News

30 October 2008 A new genetic testing methodology for pre-implantation genetic diagnosis (PGD) has been developed by scientists at the Bridge Centre in London (see the Times and the BBC news articles). According to media reports, this new methodology known as karyomapping has been hailed as a breakthrough technique which has the potential to test embryos produced via in vitro fertilisation (IVF) for almost any known genetic disorder. Currently, embryos that are produced by IVF can be screened for some chromosomal defects such as aneuploidies (known as pre-implantation genetic screening). If there is a known family history of a specific genetic disease such as cystic fibrosis, it is possible to perform prenatal genetic diagnosis (PGD) to select embryos without the condition for implantation, subject to the granting of a licence by the Human Fertilisation and Embryology Authority (HFEA). Such licences are granted on a case-by-case basis, although decisions in principle to permit licensing for specific conditions are sometimes taken; for example, adult onset hereditary forms of cancer (see previous news).

According to the news reports, the advantage of this methodology is that it can be used to screen a far wider range of genetic conditions as well as multiple genetic traits, and produces results in a shorter time period (BBC news). The technique involves the analysis of single nucleotide polymorphisms (SNPs) in DNA from parents and embryos to produce a ‘karyomap’ showing which parts of the embryo’s chromosomes have been inherited from which parent. In other words, it allows the origin of specific chromosomal segments to be identified and consequently also allows tracing of chromosomal segments that might be associated with a particular disease or phenotype. Thus far, the methodology used in producing karyomaps sounds remarkably similar to pre-implantation genetic haplotyping (PGH), which is used to identify haplotypes associated with familial disease regions (see previous news). However, a karyomap reportedly allows the identification of multiple genetic variations and aneuploidies, in addition to single gene defects.

Despite wide media coverage, the scientific basis or clinical utility of this technique is currently unclear. The divergence from (and purported superiority over) PGH remains uncertain, as there have been no scientific publications describing the details of the new methodology, and no clear explanation of how exactly multiple genetic traits are identified.

The Bridge Centre is currently undertaking clinical trials prior to applying for a licence from the HFEA for the use of the technique, and the possibility of being able to test rapidly for a wide range of different mutations associated with genetic forms of disease is exciting. However, proposals that it may be used as a “MoT” for embryos or for the production of “designer babies” are distinctly premature. Although this technique may be able to identify some genetic variants associated with physical traits or susceptibility to common diseases, the effect or risk of these individual variants on multi-factorial developmental or pathological processes could be very small, and potentially entirely non-pathogenic variants (such as copy number changes) could be found. It would not be feasible to select embryos on this basis, nor would the HFEA be likely to grant a licence for screening without a proven medical benefit.

In addition, IVF is a specialised procedure typically only undertaken where normal fertility is impaired, and may be coupled with PGD to prevent the conception of embryos with inherited forms of serious genetic diseases, the genetic basis of which is generally already known. Moreover, the process entails small but significant risks to the health of the mother and often fails to result in an established pregnancy. Together with the expense of the test (£1500), these factors mean that it is unlikely to become a routine procedure for couples who do not require IVF, but possibly as a potential additional technique to help select the most viable embryos for implantation where a couple is already undergoing IVF. However, a thorough evaluation of the clinical validity and utility of the test will be required before it can be offered even for this purpose.  

 

24 October 2008The UK Human Fertilisation and Embryology Bill had its long awaited report and third reading in the House of Commons on 22 October 2008 (see BBC news). Although MPs from all parties were given a free vote on the amendments, there was general frustration at the lack of time devoted to the Bill (less than four hours) and the way in which amendments had been timetabled, which effectively prevented substantive debate on clauses relating to abortion, or the need for a father.

Although a number of amendments went to a vote, there were comfortable Government majorities rejecting all amendments seeking to limit the scope of the Bill. There were particularly heated exchanges regarding the repeal of the Human Reproductive Cloning Act 2001 which established the ban in the UK on human reproductive cloning. Dawn Primarolo explained that although the Bill continued to provide ‘a clear prohibition on human reproductive cloning and the genetic modification of gametes or embryos that are to be used for treatment purposes’, an exception might be made in the future for the processing of embryos and eggs to avoid the risk of serious mitochondrial diseases (a wide range of rare diseases including certain types of dementia, stroke and brain atrophy).

Before such regulations are enacted, a further wide ranging consultation will take place, not least because the use of these technologies raise issues about the status of a woman who donates only mitochondria. The Bill now provides that in certain cases, the requirement for donor consent can be waived where embryos are to be used for research, so to provide that existing holdings of tissue taken for research can continue to be used for that purpose. This is particularly relevant where disability or disease is likely to result in mental incapacity or where it affects children who are never able to consent for themselves.

These final amendments to the Bill now need to be ratified by the House of Lords before the Bill can gain Royal Assent. No date has yet been set for its return to the House of Lords.

23 October 2008The US National Heart, Lung and Blood Institute has announced $25 million funding for a six-year program to fund collaborative genomics studies between different centres, focusing primarily on the genetic causes of congenital heart disease.

The NHLBI Pediatric Cardiac Genomics Consortium is to be a collaborative venture with the Institute of Circulatory and Respiratory Health (ICRH) of the Canadian Institutes of Health Research, and is calling for applications from potential researchers to to conduct research that can lead “to a comprehensive understanding of congenital heart disease” (see GenomeWeb news article). The purpose of this consortium, which will form part of a larger programme of translational research in pediatric cardiovascular disease, is to perform clinical and translational research on the genetic causes of congenital heart disease, and on genetic contributions to outcome in individuals with congenital heart disease. 

It is intended that this collaborative approach will make it feasible to recruit sufficient patients for large-scale studies; although collectively cardiac defects are the most common type of birth defect, each individual form of congenital heart disease tends to be very rare. Applicants to form one of up to six research centres will have to propose investigation of the genetics and genomics of one or more human cardiac malformations; they may focus on different aspects as set out in the announcement:

• Identification of genetic causes and modifiers of common human congenital cardiac malformations, myopathies, and rhythm disturbances.
• Identification of genetic causes and modifiers of anatomically related malformations, such as left-sided obstructions. 
• Association of genetic variants of components of specific regulatory or signal transduction pathways with cardiovascular malformations or syndromes.
• Identification of genetic variations that influence clinical outcomes in individuals with congenital heart disease, such as survival, ventricular function, arrhythmias, or neurocognitive functioning.
• Pharmacogenetics and pharmacogenomics in congenital heart disease.
• Epigenetic regulation of candidate genes for congenital heart disease.
• The influence of gene-environment interactions on congenital heart disease.

Of note, the PHG Foundation’s cardiac genetics project is reviewing current NHS provision for patients with inherited forms of cardiac disease in the UK, and working with stakeholders to develop recommendations for improving cardiac genetics care.

22 October 2008 The Nuffield Council on Bioethics has launched a study which will consider the ethical issues raised by new technologies that make healthcare more personalised (see press release). A Working Party has been formed which will examine the ethical issues raised by new technologies such as whole body CT or MRI scans, personal genomics and telemedicine, with the aim of producing a report and recommendations on policy and practice. The Working Party chaired by Professor Christopher Hood will hold a public consultation in Spring 2009 and aims to produce a report with recommendations on policy and practice by early 2010.

Many of the issues associated with personalised health care (see previous news) have already been raised in relation to personalised genomics (see previous news). This includes questions about informed consent and data confidentiality, the usefulness of such information to the individual, how it will affect lifestyle choices, regulation of direct-to-consumer tests, and the impact of such information on insurance policies and the NHS as people seek follow-up support. Although the NHS already utilises some forms of the technologies that the project is focusing on, their application as tools for ‘personalised’ healthcare is at present primarily offered by commercial companies.

The recent plethora of genome-wide association studies revealing genetic risk variants with very low penetrance has raised particular questions regarding the interpretation, validity and utility of tests that purport to predict genetic susceptibility to future disease, which are becoming increasingly availability through private providers. Although these tests, in conjunction with other biomarkers, may ultimately be useful for stratifying the population for the purpose of offering more targeting screening programmes (see previous news), their usefulness at an individual level is still in doubt, particularly in cases where there is no recommended intervention or treatment. Some of these difficulties are discussed in a recent publication [Janssens ACJW & van Duijn CM (2008) Hum Mol Genet 17(2):R166-173], which emphasises that, unlike rare single gene disorders, the complete causal pathway of common multifactorial diseases is likely to differ between individuals, and this inherent complexity means that accurate prediction of risk at an individual level may never be possible.

20 October 2008The Centre for Arab Genomic Studies (CAGS) has warned that a growing prevalence of genetic disorders in the Arab world will place greater financial strain on health systems and public health infrastructure (see UAE National news article). 

CAGS, which collects data from the United Arab Emirates (UAE), Bahrain and Oman, reports that single-gene disorders such as sickle cell disease and thalassaemia, as well as some rarer genetic diseases, are much more common in the region than elsewhere. This increased birth prevalence is attributed to a combination of factors, including a high frequency of consanguinity (marriages between cousins and other relatives), which can increase the number of carriers of mutations associated with autosomal recessive forms of genetic disease. Another problem is a lack of public awareness about such conditions, their diagnosis, identification and prevention.

Assistant director of CAGS Dr Ghazi Tadmouri reportedly spoke in favour of wider awareness of such diseases, and of improved public health and genetics services (from pre-conceptual carrier screening programmes to prenatal and preimplantation diagnosis) commenting: “Now it is becoming mandatory to do basic screening for thalassaemia and other diseases before marriage…Of course no one would oblige partners to not marry if they were both carriers of a disease”. Earlier diagnosis was also noted to be essential to reducing mortality rates associated with genetic diseases.

Chromosomal abnormality Down Syndrome (trisomy 21) is also more common in some Arab populations, with 21.4 babies per 100,000 affected in the UAE; this is much higher than in countries such as the UK, and around double the average global rate. It has been suggested that this may be related to a “social trend to have more children until menopause” (see Hindu News article), since the risk of Down Syndrome increases significantly with maternal age.

The CAGS Catalogue of Transmission Genetics in Arabs (see previous news) is planning to widen contributions to include collection of data from Qatar, Kuwait, Saudi Arabia, Egypt and Iraq.

17 October 2008 San Diego’s Scripps Translational Studies Institute (STSI) has teamed up with Navigenics, Affymetrix and Microsoft in order to conduct a study aimed at finding out if personal genome testing can have a positive impact on the lifestyle and behaviour choices of individuals (see press release). The project is aiming to recruit up to 10,000 employees, family members and friends aged over 18 of Scripps Health system in San Diego, offer them personal genome scans and assess their behaviour through self-reported health questionnaires over a 20 year period. Participants will be given information about their risk with respect to a number of conditions such as diabetes, cancer and obesity along with steps which can be taken to alleviate these risks, such as behaviour or diet. They will be able to store clinical and lifestyle information in an individual Microsoft HealthVault and share it with others such as health care providers, if they wish. Genomic, medical and lifestyle information gathered in this study will be de-identified and assembled into an encrypted database at the Scripps Genomic Medicine programme allowing researchers to evaluate the effect genome-scans have on people’s lifestyle.

Comment: Several commercial companies offer personal genome scans; however, their utility is often brought into question by regulators and it is uncertain if genetic susceptibility information can have a positive impact on lifestyle choices. This project may help us reach an understanding as to the extent that genetic information gained from such scans can influence our behaviour and health choices. Such studies can also be valuable in assessing the effectiveness of these tests for use in clinical practice and some studies to address this issue have already been initiated (see previous news).

15 October 2008

The US Food and Drug Administration (FDA) has recently licensed for marketing, a new therapy for use in the routine prophylaxis of Hereditary Angioedema attacks (see press release). Hereditary Angioedema (HAE) is a rare genetic disorder, which results in deficiencies in a plasma protein known as C-1-inhibitor. This protein is involved in regulating clotting and inflammatory responses, consequently, deficiencies can lead to excessive tissue swelling. HAE is an autosomally inherited disorder that affects approximately 1 in 50, 000 people, although in some cases it can occur spontaneously as a result of mutations in the C-1-inhibitor gene.

A HAE attack occurs spontaneously and can be caused by stress, surgery or infection and results in rapid swelling of the hands, feet, limbs, face, intestinal tract or airway which is potentially fatal. Current treatment regimes in the US and UK for HAE attacks involve the use of steroid drugs in order to control the swelling. However, these can have adverse effects is some cases, such as liver toxicity and carcinogenicity. This new drug - Cinryze™ is a C1-esterase inhibitor product derived from human plasma. It has been approved on the basis that in clinical trials it was effective in preventing or decreasing the frequency of attack in most HAE patients and had side effects that were considered mild or moderate.

A potentially more widely useful therapeutic for selected genetic diseases is currently in development; US-based PTC Therapeutics’ PTC124 is a candidate drug in phase 2a clinical trials (seeking to demonstrate proof of clinical benefit in patients). PTC124 suppresses the effect of a particular type of mutation, nonsense mutations, which normally cause premature termination of proteins. By allowing the cellular transcription process to continue past the nonsense mutation, PTC124 has been shown to allow the production of functional CTFR protein in cystic fibrosis patients with nonsense mutations in the CTFR gene, and of functional dystrophin protein in Duchenne Muscular Dystrophy (DMD) patients with nonsense mutations in the dystrophin gene. If the drug is proven to confer clinical benefits in such patients, it could potentially be appropriate for the treatment of around 15% of all patients with genetic diseases, as this type of mutation is quite a common one.

13 October 2008According to Cancer Research UK, one in nine women in the UK will develop breast cancer at some point in their life. Some major genes involved in rare inherited (familial) forms of breast cancer are well known, and a genetic test for these BRCA1/2 mutations is already available from Myriad Genetics (see previous news), they only account for a tiny proportion of breast cancer cases. ‘Normal’ or ‘sporadic’ breast cancer is believed to arise from a combination of many different interacting environmental and genetic factors, and some relatively common genetic factors have been identified as being linked to a slightly increased lifetime risk of developing breast cancer.

 

The Icelandic company deCODE has now launched a new genetic test to screen for risk of the most common forms of breast cancer (see deCODE news). The deCODE BreastCancer™ test is based on seven common single nucleotide polymorphisms (SNPs), which are each associated with a small relative risk. The results from all seven SNPs are combined to estimate a woman’s risk of breast cancer relative to the population. The company claim that the test can identify those women whose relative is 1.66 or higher, representing approximately 5% of the total female population. They suggest that such women are at sufficiently high absolute risk to meet the American Cancer Society’s recommendation for regular breast screening by MRI.

 

Comment: The test has drawn heavy criticism from a number of commentators, who assert that the test clinically useless and could lead to women be either unduly alarmed or falsely reassured, although there is currently little or no evidence for either of these outcomes. There is a valid concern that, in the absence of professional medical advice and proper counselling, members of the public may misinterpret the test, which is currently available both direct-to-consumer as part of a larger genome-wide scan for risk of numerous diseases, and through physician referral specifically for breast cancer risk . But what are the other potential problems?

 

There are a number of points to consider when assessing a test of this sort. Firstly, the legitimacy of the test – does it measure what it claims to measure, and is there strong scientific evidence linking the genetic variant to the disease? In this case, the former question is addressed by the fact that the assay is carried out in a CLIA-waived laboratory, and is therefore likely to be accurate, and the latter by a number of large studies indicating a real association between each of the seven SNPs and breast cancer. The relative risk estimate generated by the test are valid and so the test itself is scientifically legitimate. However, the exact nature of the claims and the usefulness of the test may not be.

 

The second question is therefore one of interpretation – what do the results of the test actually mean for an individual patient? The test places an individual within a sub-population with a average specific risk, but cannot locate the exact whereabouts of that individual within the distribution of risks of the whole group. The key issue in interpretation is the conversion of relative to absolute risk. However, this task is not simple, as it is age dependent and also depends on whether competing mortality is taken into account (which many published absolute risks do not). For example, the average absolute risk that a woman who has not had breast cancer will develop the disease before the age of 85 ranges from around 8% (1 in 12.5) at ages 20 or 30, through 6.5% (1 in 15) at age 50 to 3% (1 in 33) at age 70.

 

Finally, there is a question of utility – do the benefits of the test outweigh the potential harms, and can the test usefully provide guidance for action? These questions are not simple to answer, and will depend enormously upon the context in which the test is used, and ultimately upon the purpose of testing. If the purpose, as is suggested by some commentators, is to accurately inform a patient whether they will, or will not, develop breast cancer, then it is unlikely to be clinically useful. However, if the purpose is to identify women at a higher than average risk in order to target them for screening, as suggested in a recent paper in the New England Journal of Medicine (see previous news), then it could potentially be very useful.

 

However, even this final point is fraught with difficulties, as the guidance on when to offer screening (or indeed any form of intervention) is highly controversial and varies between countries. Although the American Cancer Society recommends annual mammography from age 40, the UK NHS Breast Screening Programme is only offered to women aged 50-70, who are at a substantially higher risk of developing breast cancer within the following 10 years. Determining whether this type of test will ultimately yield tangible benefits through a reduction in the breast cancer morbidity and mortality will take much more research, a long time and a lot of data.

 

Therefore, although it is certainly too early to offer such a test to women routinely, and proper provision for professional medical support should always be available, our suggestion is that providing the test in the marketplace is not in itself illegitimate. How the test is to be used, how it is to be interpreted and what interventions are offered to a woman with higher risk, however, are questions that deserve much greater scrutiny.

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6 October 2008 UK Health Secretary Alan Johnson has launched a new £12 million strategy for improving global health, based on improved global health security, more robust and equitable health and trade systems, more effective international health organizations and better use of evidence for policy and practice (see press release).

The report Health is Global: a UK Government strategy notes that health is a ‘global public good’ benefiting societies around the world, and that “Public health interventions, such as a cure for a disease, communicable disease control or the dissemination of research, are also global public goods”. Addressing issues that relate to monitoring and control of infectious diseases that could threaten public health in the UK and those that primarily affect the developing world are one of the main concerns of the report, but several other areas are also explored.

One point of note is the potential for improved information sharing and access to innovation and health-related knowledge via the internet and wireless communications. Possible benefits cited are the capacity to create global health and public health initiatives, or to keep doctors in developing countries up to date with medical developments. A key disadvantage is proposed to be the exposure to unregulated forms of health information and products (drugs and diagnostics), which poses a risk to patient safety. The Foundation is involved in international efforts to devise an appropriate system for the evaluation and regulation of genetic tests and biomarkers, to address this problem in one specific arena; the report itself recognizes that “providing technical assistance or influencing policy is a real way to make an impact on global health”.

Another major focus of the report is on health research, suggesting that the UK has much to offer in terms of health research with potential global benefits, citing the example of UK involvement in international frameworks for health research such as the Council of Europe’s Additional Protocol to the Convention on Human Rights and Biomedicine and UNESCO’s Universal Declaration on Bioethics and Human Rights.

Ways in which the UK should maximize biomedical research and development efforts and resources to benefit global health highlighted include:

• encouraging research into the diseases of the developing world
• building networks for sharing health knowledge and information
• identifying knowledge gaps to which the UK can contribute
• establishing systems to facilitate lesson learning from knowledge generated in other countries

21 October 2008 Prostate cancer is one of the most common forms of cancer affecting European men over the age of 50. Currently there is no organised screening programme for prostate cancer in the UK due to the lack of an effective screening test and detection relies on a combination of approaches including a digital rectal examination (DRE) and a blood test to establish the levels of prostate specific antigen (PSA); if these are found to be abnormal ,  a  prostate biopsy is carried out. However, an abnormal DRE and elevated PSA levels do not always correlate with a positive biopsy result, requiring the biopsy to be repeated, sometimes multiple times on those who are suspected of having prostate cancer. As biopsies can create anxiety, discomfort and result in complications, additional tests which can increase the probability of detecting prostate cancer and reduce the number of unnecessary biopsies would be a major advantage for the management of this disease.

A recent study published in the journal European Urology suggests that a prostate cancer gene test may prove helpful in identifying patients in need of a repeat biopsy (see press release). Previous studies have shown that PCA3 messenger ribonucleic acid (mRNA) is over expressed in prostate cancer tissue and an assay for this gene could be an accurate means of predicting the results of a repeat biopsy. A study by Haese et al. has replicated these findings in a larger prospective study of 463 European men who had previously had negative biopsy results [Haese et al. (2008) Eur. Urol. 54(5):1081-1088]. The authors compared the levels of PCA3 mRNA in urine to repeat biopsy results, and showed that PCA3 levels were higher in men who had a positive biopsy results and were diagnosed with prostate cancer. Furthermore, their research also indicated a relationship between the PCA3 score and the significance of the cancer, suggesting it could be used as a means of identifying those patients who may need active surveillance. However, this finding needs to be evaluated further.

Comment: This new study demonstrates the clinical utility of using the PCA3 gene test and its superiority over a PSA assay in identifying those in need of a repeat biopsy. However, the relationship between PCA3 and prostate cancer is not absolutely clear, consequently for the present it will have to be used in conjunction with existing tests such as the PSA assay in order to reliably identify those at risk.

14 October 2008Schizophrenia is a group of psychiatric conditions manifesting as hallucinations, paranoid delusions, and/or disorders of thought. A genetic basis for schizophrenia has long been suspected with twin studies suggesting a heritability of over 80%, and several candidate genes have subsequently emerged [Ross CA et al. (2006) Neuron. 52(1):139-53]. Current knowledge suggests that each risk allele identified confers a small increase in risk of schizophrenia, with the constellation of alleles producing an individual’s overall genetic risk of developing this complex disorder; environmental influences are also presumed to contribute.

Writing in Nature Genetics, O’Donovan et al. have identified twelve more genetic polymorphisms that may be associated with schizophrenia [O'Donovan MC et al. (2008) Nat Genet. 40, 1053 - 1055]. The group examined the genomes of 479 schizophrenic patients and compared them to 2,937 controls. Twelve single nucleotide polymorphisms (SNPs) were found that were seen in the schizophrenic patients, but not in the control population. When these twelve genetic loci were examined in over 5,000 more schizophrenic patients and compared with over 10,000 more controls, one polymorphism consistently appeared in the schizophrenic patients and not in the controls. This locus, the ZNF804A gene is therefore strongly implicated in the pathophysiology of schizophrenia. When the genome-wide analysis (GWA) was repeated with bipolar-disorder patients plus schizophrenia compared to controls, the ZNF804A polymorphism once again emerged as the leading difference between patients and control subjects. ZNF804A codes for a protein with a zinc binding domain and a DNA binding domain. Although the function of this gene is unknown, its related protein structure suggests a role in DNA transcription regulation.

A second study appearing in Nature Genetics by Ferreira et al. uses a similar GWA technique to look for further candidate genetic polymorphisms for bipolar disorder [Ferreira MA et al. (2008) Nat Genet. 40, 1056-1058]. The authors analysed the genomes of 1,233 bipolar disorder patients and compared these to the genomes from 1,439 controls. 14 polymorphisms emerged, but were all less significant than the main polymorphism observed in the O’Donovan et al. schizophrenia cases. Nevertheless, the most significant polymorphism seen in the bipolar patients mapped to CACNA1C, a gene encoding a calcium ion channel subunit. The GWA was then repeated using additional data from other studies giving a total of 4,387 bipolar disorder genomes which were compared with 6,209 control genomes. This larger analysis produced a further candidate genetic polymorphism situated on the ANK3 gene, which codes for a protein that regulates the assembly of sodium ion channels. Therefore, it appears as though dysfunction of ion channels, coded by genetic mutations, may be related to bipolar disorder.

Writing in PNAS, Pickard et al.  also demonstrated that a genetic polymorphism may be involved in a neurotransmitter system linked to bipolar disorder [Pickard BS et al. (2008) Proc Natl Acad Sci USA 105(39):14940-5]. The authors had previously identified a polymorphism in a gene coding for a glutamatergic receptor that appeared to reduce the risk of developing bipolar disorder. In their latest study they aimed to demonstrate a putative mechanism for how this polymorphism may be protective. They examined the mRNA of the gene in question and discovered that the mRNA from the protective polymorphism had a deletion in a region of the mRNA called the 3’ untranslated region (3’UTR). The 3’UTR component of mRNA is responsible for stabilising mRNA so that it becomes translated to a protein, in this case a GRIK4 glutamate receptor. The polymorphism causes the mRNA to become more stable so that more GRIK4 receptors were expressed, making the glutamatergic neurotransmitter system more active. Underactivity of the glutamatergic system is thought to cause bipolar disorder [Belsham B. (2001) Hum Psychopharmacol.16(2):139-146].

Comment: Together, these three publications strengthen knowledge about the genetic basis of schizophrenia and bipolar disorder. New genetic polymorphisms have been discovered as possible causes of schizophrenia and bipolar disorder. The implicated genes code for ion channels, control the expression of receptors, or otherwise control the expression of other as of yet unidentified genes. Further studies are necessary to elicit more candidate genes and elucidate the mechanisms by which these mutations lead to the symptoms of schizophrenia and bipolar disorder.

7 October 2008 A new paper in the journal PNAS from a team at Stanford University in the US has been in the news; the paper reports on the identification of Down Syndrome (DS) in a fetus using a maternal blood sample (see BBC news article). Down Syndrome (DS), also called Trisomy 21, is the most common form of aneuploidy – the presence of an abnormal number of chromosomes – that is compatible with life, and is caused by the presence of an additional (third) chromosome 21.

This non-invasive form of testing analyses cell-free DNA or RNA from the fetus, which is found in the mother’s blood during pregnancy from as early as 5 weeks gestation, which was first described in 1997 by Dennis Lo [Lo YMD et al. (1997) Lancet 350: 485-487]. Since then, research and developmental work has been undertaken on a number of potential applications including prenatal testing for certain rare genetic (inherited) disorders, identifying the sex of the fetus (which is relevant for certain sex-linked genetic disorders), and testing for blood group Rhesus D status, which is important for the management of some high-risk pregnancies. In addition, late last month another group in the USA announced early findings on a different method for non-invasive prenatal Down Syndrome testing based on a method described by Lo and co-workers in 2007 that uses mass spectrometry to detect fetal RNA [Lo YMD et al (2007) PNAS 104:13116-13121].

Currently, definitive diagnosis of genetic or chromosomal disorders requires an invasive procedure (amniocentesis or chorionic villus sampling) to sample fetal DNA, which carries a risk of miscarriage of 1-2%. Non-invasive testing not only removes this risk, but can also be performed much earlier in pregnancy. Many groups are working to develop the technique for different applications, including several in the UK.

Hitherto, one of the major technical barriers to testing using fetal DNA in the maternal blood is reliably distinguishing the small amounts of fetal DNA from the large background of maternal DNA present. To date, this problem has been solved primarily by only detecting paternally inherited sequences not otherwise present in the mother, such as DNA from the Y chromosome in the case of male fetuses. However, diagnosis of DS and other aneuploidies requires the detection of an increase or decrease of fetal chromosomal sequences, caused by the presence or absence of a specific chromosome.

Importantly, the approach described in the most recent paper does not require differentiation of fetal versus maternal DNA, and therefore has the advantage that it could work in all pregnant women. It uses a previously characterised technique known as shotgun sequencing to achieve simultaneous high-throughput sequencing of millions of short DNA sequences [Fan HC et al. (2008) PNAS October 6, doi:10.1073/pnas.0808319105]. The researchers then compared the amount of sequences produced from different chromosomes to detect any over- or under-representation caused by aneuploidy in the fetus.

Testing samples from a group of eighteen pregnant women, the researchers were able to correctly diagnose nine cases of trisomy 21 (DS), two cases of trisomy 18 (Edwards Syndrome) and one case of trisomy 13 (Patau Syndrome). The technique could theoretically also detect the rarer forms of trisomy where there is only part of a chromosome lost or gained, although it is noted that this would be technically more challenging because it would require detection of a significantly smaller increase or decrease in the amount of DNA sequences present.

It is notable that the costs of diagnosis using this technique would be quite high, with the authors’ estimating the cost of sequencing at around $700 per sample; however, they correctly observe that the cost of sequencing is likely to drop significantly as newer and faster techniques emerge in the next few years. For example, a US company has just announced that it will offer whole genome sequencing for just $5000 (see Technology Review news article). Although whole genome sequencing of fetal DNA obtained from maternal blood is not feasible, as fetal DNA in the maternal blood is present in short fragments, this twenty-fold reduction from current prices for sequencing is indicative of rapidly falling prices. Moreover, the cost of diagnosis of DS by current invasive methods is also quite high, requiring the expertise of highly trained specialists for invasive sampling and molecular analysis or karyotyping of the fetal DNA.

Comment: This new technique requires assessment in a much larger cohort of women to determine just how effective it is, but the results are an exciting development in the area of non-invasive analysis of fetal DNA. Non-invasive prenatal testing is progressing rapidly, and for this reason an expert Working Group has been convened in the UK to produce a strategy for the implementation of cell-free fetal nucleic acids for different applications within UK clinical services. This includes evaluation of the current status of the technology, consideration of the wider implications of the technique, and determination of what action needs to be taken by the NHS in order to keep track of developments and anticipate how and when it might enter routine antenatal practice and specialist clinical services in the UK.

The PHG Foundation is leading this project (see Our Current Work), and the report and recommendations of this group to the Joint Committee for Medical Genetics of the British Society of Human Genetics, the Royal College of Physicians and the Royal College of Pathologists will be released by the Foundation in January 2009.

Bodies represented in the expert group include the British Maternal & Fetal Medicine Society, the Royal College of Obstetricians and Gynaecologists, the Royal College of Midwives, the UK National Screening Committee, the Human Genetics Commission and the Genetic Interest Group and Antenatal Results and Choices charities, as well as expert scientists and clinicians, NHS managers and policy makers, and experts in law and ethics.

The group’s preliminary conclusion is that before any of these techniques can be used in routine care a number of things need to happen:

• Techniques need to be thoroughly evaluated and validated in a large number of patients to determine clinical accuracy, and consequently are unlikely to replace invasive testing for some time.
• Technological development and laboratory standardisation is required to ensure reliable and accurate results.
• Non-invasive techniques have the potential to replace current multistep Down syndrome screening tests with a single diagnostic test, and both women and healthcare professionals must be fully informed about the implications of these changes.
• Careful consideration should be given to safeguarding patient autonomy and providing for informed consent.

4 October 2008

9 October 2008Genomic medicine in developing countries
Special supplement to October issue of Nature Reviews Genetics

Explaining human uniqueness: genome interactions with environment, behaviour and culture.
Varki A, Geschwind DH, Eichler EE. Nat Rev Genet. 2008 Oct;9(10):749-63. Review.

The genetics of mammalian circadian order and disorder: implications for physiology and disease.
Takahashi JS, Hong HK, Ko CH, McDearmon EL. Nat Rev Genet. 2008 Oct;9(10):764-75.

DNA vaccines: ready for prime time?
Kutzler MA, Weiner DB. Nat Rev Genet. 2008 Oct;9(10):776-88.

Disability and genetics in the era of genomic medicine.
Scully JL. Nat Rev Genet. 2008 Oct;9(10):797-802.

Communicating about screening
Entwistle VA et al. BMJ 2008;337:a1591

Phenotype, diagnosis, and treatment of Gaucher's disease

Grabowski GA, Lancet 2008; 372:1263-1271

Clinical practice. Autosomal dominant polycystic kidney disease.
Grantham JJ, N Engl J Med. 2008 Oct 2;359(14):1477-85

Population genetic screening for hereditary haemochromatosis: are we a step closer?
Allen KJ. Med J Aust. 2008 Sep 15;189(6):300-1.

Kidney disease and African ancestry.
Pollak MR. Nat Genet. 2008 Oct;40(10):1145-6

Cell therapies for muscular dystrophy.
Blau HM. N Engl J Med. 2008 Sep 25;359(13):1403-5.

Patient confidentiality and consent to publication.
Smith J. BMJ. 2008 Sep 10;337:a1572. doi: 10.1136/bmj.a1572.

The QT syndromes: long and short.
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Casting a wider net for diabetes susceptibility genes.
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Psychiatric genetics gets a boost.
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Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
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Life-cycle of translational research on medical interventions
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Pharmacogenetics in drug discovery and development: a translational perspective
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Proteomics ponders prime time

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Proteomics. Will biomarkers take off at last?
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Clarifying best interests.
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Technology in global health: the need for essential diagnostics
Houpt ER, Guerrant RL. Lancet. 2008 Sep 13;372(9642):873-4.

Do we need "synthetic bioethics"?
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Identifying modifier genes of monogenic disease: strategies and difficulties
Génin E, Feingold J, Clerget-Darpoux F. Hum Genet. 2008 Sep 11.

New handles on genomic structural variation.
Nat Genet. 2008 Oct;40(10):1143

Emerging themes and new challenges in defining the role of structural variation in human disease.
Sharp AJ. Hum Mutat. 2008 Oct 3

Keeping your genes private.
Rothstein MA. Sci Am. 2008 Sep;299(3):64-9.

 

Big data: How do your data grow?

Lynch C. Nature. 2008 Sep 4;455(7209):28-9.

 

Scientific publishing standards

Alberts B. Science. 2008 Sep 5;321(5894):1271.

Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new.
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