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19 July 2004

The US National Alliance for Autism Research (NAAR) is co-ordinating an international research project into genetic causes of autism, a complex neurodevelopmental disorder with early childhood onset that causes a spectrum of emotional detachment and communication problems. Around half a million people in the UK have been diagnosed with some form of autism. Evidence from twin and family studies suggests that genetic factors are important in autistic spectrum disorders, but there is no straightforward model of inheritance.

The Autism Genome Project involves 170 experts from the US, UK, Europe and Canada, and aims to analyse 6000 DNA samples from members of around 1200 families with two autistic children. DNA microarrays will be analysed to identify any common patterns of gene expression that may be associated with the disorder, in the hope of using this information to identify key genes; genes identified will be studied for mutations that may contribute to autism. The project will be the largest study of genetic factors in autism to date, with results due to be released in early 2005. Speaking on behalf of the UK National Autistic Society, Lorna Wing commented that: "Autism is likely to have multiple genes responsible, rather than a single gene…The difficulty of establishing gene involvement is compounded by the interaction of genes and by their interaction with environmental factors" (see BBC news report).

30 July 2004Professor Francis Crick, who along with James Watson received a Nobel Prize for their discovery of the double-helix structure of DNA in Cambridge in 1953, has died age 88. Professor Watson commented: "I will always remember Francis for his extraordinarily focused intelligence", adding: “He will be sorely missed" (see BBC news report). Professor Crick was born in the UK and died in San Diego in the US; he was a former president of the Salk Institute in San Diego.

6 July 2004

Researchers from Cornell University in the US have reported findings on the risk of genetic disorders in children born following assisted reproduction. Concerns have arisen over the safety of assisted reproductive techniques, due to the higher incidence of genetic imprinting disorders among children born following such procedures. Imprinting is a process of differential expression of certain genes in the foetus based on whether they are present on the paternal or maternal alleles. Imprinting disorders can lead to abnormal foetal development and diseases in humans such as Angelman's and Beckwith-Wiedemann's syndromes. Speaking at the Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) held in Berlin last week, Takumi Takeuchi and Gianpiero Palermo said that they had investigated mouse embryos created from a total of 68 mouse eggs by three different methods of assisted reproduction: intracytoplasmic sperm injection (ICSI); parthenogenesis and somatic cell nuclear transfer (cloning). The embryos were grown for 3-5 days, to the blastocyst stage of development (16 cells).

They found no evidence of defects in mouse embryos created by the first two of these techniques in terms of decreased survival rate of embryos compared with naturally conceived embryos, whereas only 30% of the cloned embryos survived to the 16-cell stage. This was proposed to be the result of abnormal gene expression in cloned embryos. On further investigation, the researchers found that the histones (DNA binding proteins) in the cloned embryos had been altered to show a pattern of imprinting similar to that seen in a mature egg cell. No such alterations were observed in the other embryos studied. Commenting on their findings, Dr Takumi Takeuchi said: “We found significantly impaired development in the cloned embryos compared with those derived from more conventional ART techniques and this has made us more convinced that reproductive cloning is unsafe and should not be applied to humans". Executive director of the (ESHRE) Dr Andre van Steirteghem commented: "There is absolutely general agreement that reproductive cloning should be banned" (see BBC news item).

7 July 2004Downing Street has announced the allocation of £18 million funding for the upgrading of NHS genetics laboratories (see press release). This money is part of the £50 million pledged by the government for investment in genetics and genetics services in the Genetics White Paper of June 2003. This latest funding is intended for the modernisation of equipment and procedures to allow faster results; results from urgent genetic tests are to be available in three days. Health Minister Lord Warner observed: "As our understanding of genetics develops, we will be able to test patients for common diseases such as cancer, heart disease and diabetes”, adding that the funding would “greatly increase the capacity of the NHS to provide access to these new genetic tests and also get results to patients more quickly". The funding will go to the following centres to strengthen clinical genetics laboratories and rationalise regional genetics services:

London

£3,468,000

South and East

£3,467,000

West Midlands

£2,341,000

East Midlands and South Yorkshire

£1,355,000

North West

£2,603,000

Northern Yorkshire

£1,396,000

13 July 2004Gordon Brown’s spending review, announced on 12 July in the House of Commons, includes an extra £1 billion in funding for UK science. This increase will raise the total funding from the current level of £3.9 billion to £5 billion by 2008, doubling the amount of cash spent on science since 1997. This commitment continues the government’s pledge, as Brown stated, “…to make Britain the best and most attractive location for science and innovation in the coming years.”

The increased investment is part of a ten-year strategy, and details are provided in the ‘Science and Innovation Investment Framework 2004-2014’. The government intends to maintain the UK’s position as second to the USA on research excellence and close gaps between the UK and other European countries where the UK’s performance falls behind them. In order to do this, money will be spent to retain and build centres of research excellence. Knowledge transfer and commercialisation from universities and public laboratories will continue to be encouraged. Science education for students will be supported in order to ensure an adequate and well-qualified supply of scientists, engineers and technologists to work in science. The government also plans to improve its responsiveness to concerns and questions raised by the public and scientists, covered by the media or brought forward by policy makers.

In addition to the government’s new investment, Brown noted in his speech that the Wellcome Trust will be matching the government’s commitment by investing an additional £1.5 billion of their funds over the next five years. As Mark Walport, the Director of the Wellcome Trust stated, “It will allow continued support for research and innovation and will create the right framework for UK science to retain its premier position at the forefront of development.” However, those who hope to benefit from these increases in funding will need to examine the plans carefully to determine how, in real terms, the money will be distributed. For example, Dr Peter Cotgreave, Director of Save British Science, warns that money may there to stock laboratories with equipment but little money available to hire or retain skilled staff to work in them. Indicators on how the government intends to meet their announced targets are included in Annex B to the Framework.

26 July 2004Health Minister John Reid has announced that, amongst other changes, that the Government will merge the Human Fertilisation and Embryology Authority (HFEA) and the proposed Human Tissue Authority (HTA) to form the Regulatory Authority for Fertility and Tissue (RAFT). It its report, Reconfiguring the Department of Health’s Arm’s Length Bodies, the Government states that the RAFT will be “…responsible for the regulation and inspection of all functions relating to the whole range of human tissue – blood, organs, tissues, cells, gametes and embryos.” It will replace the HFEA, which has the role, under the Human Fertilisation and Embryology Act 1990, for licensing and monitoring clinics that carry out in vitro fertilisation, donor insemination and human embryo research, as well as regulating the storage of gametes and embryos. The HTA will be created under the Human Tissue Bill, now being considered in Parliament, to act as licensing authority for activities involving the removal, storage, use and disposal of human material as well as advisors to Government on issues related to human tissue. While its duties will be taken over by the RAFT, until the RAFT can be set up the HTA will come into existence to cover these areas. Suzi Leather, HFEA Chair, has welcomed the creation of the RAFT. “It is vital that patients and the public have complete confidence in the effective regulation of the use in treatment and research of all tissues, embryos and organs and this new organisation will bring these fields together.”

ALBs are organisations ‘at arm’s length’ from the Government departments but which act on its behalf to carry out necessary duties. Department of Health ALBs regulate aspects of public healthcare, maintain and improve standards, protect public welfare and support local services. This review of ALBs and the changes proposed reflect the Government’s on-going plan to devolve many responsibilities from central government to ‘the frontline.’ However, it was decided that there was too much bureaucracy and duplicated efforts. There is an expectation that the changes will reduce the cost of Department of Health ALBs by £0.5 billion and the number of posts by 25%.

There will be some changes for other Department of Health agencies but not for others. For example, the Medicines and Healthcare Products Regulatory Authority will remain as is. The National Patient Safety Agency will take the Central Office for Research Ethics Committees under its auspices, taking the national lead for the development of ethics committees that review the ethics of clinical trials as well as for the review of all other research studies involving NHS patients. The new Blood and Transplant Authority will combine the roles of the National Blood Authority and UK Transplant. The Commission for Patient and Public Involvement will be abolished in favour of Patient’s Forums which will enable people to influence health services. Implementation plans for these and other changes will begin over the next few months. The full implementation will take several years as some changes will need to be made through primary or secondary legislation.

22 July 2004The Human Fertilisation and Embryology Authority (HFEA) has announced that they are relaxing their current rules regarding the screening of embryos for tissue typing. This would enable all couples to seek permission to choose an embryo with a tissue type that matches a seriously ill sibling, creating a so-called ‘designer baby.’ This is a change in policy as the HFEA previously only allowed tissue typing to be conducted when there was a threat that the child to be born could also have the genetic disease suffered by the sibling. Tissue typing is an invasive procedure and possibly detrimental to the foetus. In order to protect the unborn child, the HFEA decided that if the child could not inherit the disease, then they should not be created simply to benefit their sibling.

Now the HFEA has relaxed this position and will allow all couples, regardless of whether the child they wish to create is at risk of the disease affecting the sibling, to request the procedure. Approval is not automatic; each case, as in the past, will be reviewed individually and must adhere to strict criteria. For example, the clinical team must show that all other treatments available for the ill sibling have been tried. More families may now benefit from the procedure. For example, the Fletcher family is currently seeking approval to try to have a tissue-matched child to help their son, Joshua, who suffers from Diamond Blackfan anaemia, a fatal blood disorder.

Proponents see this change in policy as a positive step for treating ill children. Dr Simon Fishel, Managing Director of the Centres for Assisted Reproduction, stated to the BBC, “Parents have the right to choose technology to help them overcome their extraordinarily painful circumstances” On the other side, Prof Jack Scarisbrick, national chairman of the pro-life charity, Life, has stated, “It can never be right to manufacture human beings to repair other human beings”. Others have concerns for the mental well being of the children born in order to treat their sibling. While the HFEA has reviewed the current evidence and found that children created under these circumstances are not disadvantaged compared with other IVF children, some believe it is still to early to judge what the future psychological effects could be on the children. In order to gather this information, families are encouraged to participate in counselling sessions and in any follow-up studies. Centres conducting these studies must report on the long-term medical and psychosocial follow up on the children born using these procedures.

16 July 2004The Human Genetics Commission (HGC) has today published their consultation document, ‘Choosing the future: genetics and reproductive decision making.’ The HGC is looking for opinions and comments on new and controversial developments in genetics such as screening embryos for genetic disorders and the ability to create 'saviour siblings' to cure ill children. The consultation is organised under three broad headings: population screening in pregnancy, genetic services and developments in genetics. Under these topics, the questions seek people’s opinions on potential future developments in genetics, what concerns these developments raise, and how they should be managed. In terms of genetic services, the HGC asks what should be acceptable in terms of testing a fetus or an embryo – should people have the right to test for specific genetic conditions? As for prenatal screening, now a routine part of medical practice, the HGC asks how people feel about the increasing number of tests that can detect genetic conditions. They also ask for opinions on existing counselling services, and whether there is a presumption that prenatal screening and diagnosis presupposes that a woman or couple will opt for a termination. As Baroness Kennedy, chair of the HGC said, "We are asking the fundamental questions that we as a society need to think about."

As well as raising questions, the consultation document also serves as a useful reference guide, explaining some of the intricacies of the current science behind reproductive decision making. Beginning with a short history of eugenics, the document gives definitions and explanations of some of the scientific terms used in this area. A chart detailing the current provision of services is provided. It also discusses the ethical ‘pros and cons’ of reproductive choice, using quotes from the HGC’s Consultative Panel to give personal, yet diverse, perspectives on the issues. The Panel is made up of a group of people with personal experience of living with genetic disorders.

The deadline for responses to the consultation document is 15 October 2004. A full report prepared for Ministers by late 2005. The HGC’s remit is to advise the UK Government “…on the ethical, legal, social and economic aspects of developments in human genetics as well as their effects on health and healthcare.”

30 July 2004Alzheimer’s disease (AD) is one of a growing number of complex diseases influenced by both genetic and environmental factors for which genetic susceptibility testing is possible. Although there are several candidate genes that may influence susceptibility to AD, the most widely confirmed is the APOE4 allele on chromosome 19, which encodes the apolipoprotein E4 variant. The presence of an APOE4 allele or alleles may increase lifetime risk of AD by as much as fifteen times, but is neither necessary nor sufficient to cause the disease. Genetic testing for the variant therefore has highly limited predictive ability and is not generally recommended. However, a paper in the latest edition of Genetics in Medicine reports initial results from a clinical trial in the US that investigated levels of interest in APOE4 testing among adult children of individuals affected by Alzheimer’s [Roberts JS et al. (2004) Genet Med. 6, 197-203].

The REVEAL study (risk evaluation and education for Alzheimer’s disease) is a randomized controlled trial designed to evaluate the impact of risk assessment for AD using APOE genotyping. A total of 375 participants were recruited via registries of families willing to participate in AD research or by self-referral on hearing of the project. They received an education session with a genetic counsellor during which the limitations of susceptibility testing for AD were carefully explained; those who opted to be tested (almost 80%) were randomly assigned to two groups, an intervention and a control group. The intervention group received further genetic counselling based on gender, family history and APOE genotype whereas genotype was not considered in counselling for the control group. Lifetime risk estimates ranged from 13-57%.

Overall uptake of the full testing process was 24% for participants who were initially contacted by researchers and 64% for those who were self-referred. The lower figure is higher than uptake rates previously reported for genetic tests for conditions without effective prevention or treatment options; the higher figure among the self-referred group is not surprising because these individuals had actively sought participation in the trial and hence may reasonably be assumed to have had an interest in genetic susceptibility testing for AD. Among study participants, key reasons cited for opting for testing included to contribute to research and hope that effective treatments would be developed, to inform arrangements for long-term care and personal affairs and preparation of family members for possible illness. Significant predictors of test uptake were found to be age below 60 and college (university) level education. Most self-referred participants were female.

Comment: The number of patients with late onset Alzheimer’s disease is already over half a million in the UK alone; adults with parents affected by AD therefore represent a large (and increasing) group, many of whom may be interested in options for genetic susceptibility testing. Although the participants in this study were, as the report notes, not representative of the general US (or UK) population, being predominantly well-educated Caucasians with an active interest in AD research, even levels of interest in genetic testing for Alzheimer’s much lower than those found in this trial would represent a significant number of people. If genetic susceptibility testing for the disorder improves in the future (for instance, should more predictive genetic risk factors be identified) or more effective treatment options become available, the demand for testing services could prove to be substantial. Policy and service development would need to take this into account.

1 July 2004The rise in childhood asthma suggests that environmental factors, such as exposure to environmental tobacco smoke (ETS), play a role in the aetiology of the disease. However, there is increasing evidence that both genetic and environmental exposures play roles in determining an individuals’ susceptibility to the disease. Recently, the glutathione S-transferase (GST) gene, one of a number of genes proposed to be involved in the detoxification of ETS, has been suggested to modify the risk of childhood asthma in children. This finding builds on a body of evidence that suggests a role for GST in the detoxification of tobacco smoke carcinogens.

The research, published in the journal Thorax, determined the GST genotypes and exposure to ETS (both in utero and after birth) in over 3,000 German schoolchildren. The results have been reported by the BBC, New York Post and Reuters news agency websites. The authors found that among children with a specific GST genetic defect, children whose parents were smokers were at an increased risk of developing respiratory problems compared to those whose parents were non-smokers. The findings suggested that children possessing the genetic defect and whose parents smoked were approximately five and three times more likely to have current asthma or to have ever wheezed, respectively. Similar effects, although of a smaller magnitude, were also observed for a second genetic defect in the GST gene. Neither genetic defect appeared to have an effect on the development of asthma in children when exposure to ETS was not included in the analysis.

Comment: Both genetic and environmental factors play a role in determining an individual’s risk of developing a complex disease, such as asthma. The current research provides an indication that defects in the GST gene may increase the risk of respiratory problems in children exposed to ETS. However, despite the relatively large number of children (n=3,054) in the overall study, the number possessing the genetic defect(s) and who were exposed to ETS were relatively small (n=11 and n=45). This, coupled with the small number of cases of respiratory problems in these individuals, requires a cautious interpretation of the findings. Deficiencies in GST, together with other genetic defects, may contribute to the adverse respiratory problems caused by exposure to ETS and these should be studied further in larger numbers of individuals.

21 July 2004Definitive prenatal diagnosis of many genetic and chromosomal disorders currently requires fetal cell sampling by amniocentesis or chorionic villus sampling, invasive procedures with an associated risk of miscarriage of about 1%. As the number of disorders for which prenatal screening and diagnosis is offered increases, interest in alternative non-invasive means of obtaining fetal cell samples has grown. Fetal DNA is present in small quantities (around 3-6% of total DNA) in maternal plasma, and the potential for diagnostic approaches using maternal blood samples is an area of particular interest. The major difficulty is in accurately discriminating fetal from maternal DNA; the specificity and sensitivity of analysis for fetal markers is a key factor in determining the reliability of such approaches. A technique called real-time quantitative PCR (polymerase chain reaction) has proved valuable for allowing amplification of fetal-specific DNA sequences. However, for many genetic diseases the genetic differences between maternal and fetal sequences are very subtle.

A paper published in Proceedings of the National Academy of Sciences of the USA (PNAS) this month reports on a novel method for prenatal diagnosis of ß-thalassemia.Researchers at the University of Hong Kong previously developed a method to identify the most common mutation associated with Southeast Asian ß-thalassemia, a CTTT deletion in the ß-globin gene HBB. To be affected by the disease, which shows autosomal recessive inheritance, a baby must inherit a mutant allele from each parent. Failure to detect the paternal mutation in maternal plasma suggests that the fetus has not inherited the paternal mutant allele and will therefore not be affected by the disease. However, this technique does not identify the status of the fetus if both parents are carriers of this mutation; moreover, many other mutations associated with ß-thalassemia are point mutations. Discrimination of these subtle, single-nucleotide differences between circulating maternal and fetal DNA species is much more difficult.

The report [Ding C et al. (2004) PNAS 101, 10762-10767] presents a MS (mass spectroscopy) based technique to determine whether the fetuses in at-risk pregnancies would have ß-thalassemia major by analysing maternal serum samples for the presence of paternally inherited mutations. MS can be used to identify the presence of even trace amounts of specific molecules. Twelve pregnancies at risk for ß-thalassemia were recruited in Hong Kong, Thailand, Singapore, and Malaysia. Detection of paternal mutant HBB alleles in maternal plasma between weeks 7 and 21 of gestation was performed using the Sequenom MassARRAY system, which amplifies fetal and maternal alleles using PCR followed by a base extension reaction and MS analysis. The paternal and maternal mutations were different in 11/12 of the at-risk pregnancies. Selectively amplified DNA samples from maternal plasma were analysed for the presence of one of four of the most common ß-thalassemia mutations (the CTTT deletion and three point mutations, together accounting for around 90% of ß-thalassemias in Southeast Asia) present in the father. Fetal genotype was successfully predicted in all cases. The 12 at-risk samples were also analysed for a fetal-specific (paternally inherited) single nucleotide polymorphism (SNP) located 1.3 kb downstream of the HBB gene on chromosome 11 and found to show linkage with the paternal HBB mutation. Haplotype analysis excluded the possibility of ß-thalassemia in the pregnancy where both parents carried the same HBB mutation (but had different haplotypes with respect to the SNP).

Comment: This report demonstrates some of the potential of non-invasive techniques for prenatal diagnosis, especially the ability to identify point mutations. Exclusion of the presence of a paternal mutant allele successfully diagnosed the absence of disease in at-risk couples where each parent carried different disease-associated mutations. In the case of the couple with identical mutations, diagnosis was also possible because (and only because) the parental haplotypes at an SNP linked to the disease-associated gene were different. If analysis were extended to multiple linked SNPs, the probability of being able to distinguish between parental haplotypes for a given couple would substantially increase. One caveat is that this form of diagnosis requires analysis of DNA from both parents, which would not always be possible. Such non-invasive methods need not be applicable for all couples to be useful, however. Even if only a proportion of invasive procedures for prenatal diagnosis could be avoided, this would nevertheless reduce the overall number of pregnancy losses.

12 July 2004Trisomy is a condition in which a fertilised egg contains three copies of a particular chromosome rather than the normal two copies, producing a total of 47 chromosomes in the cell. For most chromosomes, the presence of an additional copy is lethal and embryos will not develop properly, leading to pregnancy loss. Some forms of trisomy may permit embryonic development and even live births; the ‘viable trisomies’ are those affecting chromosomes 13, 18, 21, X or Y, although the majority of pregnancies affected by these trisomies end in spontaneous abortion (miscarriage) or stillbirth. The most common and mildest form of trisomy is trisomy 21, which causes Down Syndrome. Trisomy 18 or 13 causes Edwards Syndrome and Patau Syndrome respectively; these conditions cause multiple severe congenital abnormalities. Trisomies XXX and XXY (X-aneuploidy) have less severe affects and liveborn children survive and may show virtually no effects. All other trisomies are considered non-viable, and are usually only identified following spontaneous abortions (miscarriages). The incidence of many trisomy disorders (especially trisomy 21) increases with advancing maternal age. In the UK, antenatal screening for biochemical markers of trisomy 21 is routine; women who are considered to be at high risk of fetal chromosomal disorders (whether due to screening results or other risk factors such as advanced maternal age) are offered chorionic villus sampling or amniocentesis to allow diagnostic testing.

A recent paper in the American Journal of Human Genetics analyses antenatal diagnostic data from women who had shown a single prior trisomy in a previous pregnancy. Women with a prior chromosomal abnormality that arises by a different mechanism to those involved in trisomy (monosomy X, triploidy or trisomy XYY) were included as a control group for the study; this group was expected to show only the maternal age-related incidence of trisomy. Karyotype data from prenatal diagnoses were obtained from two sources, a Canadian hospital (1027 results from 748 women) and the US company Genzyme Genetics (1829 results from 1702 women). The authors sought to determine the risk of recurrence for trisomies in an individual woman, and to consider whether a trisomy in one pregnancy is associated with an increased risk of the same or a different chromosomal trisomy in subsequent pregnancies [Warburton D et al. (2004) Am. J. Hum. Genet. 75, advance electronic publication].

The authors identify three possible causes of trisomy recurrence for a given couple: (1) chance, due to maternal age-associated risk; (2) parental gonadal mosaicism for trisomy and (3) increased error rates during meiosis. Mosaicism occurs when non-disjunction of a chromosome takes place in one of the initial cell divisions after fertilization, resulting in a mixture of two types of cells in the body, some with 46 and some with 47 chromosomes. The authors note that trisomy mosaicism in the parental ovary or testis would account for an increased recurrence risk for trisomies affecting the same chromosome (homotrisomy), but would not explain an increased recurrence risk for trisomies affecting a different chromosome (heterotrisomy). An increased risk of heterotrisomy recurrence suggests that some couples have a higher risk of meiotic non-disjunction than other couples of the same age, probably maternal in origin.
The recurrence risk of homotrisomy for all potentially viable trisomies other than X-aneuploidy was found to exceed that expected based on maternal age alone by around two-fold. The affect of age on homotrisomy 21 was analysed, and the recurrence risk in women for whom the initial affected pregnancy and the subsequent prenatal diagnosis took place under the age of 30 was found to be eight times higher than expected, whereas the risk for women of age 30 and above was only twice the expected figure. The calculated recurrence risk of heterotrisomy following trisomy 21 was also around two-fold, with no significant effect related to maternal age observed. The risk of heterotrisomy following the other potentially viable trisomies was found to be lower at 1.6-fold. The risk of a viable trisomy in the control group (following a pregnancy affected by monosomy X, triploidy or trisomy XYY) showed no increase over the age-related rate of trisomy.

The authors attribute the higher recurrence risk for trisomy 21 among younger mothers to a greater proportion of cases caused by trisomy mosaicism in the parental gonads for this group. The smaller increased risk for heterotrisomy is presumed to indicate a variable risk of meiotic error in women at a given maternal age. They propose that women under the age of 35 who have had a previous trisomy 21 might prefer the first-trimester screening and/or chorionic villus sampling for prenatal diagnosis. The authors’ conclusion that there is a 1.6- to 1.8-fold increase in risk for a different viable trisomy after a previous trisomy 13, 18, or 21 or a previous nonviable trisomy detected in a spontaneous abortion leads them to suggest that first-trimester screening or prenatal diagnosis should possibly be offered to women under the age of 35 who have had a previous trisomic pregnancy.

Comment: The ability to identify women who have an elevated risk of trisomy in future pregnancies following diagnosis of trisomy in a live birth or pregnancy loss would be useful in determining which women should be offered prenatal diagnosis. Genetic counselling following the incidence of trisomy in a pregnancy is reportedly based on the conclusion from earlier analyses that such women did not have an increased risk for trisomy in subsequent pregnancies. These results suggest that women with previous trisomic pregnancies who might not normally be offered first trimester screening or prenatal diagnosis (those under age 35) may in fact be at increased risk of subsequent trisomies and could therefore benefit from this option.

For more information on trisomy 21 (Down Syndrome), see the disease profile section.