The main causes of female infertility are anovulation and anatomical causes such as obstruction in the genital tract. Many aspects of female reproductive function are strongly influenced by genetic factors. Androgen insensitivity syndrome is an X-linked disorder characterised by variable defects in virilisation of 46,XY individuals. A genetic contribution to spermatogenic failure is indicated by several families with multiple infertile or subfertile men. Klinefelter syndrome (47,XXY) is the most frequent cause of gonosomic anomalies, occurring in 0.1-0.2 % of newborn males. Chromosomal translocations are found with a frequency 8-10 times higher in infertile men and may be acrocentric Robertsonian translocations or reciprocal translocations. The prevalence among infertile men is high, from 5 % in those with severe oligozoospermia to 10 % in those with azoospermia. Understanding of the genetic basis of infertility is likely to increase dramatically in the future. New technologies are available that permit high-throughput detailed genetic analysis.

This chapter reviews some recent advances in our understanding of human sex development, and discusses a newly suggested nomenclature and classification system for disorders of sex development (DSD). It provides a brief overview of some known genetic causes of DSD, and outlines some challenges for research and clinical practice in this field related to the theme of reproductive genetics. Sex chromosome DSD includes all cases of sex chromosome aneuploidy. Complete gonadal dysgenesis results in a complete lack of androgenisation and a female phenotype. The most common cause of androgen excess is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Increasing number of cases of DSD are being diagnosed earlier owing to discordance between a karyotype performed in the first trimester and genital appearance on prenatal ultrasound or at birth. The early postnatal management of a child born with ambiguous genitalia or karyotype/phenotype discordance is very important.

Preimplantation genetic diagnosis (PGD) is a complex process comprising many stages and involving a multidisciplinary team of healthcare professionals. PGD allows a couple to conceive pregnancy that is biologically their own and is unaffected by the genetic condition in the family. Embryos are created by using assisted reproductive technology (ART) and are tested for the relevant genetic condition by polar body, blastomere or trophectoderm biopsy. It is important to distinguish the difference between PGD and preimplantation genetic screening (PGS) for sporadic chromosome aneuploidy. PGS is distinct from PGD and it is mainly used within the ART arena as an adjunct to fertility treatment with the aim of improving in vitro fertilisation (IVF) outcome. The potential use of PGD to select embryos with desirable nonmedical traits such as intelligence, beauty or longevity perhaps represents a more distant future for PGD.

A great deal has been written on the ethical aspects of saviour siblings, with views largely converging on similar basic position: easy case saviour siblings are permissible and hard cases are not. The important distinction to draw here is between the reasons for having a child and the treatment of the resulting child. Saviour siblings are children whose tissue or organs will be donated so that a brother or sister will be saved. The treatment of existing saviour siblings immediately involves ethical questions about live organ donation by children. This chapter suggests that the appropriate standards for live organ donation by children should be adopted to decide the acceptability of the use of preimplantation genetic diagnosis (PGD) for saviour siblings. This amounts not to an ethical judgement about the procreative reasons of prospective parents; instead, it is a practical judgement based on the permissibility of particular ways of treating children.

The relationship between assisted reproductive technologies (ART) and deregulation of genomic imprinting is thought to have particular relevance to fetal growth because fetal growth is suggested to be the main drive for the evolution of imprinting or the conflict between the parental genomes. The link between embryo culture and phenotype is thought to be, at least in part, epigenetic. Genomic imprinting is an important epigenetic mechanism through which some aspects of fetal growth and development are regulated. Imprinting is controlled by allelic methylation, and the setting up of imprints in the female germline is a process that occurs throughout reproductive life. Inappropriate methylation or expression of imprinted gene clusters cause a range of pathologies, often involving aberrant growth and development. Similarly, the use of ART has been shown to cause disorders of growth in humans and other mammals.

This chapter addresses the current status of fetal stem cell therapy, its limitations and its future development. Haematopoietic stem cells (HSCs) from cord blood have greater proliferative capacity than their adult counterparts but are limited in number. Fetal MSC (mesenchymal stem cells) have properties intermediate between embroyonic stem cells (ES) and adult stem cells and can be derived from a range of pregnancy-related tissues, including first-trimester fetal blood, liver and bone marrow, second-trimester liver, lung, pancreas, bone marrow and amnotic fluid, placenta, cord and membranes. A wide range of metabolic and haematological disorders in children can now be successfully treated by bone marrow transplantation (BMT). Number of animal models of human diseases suitable for fetal stem cell therapy have been investigated, particularly muscular dystrophy and osteogenesis imperfecta. Clinical trials using MSCs will require ready access to safe and functionally intact cells in sufficient numbers for transplantation into human patients.

Prenatal gene therapy has the ability to target rapidly dividing cells, thus providing a large population of transduced cells that should provide a better therapeutic effect. The list of candidate diseases for prenatal gene therapy includes not only many single-gene disorders but also some pregnancy-specific conditions and structural abnormalities of the fetus. The ideal vector for fetal somatic gene therapy is the one that can produce long-term regulated and therapeutic expression of the transferred gene through the use of a single and efficient gene delivery method. Over the past few years, proof-of-principle studies in small-animal models have shown that prenatal gene therapy can result in permanent phenotypic correction of early single-gene disorders. Prenatal gene therapy in humans will depend critically on the ability to demonstrate its safety and efficiency in treating severe genetic disease. Improvements in vector design and safety and in delivery techniques to the fetus are the key.

Stem cell and gene therapies may involve either permanent or temporary insertion of stem cells or genetic material. Both stem cell therapies and gene therapies can have reproductive effects in the sense that the genetic changes introduced are transmitted in the germline or the stem cells can give rise to germ cells. Some stem cell or gene therapies may therefore actualise the continuing treatment-enhancement debate; that is, whether there is an ethical difference between treating disease and enhancing normal function and whether such a difference makes some or all enhancement morally problematic. Many stem cell and gene therapies will have to be given in the fetal period or during early childhood to be effective or to have their full effect. This raises the issue of proxy consent for very young children. A final set of issues arises in relation to resource allocation within the healthcare system.

The management of pregnancy at known high risk for fetal abnormality because of an affected family member can be more straightforward but there are still many cases where a joint consultation between the geneticist and fetal medicine unit could be advantageous. A specialist in fetal medicine would not be expected to know the variability of a condition, the likely gestation at which the abnormality could be identified or the prognosis of a rare disorder in the absence of the clinical geneticist. Abnormalities that may be identified at the early scan that warrant input from the geneticist include holoprosencephaly and omphalocele. Cleft lip and palate, arthrogryposis, hydrops, renal disorders and skeletal dysplasias can be better handled with the aid of the geneticist. Examination of parents and the family history can give helpful clues to the underlying diagnosis of a dysmorphic fetus and this is best done by the geneticist.

In the context of developing prenatal diagnosis (PND) service delivery models, there is no doubt that the most significant innovation will come from the application of a technology known as array comparative genomic hybridisation (aCGH), which in some postnatal clinical scenarios will soon replace conventional karyotyping as the front-line 'whole-genome test'. There are a number of scenarios that may provide drivers for the adoption of aCGH as the first-line whole-genome test following invasive PND, of which the following two appear the most probable: cases that, following invasive PND, are reported to be normal following quantitative fluorescence polymerase chain reaction (QF-PCR) and/or karyotyping but have abnormal ultrasound findings; and cases that are normal following non-invasive PND (NIPD) for the autosomal aneuploidies but have abnormal ultrasound findings (first trimester or at the 18-20 week anomaly scan).

This chapter describes the current clinical applications of noninvasive prenatal diagnosis (NIPD) for genetic conditions and the potential use for aneuploidy screening or diagnosis. It also highlights ethical, educational and laboratory aspects that require evaluation before introduction into routine clinical practice. The main clinical indications for fetal sex determination are risk of X-linked genetic disorder and family history of congenital adrenal hyperplasia (CAH), with occasional indications including some fetal ultrasound findings and discrepancy between genetic sex and the appearances of the external genitalia on fetal ultrasound. Regardless of the approach taken, results from relatively small numbers have been reported to date and therefore considerable effort is now needed, including formal validation, standardisation, education and other work, before NIPD for aneuploidy can be considered ready for implementation in routine clinical practice. NIPD based on cell-free fetal nucleic acids circulating in the maternal plasma will gradually move into clinical practice.

A problem in all tests on fetal DNA derived from maternal plasma arises from the large quantity of maternal DNA present in the DNA preparation, complicating the inclusion of satisfactory internal controls to test for successful amplification of the fetal DNA. As increasing number of laboratories internationally are introducing non-invasive fetal blood group testing, it is important that their performances are monitored through external quality assurance schemes. Fetal RHD screening provides a way of significantly reducing the quantity of blood products given routinely to pregnant women. To date, the enormous promise of the application of free fetal DNA in maternal plasma to prenatal diagnostics has only been realised in fetal blood grouping and fetal sexing. Fetal blood grouping often plays an important role in avoidance of unnecessary procedures and is the standard of care in England for pregnant women with significant level of anti-D immunoglobulin.

This chapter considers some of the ethical issues at stake in the legal interpretation of the grounds for selective termination of pregnancy and preimplantation genetic diagnosis (PGD). It briefly discusses the distinction between a life that someone may not think is worth living and one that someone will think is worth living, and considers its implications for the question of whose interests may be at stake in prenatal diagnosis (PND) and PGD. The chapter also briefs the recommendations that laid the groundwork for the current criteria for PGD, which have been accepted by the Parliament in the Human Fertilisation and Embryology (HFE) Act 2008. Finally, it raises some questions about the interpretation of the relevant provisions of the new Act and two aspects of the draft guidance in the forthcoming Human Fertilisation and Embryology Authority (HFEA) Eighth Code of Practice.

NHS practice is largely compliant with international recommendations such as those adopted by the Organisation for Economic Co-operation and Development in 2007 for quality assurance in molecular genetic testing. The UK Genetic Testing Network (UKGTN) gene dossier asks the service provider to define their proposed test in the context of the disease and associated gene(s) targeted, the mutation spectrum detectable by the set of assays used, the patient group targeted and, most importantly, those clinicians from whom referrals are acceptable. Clinical utility is the measure on which the evaluation of a test by the UKGTN may stand or fall. The evaluation of new genetic tests cannot be separated from the enabling technologies that will allow them to be realised. Next-generation genomic technologies (such as microarrays and parallel DNA sequencing) will require full health technology and economic assessment.

This chapter uses Antenatal Results and Choices' (ARC's), extensive experience with expectant parents to explore the potential implications for them of new techniques in prenatal genetic testing, particularly advances in non-invasive prenatal diagnosis (NIPD). The fact that NIPD is likely to be offered well within the first trimester will be welcome to many parents as potentially providing earlier reassurance. Although information provision to women about the purpose of antenatal ultrasound is improving, we cannot overestimate the profound impact when the scan shows that there may be something wrong with an unborn baby. Media interest in advances in prenatal genetic testing is high and news stories almost always spark debates about ethical issues. From ARC's perspective, advances in NIPD and other forms of genetic testing that can offer a safe way to obtain diagnostic information will be of significant benefit to parents and families.

This chapter considers how healthcare services can support informed decision making within prenatal screening programmes. It discusses potential approaches to evaluating screening programmes that use informed choice rather than test uptake as the outcome measures. In the latest version of the Multi-dimensional Measure of Informed Choice (MMIC), ten knowledge items are measured. Of these ten, five are concerned with understanding the screening risk result and two with assessing knowledge of down syndrome. The emphasis on increasing informed decisions rather than promoting test uptake brings an additional challenge to the evaluation of fetal anomaly screening programmes. Central to the notion of informed choice, and to the definition on which the MMIC is based, are personal values. There are now a number of well-validated measures of decision making, for example the decisional conflict scale, that may be suitable for evaluating quality of decision making in prenatal screening programmes at the individual level.

This chapter discusses the consensus views obtained from the 57th Study Group on various aspects of reproductive genetics. It emphasizes that fetal karyotyping should remain the gold standard test following invasive prenatal diagnosis until appropriately tested and evaluated higher-resolution whole-genome analytical methods can be introduced. Preimplantation genetic diagnosis (PGD) for saviour siblings should be permitted or denied based on the permissibility or impermissibility of live-organ donation by children. Focused basic research is needed to understand the normal genetic and epigenetic events that occur during primordial germ cell specification from embryonic stem (ES) cells and in the differentiation of primordial germ cells. Improvements in vector design and safety will be needed before safe targeted delivery to the fetus can be achieved; studies into long-term safety in large animal models (non-human primates) should be supported. Research is needed into the long-term outcomes of novel therapeutic interventions.