPAM typically derive their blood supply from the pulmonary artery and drains via the pulmonary veins, with the exception of hybrid lesions, which have a systemic blood supply. CDH occurs more commonly on the left side probably due to the earlier closure of the right pleuroperitoneal canal. The risk of karyotype abnormality in isolated cleft lip and palate is extremely low, but midline cleft is invariably associated with karyotype abnormalities.

• 21.
  

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

The ventricles of the brain are cavities filled with CSF fluid. These ventricles become enlarged when there is an obstruction to the flow of the CSF fluid. Non obstructive causes include congenital CNS malformation, where there is failure of normal development of the brain. Brain destruction by congenital infection (CMV, toxoplasmosis), vascular malformation or mechanical insults are other aetiologies. Overproduction of the CSF in conditions such as choroid plexus papilloma is another non obstructive cause of ventriculomegaly.

• 22.
  

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

The physiological gut herniation occurs up to 12 weeks of gestation after which, this would represent an anterior abdominal wall defect or exomphalos. Gastrochisis is not associated with chromosomal abnormality but 60% of exomphalos is associated with trisomy 18. In bilateral renal agenesis the absence of fetal urine production leads to oligo or anhydramnios which results in pulmonary hypoplasia. Achondroplasia is a late development which is not amenable to detection by scan in the 1st trimester but only in late 2nd or early 3rd trimester. CTEV is an abnormality of the ankle joint (subluxation of the talo-calcaneo-navicular joint) which occurs secondary to a neurological deficit resulting in underdevelopment and weakness of the muscles on the lateral side of the calf or from intrauterine crowding.

• 23.
  

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

Beckwith-Weidemann syndrome is characterised by triad of macrosomia, macroglossia and exomphalos. The stem answer in the question c are features of thanatophoric skeletal dysplasia. Meckel Gruber syndrome presents with occipital encephalocele, multicystic dysplastic kidneys and postaxial polydactyly. The stem answer e in the question are features of triploidy of maternal origin.

• 24.
  

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

Estimates suggest that up to 75% of cases of neural tube defects can be prevented by appropriate folic acid supplementation. At the same time, option e is false as there is a residual risk of neural tube defects in women who take supplements. The prevention of these folic acid-resistant cases is the subject of ongoing research. Option c is correct as it conveys the current recommendation. The neural tube closure is normally completed by day 28 of pregnancy, which is often before the diagnosis of pregnancy. The basis of folic acid supplementation is the need for adequate levels during the key period of organogenesis and option b is false. Though folic acid supplementation is also used to prevent recurrence of neural tube defects (the recommended dose is higher), it should be taken for prevention of first occurrence of the malformation.

• 25.
  

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

All the options relate to the autosomal recessive mode of inheritance of cystic fibrosis. In order for the couple to be at risk of having affected children, both prospective parents need to be carriers of mutations that cause the condition. So, option c is false as the fact that the woman is unaffected does not remove the risk as we already know that she is a carrier. The unknown factor here is the carrier status of the husband (we know that he is not affected so he could be either a carrier or not a carrier). It is important that we already know that there is no consanguinity as this would have increased the chances that the husband would also be a carrier. As things stand, this chance will increase if the husband is found to have a family history of cystic fibrosis (this should be established during the interview). For this reason, option a is false. If there is no history on the husband’s side of the family, then the chance of the husband being a carrier would be the carrier frequency for cystic fibrosis in the population that the husband is coming from. For this reason, option e is true. This background carrier risk could be significantly reduced if the husband has genetic screening for the common cystic fibrosis mutations in the specific population according to existing guidelines. If the husband were shown not to have any of the common mutations, his chance of being a carrier would be significantly reduced (but not eliminated). So, option d is true. This option would also be valid even if the husband had a family history of cystic fibrosis in which case he could be offered testing for specific mutations (if those had already been identified in other family members). Finally, if the couple do have an affected child, the carrier status of the husband will be confirmed and, in any subsequent pregnancy, the risk of having affected children will be 1 in 4.

• 26.
  

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

Folic acid was shown in a seminal Medical Research Council study in 1991 to significantly reduce the rate of recurrence of neural tube defects. In the case of women with a previously affected child, the recommended daily dose is 4–5 mg. Neural tube defects provide an important paradigm of a congenital malformation with multifactorial aetiology combining both environmental and genetic contributions. Empirical data from the pre-folic acid era demonstrate a significant recurrence risk which correlates with the number of affected siblings, pointing towards a genetic contribution. Multiple studies have shown a significant reduction in the incidence of neural tube defects with folic acid supplementation. There is, however, a residual risk as not all cases can be prevented and there has been significant work aiming to develop strategies to deal with these folic acid-resistant cases. The vitamin-like substance Inositol has received significant attention in that respect and work in mice and preliminary human studies have identified the need for large scale trials.

• 27.
  

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

A number of studies have also suggested that, in addition to its effect on neural tube defects, periconceptional folic acid supplementation reduces the risk of specific types of congenital heart disease such as conotruncal defects. A recent meta-analysis of epidemiological observational studies has also provided evidence that folic acid supplementation reduces the risk of congenital heart disease. This is a potentially significant additional protective effect and more research is needed in order to explore its basis.

• 28.
  

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

Despite the weight of evidence, many pregnant women either miss out on folic acid supplementation or only start taking the supplements after the pregnancy has been confirmed, which is often after the critical period of development of the neural tube in the embryo. The reasons are multiple and include an unplanned pregnancy or the absence of counselling or advice in the preconception period. Conversely, a planned pregnancy, a preconception visit to a medical professional and preconception counselling positively correlated with the use of folic acid before the pregnancy. Other factors that were associated with higher levels of preconception supplementation were higher maternal age and higher level of education. In view of the significant percentage of unplanned pregnancies, it can be argued that folic acid supplementation should be used by all women of child-bearing age.

• 29.
  

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

There are a number of circumstances that raise concerns including the previous birth of an affected child, a complicated obstetric history featuring recurrent pregnancy losses, a confirmed or possible genetic (or other) diagnosis in either of the prospective parents, and a family history of known (or suspected) genetic disorders or of children born with congenital anomalies. Moreover, the ethnic background of the prospective parents and the possibility of consanguinity need to be explored.

• 30.
  

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

On a global scale, cystic fibrosis, thalassaemia, sickle cell disease and Tay-Sachs disease represent common autosomal recessive conditions in terms of carrier frequency with significant variation in different populations. Haemophilia A is X-linked recessive.