Genetics

To the Editor: Handelsman and colleagues raise concerns1 about medical confidentiality with regard to legislation in New South Wales and a recent National Health and Medical Research Council (NHMRC) guideline. We wish to correct some of their statements related to the NHMRC guideline. The NHMRC recently released two documents about the use of genetic testing and genetic information in health care. The first describes the mandatory process by which clinicians can utilise new provisions in federal privacy legislation.2 This guideline was the subject of our editorial3 in the same issue of the Journal as Handelsman et al’s Viewpoint article. The second document is an information paper on medical genetic testing, including reference to disclosure of information, and directs readers to relevant resources.4 Handelsman et al cited the second document, but their concerns pertain to the first. Disclosure of genetic information without consent for the benefit of relatives was considered by the Australian Law Reform Commission (ALRC) in 2001–2003. The Commission consulted widely in preparing its two-volume report on genetics and ethics.5 The Commission recommended amending the Privacy Act 1988 (Cwlth) to allow disclosure in certain circumstances. It is incorrect to suggest that the proposal had the potential to “silently harm individuals who do not form sufficiently clamorous rights-demanding groups”.1 The federal government responded by amending the Privacy Act, and the NHMRC was charged with drafting a mandatory guideline2 for clinicians using the amendment. We were members of the working committee who, together with the NHMRC and the Office of the Australian Information Commissioner, ensured the guideline complied generally with federal privacy legislation and reflected the intent of the ALRC. The guideline was subject to public and targeted consultation — it does not represent an arbitrary standard, as suggested by Handelsman et al.1 The guideline emphasises the importance of confidentiality and the need to balance the rights of patients and genetic relatives. It carefully defines what information can be used or disclosed, and to whom. In contrast to Handelsman et al’s assertion, the legislation does not allow disclosure of a patient’s identity or genetic status. Disclosure is only permitted after extensive, documented consultation. It is incorrect to suggest that disclosure occurs at the “sole discretion” of a doctor or is the “lazy path”. Disclosure without consent represents a major change in the use of medical information, and best practice involves communicating with patients to avoid the very situation that the legislation and guideline address. But we must also recognise that, for each of us, our genetic heritage — and the right to access that heritage — is something that we share with our relatives.

Graeme K Suthers · Elizabeth A McCusker · Samantha A Wake

To the Editor: I write to clarify the National Health and Medical Research Council’s (NHMRC’s) role in supporting the dissemination of the Privacy Act 1988 (Cwlth), which regulates information privacy, and to correct some statements made by Handelsman and colleagues in their Viewpoint article.1 The process of using or disclosing genetic information to a patient’s genetic relatives in circumstances where patient consent is not given is complex. In 2006, the Privacy Act was amended to enable a health service provider to disclose the genetic information of a patient (and not specific information about an individual) to their genetic relatives. This may be done in certain circumstances and in accordance with guidelines2 developed by the NHMRC to assist health practitioners faced with the difficulty of making decisions about use or disclosure. The guidelines, approved by the Privacy Commissioner and then released in December 2009, establish when, by whom and in what manner the use or disclosure of genetic information may take place, with particular reference to the statutory test set out in the National Privacy Principles. That test provides for use and disclosure when there is: a serious threat to the life, health or safety of a genetic relative; and the use or disclosure is necessary to lessen or prevent that threat. The NHMRC agrees that such situations are likely to occur rarely, as patients in the great majority of cases agree to communicate their genetic information to relatives, particularly if there is potential for that information to benefit their relatives’ health. Furthermore, the amendments do not oblige use or disclosure. Rather, they provide the framework for this to occur in certain circumstances. Handelsman et al’s criticism of the guidelines and interpretation that “disavowal of patient confidentiality [is] at a doctor’s sole discretion” suggest they may have confused the guidelines with another NHMRC document titled Medical genetic testing: information for health professionals.3 This document discusses the legislative amendments briefly but aims, more broadly, to provide a source of information for health professionals and to assist them in communicating with patients when genetic testing is being considered. It provides support for the ordering and interpretation of results in the context of clinical decision making. The guidelines, in contrast, explore the complex issues associated with disclosure, and provide practical tools, including scenarios, key points for good practice, and flowcharts to assist in decision making. Disclosure is only permitted if it is in accordance with the guidelines, and is likely to be a lengthy and involved process.

Warwick P Anderson

Guidelines for private sector practitioners implementing the new provisions in the Privacy Act Every health care practitioner must respect confidentiality. Patients reasonably expect that private information offered or identified during an episode of care will not be divulged without their consent. The fundamental importance of confidentiality finds formal expression in the National Privacy Principles. Practitioners in the private sector must comply with the National Privacy Principles, which are embodied in the Privacy Act 1988 (Cwlth).1 Public sector employees are obliged to comply with the relevant legislation in each jurisdiction. Knowledge of a history of disease in relatives can be crucial for making a diagnosis in a patient. Similarly, medical care of relatives may be affected by the patient’s diagnosis. For example, a family history of colorectal cancer may assist in identifying the cause of a patient’s abdominal pain, and the diagnosis of colorectal cancer in the patient would then place his or her close relatives at increased risk of the same condition. In general, a practitioner is not obliged to inform relatives about the diagnosis of a familial disorder. There are some situations in which a practitioner may be required to advise a third party about a patient’s non-genetic diagnosis because of an immediate threat to the safety of others, as is the case with certain infections such as hepatitis A.2 These legally sanctioned breaches of confidentiality do not apply to the risk of a relative developing a familial disorder at some unspecified time in the future. Nonetheless, a practitioner cannot ignore the medical implications of a familial diagnosis for the patient’s relatives, and must inform the patient (or the patient’s authorised representative) of these implications and recommend that they seek medical advice in their own right.3 It is unusual for a patient to refuse to share such information with relatives,4 but such situations do arise and present the practitioner with a challenging dilemma.5 On the one hand, the patient has a right to make an autonomous decision about the use of personal information. On the other hand, this information has a direct bearing on the future health of relatives who may welcome the opportunity to make strategic decisions regarding their health. Whose rights should prevail? Before 2006, the privacy legislation in Australia was unequivocal: in the absence of an immediate threat to the health or wellbeing of a third party, the patient’s right to privacy prevailed and relatives could not be informed without the patient’s consent. This situation has since changed. In response to a recommendation from the Australian Law Reform Commission,6 the federal government amended the Privacy Act in 2006 to make specific provision for this situation.7 The Privacy Legislation Amendment Act 2006 (Cwlth) allows for the disclosure and use of information without consent, provided that such disclosure is necessary to lessen or prevent a serious threat to the life, health or safety (whether or not the threat is imminent) of an individual who is a genetic relative of the individual to whom the genetic information relates ... The significant provision is that the threat need not be imminent and may occur at an unspecified time in the future. There are some important features of this amendment that must be borne in mind. First, the amendment applies only in the setting of managing a familial disorder in a health care setting. A medical practitioner must authorise disclosure, and there must be consultation with appropriate colleagues. Second, the amendment does not require the practitioner to notify relatives about a familial disorder. The amendment provides a potential legal mechanism for doing so but does not create an obligation. Third, the amendment only applies to the disclosure and use of genetic information that is necessary to lessen the risk of a familial disorder for a genetic relative. There is no provision to release other information about the patient (including the patient’s identity), or to release information to a non-genetic relative (other than the authorised representative of a genetic relative). Finally, the Privacy Act currently applies only to practitioners in the private sector. The amendment does not apply to health care practitioners in the public sector. It is anticipated that similar provisions and processes will be developed in the local legislation of the states and territories, which would apply to practitioners in the public sector. The potential to disclose a patient’s confidential information to a relative against the patient’s wishes represents a major departure from longstanding views on confidentiality in health care. It is appropriate that such an action be taken rarely and with great circumspection. Furthermore, the process for disclosure must recognise that many relatives do not use the genetic information provided to them.8 The National Health and Medical Research Council (NHMRC) has developed guidelines for practitioners who might use this amendment;1 the principles that form the heart of the document are summarised in the Box. Readers should refer to the full guidelines for details, and to a more general NHMRC discussion paper on genetic testing in health care.9 It is important to note that the guidelines1 are not simply recommendations regarding best practice — they are the formal mechanism for implementation of this federal legislation, and practitioners who wish to use the provisions of the Privacy Legislation Amendment Act must comply with the guidelines and requirements of the Privacy Commissioner.10 There is another important sense in which the guidelines do not reflect “best practice”. With careful and considerate communication, especially before embarking on genetic tests that might diagnose a familial disorder, it is usually possible to resolve issues of concern that a patient may have about sharing this personal, confronting, and potentially useful information with relatives. Best practice is represented by striving to avoid the need to use the provisions of this amendment. With a combination of professionalism and patience, most apparent conflicts can be resolved without recourse to disclosing private information without consent. NHMRC guidelines for the use or disclosure of genetic information to a patient’s genetic relatives1 The guidelines developed by the NHMRC* for implementing the new provisions of the Privacy Act 1988 (Cwlth) are as follows: 1. Use or disclosure of genetic information without consent may proceed only when the authorising medical practitioner has a reasonable belief that this is necessary to lessen or prevent a serious threat to the life, health or safety of a genetic relative. 2. Specific ethical considerations must be taken into account when making a decision about whether or not to use or disclose genetic information without consent. 3. Reasonable steps must be taken to obtain the consent of the patient or his or her authorised representative to use or disclose genetic information. 4. The authorising medical practitioner should have a significant role in the care of the patient and sufficient knowledge of the patient’s condition and its genetic basis to take responsibility for decision making about use or disclosure. 5. Prior to any decision concerning use or disclosure, the authorising medical practitioner must discuss the case with other health practitioners with appropriate expertise to fully assess the specific situation. 6. Where practicable, the identity of the patient should not be apparent or readily ascertainable in the course of interprofessional communication. 7. Disclosure to genetic relatives should be limited to genetic information that is necessary for communicating the increased risk and should avoid identifying the patient or conveying that there was no consent for the disclosure. 8. Disclosure of genetic information without consent should generally be limited to relatives no further removed than third-degree relatives. 9. All stages of the process must be fully documented, including how the decision to use or disclose without consent was made. NHMRC = National Health and Medical Research Council. * NHMRC’s Working Committee (Dr Sandra Hacker, Ms Sharon Caris, Dr Elizabeth McCusker, Dr Graeme Suthers and Dr Samantha Wake) developed the guidelines in collaboration with the NHMRC’s Australian Health Ethics Committee and Human Genetics Advisory Committee.

Graeme K Suthers PhD, FRACP, FRCPA · Elizabeth A McCusker MB BS, FRACP · Samantha A Wake BSc(Hons), PhD, FHGSA

Legislative changes made without public discussion allow disclosure without patient consent Of all the ethical principles underlying medical practice, confidentiality is so fundamental that its breach is an illegal, high-order betrayal of responsibility. Disclosing personal medical information without consent profoundly violates the autonomy, beneficence and privacy that patients have always rightly expected.1 Although disclosure without consent has only rarely been necessitated by an urgent threat to life or health, two recent legal erosions of doctor–patient confidentiality illustrate how privacy-invading legislation can so easily and silently harm individuals who do not form sufficiently clamorous rights-demanding groups. In one, a state government directs that private medical records be lodged in an Orwellian sounding “Central Register” without regard for the individual’s knowledge, and risking privacy breaches by seeking consent for disclosure to third parties. The other permits disclosures of a patient’s medical information against their wishes even without any urgent threat to the life or health of another person. Both represent unreasonable intrusions on privacy and erosion of personal liberty. Recently, the New South Wales Government made a legislative amendment, without parliamentary debate or public discussion, in the last days of their current term. This amendment to the Assisted Reproductive Technology Act 2007 (NSW)2 forces doctors to provide the identity of anonymous sperm donors to a central register when their genetic offspring submit a request for information to the Director-General of NSW Health. This transfer of identifying information can occur regardless of the sperm donor’s consent, and overrides any prior condition of strict confidentiality guaranteed at the time of sperm donation. Although it is argued that identifying information cannot be released without the donor’s consent, the Director-General’s possession of donor contact details creates a situation where a stranger to the donor might try to contact him to seek consent for disclosure. The donor, however, did not ever consent to such an approach from a government instrumentality which, in itself, is virtually certain to breach the donor’s strict confidentiality. Inevitably, once the Director-General possesses identifying information and this contact and consent process proves unworkable, the logical next step is eliminating the troublesome consent requirement. This retroactive legislation is starkly at variance with the recent Australian Senate’s report of its inquiry into donor conception in Australia,3 which recognised that all states’ legislation on donor conception respected the time-honoured principle of rejecting legislative retrospectivity. Sperm donors have often long forgotten their altruistic act, two decades previously, motivated by a wish to help infertile couples and thought of as akin to blood donation; certainly they would not have provided sperm without the guarantee of enduring and strict confidentiality. Now, merely expecting undisturbed privacy, they do not constitute any sort of group to oppose the persistent, vocal donor-conception lobby groups demanding involuntary disclosure that overrides donors’ legal and moral rights. Sperm donors’ lives over the decades since donation could have changed in every imaginable way so that forced disclosure may be unwelcome, and damaging to some. It denies natural justice to disregard the usual requirement for their consent. We hope that a new NSW Government will show regard for consent and amend the retrospectivity of this assault on the privacy and personal liberty of well intentioned individuals. The other legal assault on privacy is highlighted in a recent update of the National Health and Medical Research Council (NHMRC) guidelines on medical genetic testing.4 These guidelines endorse a recent amendment to Commonwealth privacy legislation that widens the legal exemption allowing disclosure of patients’ genetic information to others, even against a patient’s wishes. Rarely, the situation arises where a patient is unwilling to inform relatives of a genetic test result that, in a doctor’s opinion, should be disclosed. Such disclosure was previously only permitted to resolve an imminent danger to another person’s health. After the previous exemption for imminent medical danger created a precedent, a recent amendment has removed the requirement altogether. In effect, this now creates genetic testing without consent by proxy — a situation where the relative may be informed, against the patient’s wishes, of the patient’s genetic status without the relative soliciting the information and possibly without wishing to know. The arbitrary nature of this new standard is illustrated by its vague boundaries — only a “serious threat to life, health or safety” extending to “third-degree relatives” is required to override the patient’s denial of consent. The NHMRC guidelines even encourage not disclosing that the original genetic testing occurred, piling dishonesty upon breach of faith. The widened loophole creates an elastic legal excuse for the well meaning (but impatient) to breach individuals’ privacy. This disavowal of patient confidentiality at a doctor’s sole discretion has the net effect of allowing one individual’s subjective, value-laden judgement, triggered by any remote threat to health or welfare, to override a patient’s refusal of consent. Inevitably, unintended perverse outcomes should be expected — bringing to mind the legal maxim “hard cases make bad law”. In practice, this loophole will encourage the taking of the lazy path of legal coercion rather than gradual persuasion and ultimate acceptance of a patient’s decision. If forced disclosure is really required, such a momentous breach of a patient’s expressed wishes in the absence of genuine life-threatening circumstances should require approval from an independent legal tribunal, a standard well established for surgery on children whose parents refuse consent, or for sterilisation operations or other major elective procedures for those unable to consent. Both these legislative assaults on privacy reflect the fashionable belief in genetic determinism prevailing over any ethical, moral and legal constraints of everyday life. But ditching the trusted confidentiality of medical information for doctors’ convenience or to satisfy lobby groups permits arbitrary and damaging intrusion on personal liberty — the price of which remains eternal vigilance.

David J Handelsman MB BS, FRACP, PhD · Leo A Turner RN, MSc Med · Ann J Conway MB BS, FRACP

To the Editor: As a family history of cystic fibrosis (CF) is uncommon among children diagnosed by newborn screening, offering carrier testing in the general population is warranted Cystic fibrosis is the most common severe autosomal recessive genetic condition in children. The carrier frequency in populations of Northern European ancestry is one in 25 and the incidence of CF in Victoria, Australia is 1 in 2874.1 There is no cure for CF, but advances in management have improved life expectancy. A question about a family history of CF is often asked as part of preconception or prenatal care in populations in which CF is more prevalent. However, anecdotally, most parents of a baby with CF do not report a family history and the diagnosis is unexpected. Carrier testing would provide information that may be used by couples to make reproductive decisions, such as prenatal and preimplantation genetic diagnosis of a fetus or embryo, respectively. Australia, the United Kingdom, other European countries, and all states in the United States now offer newborn screening for CF. Apart from records of affected older siblings,1 there are no clinical data for the existence of a family history of CF among children diagnosed with CF through newborn screening. We audited the family pedigrees, collected soon after diagnosis, of all children born in Victoria in 2000–2004 who were diagnosed with CF through newborn screening. From the extended pedigrees of 82 children, we identified five families with a family history of CF. In two pedigrees, the children were first cousins; in another two pedigrees, the children were first cousins once removed; and in one pedigree, the children were second cousins. There were no families in which older siblings had been previously diagnosed with CF, but in two families the diagnosis triggered further examination of older siblings who were subsequently diagnosed. These empirical findings that most babies with CF (77/82; 94%) are born to families with no family history of CF support clinical observations. Although inquiry about a family history of CF is necessary as part of prenatal or preconception care, this is not sufficient. Even when a family history is known, most relatives do not undertake carrier testing. For example, in an audit of cascade carrier testing after a diagnosis of CF through newborn screening, only 11.8% of eligible (non-parent) relatives were tested.2 Not surprisingly, a family history-based approach to offering carrier testing will not provide the vast majority of couples with the opportunity to learn their carrier status and make informed reproductive decisions. Therefore, in addition to newborn screening to diagnose affected babies, CF carrier screening in the general population (of individuals with a risk of one in 25)3 is needed.

Belinda J McClaren · Sylvia A Metcalfe · David J Amor · MaryAnne Aitken · John Massie

Objective: To determine the prevalence and diagnosis rates of Klinefelter syndrome (KS) in Victoria, Australia, and compare these to previous international findings.Design, setting and participants: A Victorian population-based descriptive study of all cytogenetic examinations resulting in a diagnosis of KS, including prenatal diagnoses from 1986 to 2006 and postnatal diagnoses from 1991 to 2006.Main outcome measures: Birth prevalence and diagnosis rates of KS.Results: The birth prevalence of KS in Victoria is estimated to be 223 per 100 000 males (95% CI, 195–254), with about 50% of cases remaining undiagnosed.Conclusions: KS may be occurring more frequently than has been reported previously, yet many cases remain undiagnosed. Our results highlight the need for increased awareness leading to timely detection.

Amy S Herlihy BSc, GradDipGenCounsel · Jane L Halliday BSc(Hons), PhD · Megan L Cock BSc(Hons), PhD · Robert I McLachlan MB BS, PhD

To the Editor: In their recent editorial, Bower and colleagues effectively summarised the problem of apparent governmental indifference to congenital anomalies.1 This is not unique to Australia and probably exists worldwide. National systems to collect congenital anomalies data were set up in many countries in the mid 1960s, including the National Congenital Anomaly System in the United Kingdom and the Canadian Congenital Anomalies Surveillance System. This followed the thalidomide tragedy and exemplified that it often takes an acute crisis to stimulate politicians into action. However, due to a lack of leadership, foresight and finances,2-4 these systems gradually declined to the extent that they became of very little value, lacking in accurate ascertainment and pregnancy termination data. As a result, regional registries were set up in England and Wales, and Canada was left with only two provinces (British Columbia and Alberta) collecting data. Prevention is one of the new driving forces for collecting good data, and the advent of using folic acid to effectively reduce neural tube defects brought a new urgency to the need for comprehensive useable data. Accordingly, the Canadian government set up a task force and formed a new entity in 2002, the Canadian Congenital Anomalies Surveillance Network, with a mandate to provide logistical and financial help to all 10 provinces and three territories. While progress has been slow, it has been very encouraging, with three additional provinces and one territory developing new surveillance systems this fiscal year (April 2010 – March 2011). The Network has set up guidelines and standards to enable all provinces and territories to collect data in a comparable format,5 which can then be forwarded to a central database in the national capital, Ottawa. The quality of the data should be improved because they are gathered at a local level. This model could be adapted for use in Australia because, according to Bower et al,1 a nucleus of good data from at least three states already exists.

R Brian Lowry

To the Editor: I agree with Emery and colleagues1 that family history can add much to downstream clinical interventions that provide tangible benefits to the presenting patient and his or her kin. The pedigree chart has some advantages over simple narrative recording of the same details, including the ability to instantly visualise relationships between individuals and the ease with which the chart can be updated and annotated.2 There is a familial aggregation (commonly an affected first-degree relative) in up to 25% of presenting cancer patients, while around 5% will harbour a highly penetrant genetic predisposition to cancer. In the cancer clinic, an acceptably detailed family cancer pedigree can typically be obtained in even less time than the 30 minutes suggested by Emery et al.1 Steps in drawing pedigrees have been outlined elsewhere2,3 and typically involve collecting information such as simple demographics, naming and symbolising different cancer types, and recording age of onset and age of death (if relevant) for the different individuals, starting with the presenting patient. The time required to construct a three-generation pedigree would typically be around 10 minutes, making it an attractive addition to routine history taking. If a cancer pattern emerges, the pedigree should be extended as far as possible. Of course, diagnosis verification (through death registries, etc) would be required before surveillance, prophylaxis and therapy decisions are addressed in the familial cancer setting. A convenient refresher for doctors who do not routinely draw pedigrees might be to first construct their own family tree, with reference to the symbols and relationship illustrators commonly used.2,3 It is likely that pedigrees in most clinics will be drawn by hand, at least initially, although there are software programs for pedigree creation available (eg, Family Tree Builder; <http://www.myheritage.com/family-tree-builder>). Over the years, I have informally asked my specialist oncology trainees to routinely construct family pedigrees. I do not recall, among these highly clinically skilled doctors, one that was able to correctly draw a family pedigree until we had worked on it together. Given the benefits of family pedigree analysis across many disease categories, a little practice in pedigree drawing may be a useful exercise for many of us. Even without the requisite confirmation of disease status of the individuals represented, a simple pedigree chart, combined with quick reference to information on the potential clinical significance of any patterns it shows (eg, by consulting National Health and Medical Research Council guidelines),4 can help prioritise referrals to busy familial cancer clinics.

Michael J McKay

To the Editor: Langlands and colleagues show that family history is poorly taken in patients presenting to an acute medical unit at a major tertiary hospital.1 However, their article and its companion editorials2,3 do not adequately stress the settings in which family history taking may be both easily achievable and most cost-effective. The nihilism that Thomas and Thompson2 convey about recording family history in the acute setting is of more concern, given that a tertiary hospital may offer the best opportunity to initiate the process of case detection for a number of heritable and lethal diseases, such as autosomal dominant familial hypercholesterolaemia (FH), the most common monogenic cause of premature coronary artery disease (CAD). We previously demonstrated that a family history of cardiovascular disease was almost never recorded by coronary care unit medical staff at Royal Perth Hospital.4 For 509 patients aged < 60 years presenting with symptomatic CAD to the coronary care unit, we found that 70% had insufficient clinical data documented in the medical records to enable a diagnosis of FH. In a follow-up study of 103 patients with premature CAD admitted to the coronary care unit, a nurse practitioner was able to record a positive family history of premature cardiovascular disease in a primary relative for 43% of patients, of whom 95% had phenotypic FH based on a recognised clinical diagnostic tool (the Dutch Lipid Clinic Network score).5 Patients detected in this way in Western Australia are now referred to a statewide FH program run by staff from a lipid clinic.5 In this program, where detailed pedigree drawing and family tracing is performed by trained nurses, we have found a causative mutation for FH in up to 85% of patients with a clinical phenotype strongly suggestive of FH. Additionally, we find that for every index case so detected, we can additionally diagnose at least three new cases of FH in the patient’s relatives, many of whom are young. This method of case detection and subsequent treatment with cholesterol-lowering therapies is highly cost-effective and, more importantly, enables therapy to be targeted at younger patients, thereby maximising the potential for preventing CAD. Our experience illustrates that for a lethal condition such as FH, an accurate family history recorded by a nurse can spark a cascade of action that leads to a definitive diagnosis of FH in the index patient and the subsequent detection of otherwise undiagnosed FH in the community, with significant associated cost savings.6 Hence, we propose that nursing staff can efficiently bridge this gap in medical care while we are getting our house in order by training medical staff to effectively take a family history.

Timothy R Bates · Elissa B Poulter · Frank M van Bockxmeer · Gerald F Watts

To the Editor: I read the article by Langlands and colleagues1 with some dismay, and a sinking heart. Their report is further evidence of the dangers of moving away from the basic skills of comprehensive history taking and performing a detailed physical examination. Interestingly, in the United States, the debate regarding performing a physical examination has come full circle, from virtually ignoring its importance to now telling us how vital it is and how to perform it.2 But it is the taking of a comprehensive history that, as one of my mentors told me, “is where the money is”, and a detailed family history is an integral part of this. Eliciting a detailed family history is arguably more important for paediatric patients, who have a longer potential life span and hence have more to gain from this information. In my paediatric practice, for example, I see numerous overweight children, some of whom have a strong family history of hypercholesterolaemia, vascular disease or type 2 diabetes mellitus, which places them at considerable risk of cardiovascular disease in their adult years. A detailed family history may also “unmask” the genetic contribution to a child’s history of deafness or learning disability. Time constraint is the main impediment to taking a comprehensive family history, but it is worth keeping in mind that it is time well spent and that, in the paediatric population, it may make a significant contribution to the long-term health of the child. With the impending advent of personalised genomic screening, there will be an even greater imperative to formalise the gathering of family history details.3,4

Simon E P Hauser

To the Editor: The editorial on the Human Variome Project by Cotton and Macrae1 neatly lays out the reasons for government funding for gene mutation databases for inherited diseases. Most of these diseases are rare, but collectively, they are common. The article highlights the key principles of detecting gene mutations and establishing pathogenicity in order to offer individuals (or couples) relevant health information for themselves and/or their (future) offspring. Cotton and Macrae mention a number of specific diseases, but do not mention the commonest life-shortening inherited disease affecting Australian children — cystic fibrosis (CF). Far from being theoretical, nearly all of the principles outlined by Cotton and Macrae are already in place for CF, including clinical databases (in Australia, the Australian Cystic Fibrosis Data Registry), an international gene mutation database (at http://www.sickkids.on.ca, which is contributed to by Australian genetics laboratories) and programs to offer carrier screening to the population. Unfortunately there is very little government funding for these initiatives, so they are not coordinated. In particular, screening for CF carriers in the population, which is of considerable clinical utility, has only small, fee-for-service programs that reach very few people.2,3 These programs are inequitable in that many people are unaware of the existence of such screening programs and, of those who are, many cannot afford the cost of testing. CF provides an excellent model for the development of a coordinated approach to inherited disease screening and, given that 800 000 Australians are carriers of CF mutations, funding CF screening should be a major government priority.

R John Massie · Martin B Delatycki

On 22 August 2010, the Australian Mitochondrial Disease Foundation will hold its annual Stay in Bed Day to raise awareness of a genetic disorder that robs thousands of Australians of their energy Mutations in mitochondrial DNA (mtDNA) were discovered to cause mitochondrial disease over 20 years ago.1 Initially thought to be a rare group of neurological disorders predominantly affecting children, it is now known that patients with mitochondrial disease can develop a broad range of symptoms (Box) and may present at any age from early in the neonatal period to very late in adulthood. Debilitating or fatal forms of mitochondrial disease are more frequent in children than in adults, but adult patients often have chronic multisystemic manifestations that require symptomatic treatment and regular long-term surveillance to minimise the chance of life-threatening episodes of acute illness. Mitochondrial disease may present a diagnostic challenge to the clinician. Clinical manifestations are variable (see Box), and family histories suggestive of an inherited condition may not be obvious due to the variability in phenotypic expression that characterises this group of disorders. Moreover, the lack of a “gold standard” test for its diagnosis and the fact that mtDNA analysis is not freely available to all Australians (only in Victoria) exacerbate the difficulties in diagnosing affected individuals. Why are mitochondrial disorders highly variable? This is due to a number of factors. First, there are hundreds of mtDNA mutations that cause a variety of different mitochondrial disease syndromes. Notably, most disease-causing mtDNA mutations are heteroplasmic. Heteroplasmy is the co-existence of both normal (wild-type) and abnormal (mutant) mtDNA within the same cell. Because there are multiple mitochondria within any given cell, the proportion of mutant mtDNA may vary between 0 and 100% within any given tissue. Thus, the tissue used for diagnosis becomes critical, with blood not being the most ideal tissue to sample.2 There is substantial evidence to indicate that the higher the heteroplasmic mtDNA mutational load within the tissue or cell, the greater the level of mitochondrial dysfunction.3,4 A minimum number of mutant genomes are required for the expression of disease, a phenomenon referred to as the threshold effect. The threshold effect is a relative concept, because the critical amount of mutation required to impair mitochondrial function will vary depending on the particular mtDNA mutation involved and the relative metabolic requirements of the tissue’s cells at any given time. Although there are occasional exceptions, higher proportions of mutant mtDNA have typically been observed in more severely affected patients.5 Finally, the proportion of mutant mtDNA may change rapidly between parent and daughter cell. This phenomenon, referred to as mitotic segregation, combined with the concept of heteroplasmy, at least partly explains why some family members may be more severely affected than others and how some patients manifest different clinical manifestations at different stages of their lives. Several studies have now found that pathogenic mtDNA mutations occur frequently in the general population. The first true population-based study showed that the most common pathogenic mutation, known as m.3243A→ G (typically associated with MELAS — mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes — syndrome), was found in one in 500 community-based Australians.6 All mutation carriers aged over 50 years had few or minor symptoms, but none had the clinical features of MELAS syndrome. Although age and other risk factors were not accounted for in the analysis, all m.3243A→ G mutation carriers had developed sensorineural hearing loss, a common but non-specific clinical symptom that frequently affects patients with mitochondrial disease. A second study in the United Kingdom confirmed this frequency of the m.3243A→ G mutation, reporting that it was found in one in 700 live births, although no clinical information on mutation carriers was given.7 The authors analysed a total of 10 common mitochondrial point mutations, and found a population prevalence of pathogenic mutation of more than one in 200 live births. Later, two studies investigating the population prevalence of a different point mutation, m.1555A→ G (originally associated with antibiotic-induced hearing loss), independently showed that this mutation was similarly found in one in 500 subjects.8,9 Children with this mtDNA mutation were asymptomatic, but older individuals were more likely to have developed associated symptoms. In addition to determining that mtDNA mutations were prevalent and usually unrecognised in the community,10 these findings raised questions about how and when mutation carriers become symptomatic during their lives. Should we consider mtDNA mutation carriers in the spectrum of mitochondrial disease? Given the lack of data about the factors that contribute to disease penetrance in mutation carriers, this approach could easily be justified. Patients who develop severe disease caused by their pathogenic mtDNA mutation could represent just the “tip of the iceberg”, with the vast majority of mutation carriers remaining only mildly affected. Changes in lifestyle and use of preventive strategies to delay the onset of symptoms (such as tailored exercise programs and avoidance of metabolic and physiological stressors) should be recommended to all mutation carriers in an attempt to reduce the individual’s risk of developing symptoms, although this may be ineffective in those who are destined to develop severe clinical manifestations. Longitudinal clinical studies of mutation carriers are warranted, to determine the natural history of mitochondrial disease and identify risk factors that contribute to developing severe or life-threatening disease versus mild or no symptoms during life. If the prevalence of mtDNA mutations in Australia is at least one in 250, then 90 000 Australians are potentially at risk of developing symptoms of a mitochondrial disorder. To raise community awareness of this genetic disorder, which robs thousands of Australians of their energy, the Australian Mitochondrial Disease Foundation will hold its annual Stay in Bed Day on 22 August 2010 (see http://www.amdf.org.au for details). Clinical manifestations of mitochondrial disease* Organ system Common clinical manifestations Adults Children Brain Stroke-like episodes, seizures, migraine-like headaches Epilepsy, stroke-like episodes Muscle Proximal myopathy Muscle weakness Ears Sensorineural hearing loss Sensorineural hearing loss Eyes Ptosis, external ophthalmoplegia, retinal pigmentary changes, optic atrophy Ptosis, external ophthalmoplegia, retinal pigmentary changes, optic atrophy Heart Cardiac arrhythmia, cardiomyopathy Cardiomyopathy, hypertrophic cardiomyopathy Endocrine Diabetes Diabetes Gastro−intestinal Intestinal pseudo-obstruction, constipation, abdominal bloating, dysphagia Vomiting, failure to thrive Respiratory Respiratory failure, recurrent aspiration, nocturnal hypoventilation Apnoea Renal Renal tubular acidosis Liver Liver failure * If a mitochondrial disease is suspected due to the presence of one or more of these clinical features, a muscle biopsy, genetic testing or referral to a specialised centre for assessment should be considered.

Carolyn M Sue MB BS, PhD, FRACP

Cystic fibrosis (CF) carrier testing can be used to inform reproductive decision making, allowing carriers to avoid having a child with CF. A government-funded, population-based CF carrier screening program would allow greater equity of access to this test. The setting in which CF carrier screening is offered significantly affects the extent to which participants make well informed, voluntary decisions to accept or decline testing. Screening offered before pregnancy and in non-clinical environments better promotes participant autonomy than screening offered in the prenatal consultation.

Lucy J Modra MB BS(Hons), BMedSci, GDipArts(Phil) · R John Massie MB BS, FRACP, PhD · Martin B Delatycki MB BS, FRACP, PhD

Genomic research can link specific molecular genetic information with specific diseases. Implications of genomic medicine in general practice include developments in screening and diagnosis, predicting disease prognosis, and optimising preventive and therapeutic care. As users or co-producers of genomic information, or as collaborators in genomic research, general practitioners can help realise the potential of advances in genomic research.

Frank M Sullivan PhD, FRCP, FRCGP · Pauline M Lockhart MB ChB, MRCGP, MPH · Timothy P Usherwood MD, FRACGP, FRCP

Family history has a role, but who should be responsible for exploring and recording it? The increasing age, number and comorbidities of hospital inpatients has increased the load on emergency departments and necessitated significant redesign, including the introduction of short-stay and medical assessment units. These units are diverse in their casemix, but common factors include higher acuity of illness and expedited discharge. Obtaining a complete history of a patient’s acute illness and longstanding comorbidities, as well as his or her social and psychological issues, represents the ideal standard of care. Obviously, however, there are tensions between providing holistic care and continuity of care to the patient and achieving the rapid turnover required in such units. Genetic markers and tests are increasingly available for an expanding range of conditions. Genetic counselling has moved from specialised clinics into the mainstream practice of many disciplines. The inheritance of disease is rarely a simple algorithm, and these new genetic tools provide complexity rather than clear direction. Relevant guidelines are uncommon outside cancer medicine. Family history is a frequent criterion for determining further genetic testing. For example, the Amsterdam criteria for diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) include a family history of at least three relatives with HNPCC-associated cancer.1 There can be harm in failing to interpret genetic tests correctly, and the complexity of many conditions demands a high level of knowledge. “Genetic literacy” is a term that has been used to describe competence in this area.2 However, it seems unreasonable to expect all doctors to be skilful at all times in eliciting and interpreting the family history and then appropriately counselling and testing each patient. Family history is an older tool than genetic testing and is poorly defined, applied and understood.3 Even now, there is not enough evidence to gauge its reliability and role.4 The family history can aid stratification of a patient’s risk of heritable conditions, and it has diagnostic utility for disorders with classic Mendelian inheritance, but it may be less useful in disorders with multifactorial inheritance or more complex genetic expression. In this issue of the Journal Langlands and colleagues report that family history is not recorded in the case notes of most medical short-stay patients.5 They argue that a family history offers potential health gains for the patient and relatives and suggest that there should be increased focus on this element of the medical history. However, this seems unrealistic in the context of increased workload and time pressures, particularly in a hospital short-stay unit. The acute admission is not an ideal setting for detailed and accurate history taking; patients are usually unwell and access to their family is compromised. The family history recorded is often inaccurate4 or misleading, not only because the level of health literacy among patients is variable but also because familial clustering is not distinguished from heritable disease. The accuracy of reporting of family history is rarely studied, but it has been shown that it can be poor in patients with cancer4 or cardiovascular disease.6 The primary care setting affords better opportunities to explore and record family history and to make adjustments after clarification with relatives. Certain conditions (eg, malignant hyperthermia, Huntington disease) drive consideration of genetic testing of the affected individual and sometimes lead to testing of family members. The counselling required should form part of an ongoing relationship with the patient and family. As Langlands and colleagues state,5 the family history may be a casualty of increasing numbers of acute hospital admissions. Perhaps it is a justifiable casualty in the acute health care environment, as long as information is elicited accurately afterwards. Ideally, a patient should have his or her acute illness diagnosed and managed within the acute admission, with a clear plan then delineated for follow-up, which includes notification of those who will be responsible for doing so. It is important to have a use for any family history information once it is accurately obtained. In future, the acquisition of a family history must embrace the developments in our understanding of genetic disease. Without diminishing the role of specialised genetic units, primary care clinicians and specialists in chronic care will need to assume greater responsibility for exploring family history. Screening assessments can identify those requiring a more comprehensive review. We would argue that, under present circumstances and with doubt hanging over its sensitivity, specificity and effect on health outcomes,3,4 the family history is a justifiable omission from many acute hospital admissions. The concept of holistic care is a noble one and, if we are to work within a new paradigm of shorter hospital inpatient stays, we will need to develop a strategy for preserving this concept. Certain diseases, such as unprovoked venous thromboembolism, should trigger an immediate focus on family history, but a routine family history is best ascertained when people are not acutely unwell. If we are serious about disease prevention and the role of genetics in modern medical management, more guidance is needed in terms of which patient groups will benefit from genetic testing and how any positive results will be managed. An integrated approach should include guidance for screening that is based on a better defined family history that has been obtained in the non-acute setting. This approach requires protocols for disease-specific genetic testing and specialist referrals for further assessment and management. A recent National Institutes of Health conference offers hope in this regard.3

Josephine S Thomas BM BS, FRACGP, FRACP · Campbell H Thompson DPhil, FRACP, MD

It is time to reconsider the clinical benefits arising from family history and start making better use of it A patient’s family history may aid clinical diagnosis and contribute to disease risk assessment and prediction. It frequently yields valuable social history, including information about family support structures and insights into individual beliefs about illness.1 Although taking family history is traditionally regarded as a routine part of the medical history, it is not used in a systematic way in clinical practice. In this issue of the Journal, Langlands and colleagues report the results of an audit in an Australian teaching hospital, which found that nearly three-quarters of patients admitted to a short-stay medical unit had no documentation of family history having been considered as part of the diagnostic assessment.2 A similar situation exists in primary care. Although there are no published comparable data from Australian general practice, a primary care study in the United States found that only 16% of subjects (n = 362) had any record of their family history in their clinical chart, including 15 individuals at high risk of an inherited cancer syndrome.3 Internationally, there is growing recognition that a family medical history can support tailored disease prevention, which may be more effective than existing approaches.4 This is also reflected in the Australian Medicare-funded adult health assessment for people aged 45–49 years at risk of developing chronic disease, which specifically includes assessment of the family history of chronic diseases such as diabetes and cardiovascular disease. Family history can also inform the formulation and weighting of differential diagnoses in presentations for a range of common conditions. The risk of many serious diseases is increased in the presence of a family history of the disorder, representing not only shared genetic factors but also environmental and behavioural exposures. For example, the relative risk of breast cancer is 1.4 times higher for women aged 60 years or older if they have a first-degree relative diagnosed with the disease after the age of 60 years; this risk is more than five times higher for women younger than 40 years with a first-degree relative diagnosed before the age of 40.5 Eleven per cent of women with breast cancer have a first-degree relative with the disease. The relative risk of colorectal cancer for a 50-year-old is increased from around twofold with one affected first-degree relative to almost fourfold in people with at least two affected first-degree relatives.6 About 15%–20% of people with colorectal cancer have an affected first-degree relative. In a US population-based study, 14% of the population had a family history of ischaemic heart disease, but these people accounted for 72% of early ischaemic heart disease and 48% of all cases of the disease.7 A parental history of type 2 diabetes is associated with a relative risk of 2.2 and a lifetime risk of 40%.8 These familial disease risks should be compared with other traditional risk factors that are routinely screened for in general practice. For instance, isolated hypertension is associated with a relative risk of 1.8 for ischaemic heart disease and is present in 14% of men and 5% of women with a coronary event.9 There are effective interventions for primary and secondary prevention of all these common diseases, ranging from disease surveillance to drug treatments and lifestyle management. There is some evidence that having knowledge of a family history of a specific condition is associated with improved uptake of a range of disease-preventive activities for breast, colorectal and skin cancer.10-12 Therefore, it is possible that identifying people with a family history of disease could act as an additional motivator for them to change their lifestyle or participate in disease screening. Why then do clinicians continue to neglect the family history as part of routine diagnostic assessment and disease prevention? The experienced clinician will know that recording a patient’s family history to assess disease risk ideally requires a three-generation pedigree, but this can take up to 30 minutes, which is unrealistic in most clinical settings. However, not all patients require such a detailed assessment. Simple, self-completed family history screening questionnaires could provide an answer. Several of these already exist, but many are disease-specific and few have been formally tested to determine their screening characteristics.13 Clinicians also cite patients’ uncertainty about their family history as a barrier. However, a systematic review of self-reported family history found high positive predictive values for cancer in first-degree relatives (breast, 93%; prostate, 85%; colon, 81%), although information was less accurate about second-degree relatives (breast, 91%; prostate, 80%; colon, 77%).14 Of course, sometimes the patient’s perception of his or her family history can be just as important as the reality in determining the patient’s risk perception, illness beliefs and likely response to medical advice. Better methods of recording family history are also required, particularly as we move towards an electronic health record in Australia. Tailored clinical software is potentially the most effective tool for recording and updating a patient’s family history, although current clinical software systems do not support the creation of pedigrees. Previous trials have demonstrated the capacity of computerised pedigree tools to improve the assessment of disease risk and identify those individuals who may benefit most from seeing a clinical geneticist.15 However, while clinicians continue to ignore the importance of the family history in diagnosis and risk assessment, software companies have little incentive to integrate family history tools into their systems. Raising awareness among consumers is an alternative approach that may drive clinicians to consider family history more often. A family health history campaign run in New South Wales in 2007 resulted in increased community awareness and discussions about family history within families and between patients and their general practitioners.16 While DNA-based disease risk prediction remains to be proven as an effective clinical tool, family history is a simple but potent tool that is available now for disease prevention. Langlands and colleagues audit findings show that this important element of the clinical history is seldom included in routine patient assessments.2 The family history should not be seen as a relic of medical school teaching; it is time to reconsider the clinical benefits arising from family history and start making better use of it in clinical practice.

Jon D Emery MB BCH, FRACGP, DPhil · Fiona M Walter MB BCh, FRCGP, MD · David Ravine MB BS, MD, FRCPath

The worldwide availability of preventive genetic health information will benefit millions of families In Australia, it has been estimated that around a million people are affected directly or indirectly by inherited disease. An audit of admissions to a major paediatric hospital in the United States showed that, in 71% of admitted children, their condition had a significant genetic component and, of these, 10% had an inherited disease.1 However, inherited diseases have received little attention in health budgets and research grants. One of the reasons is that each of the thousands of different inherited diseases caused by gene mutations is extremely rare and, as a consequence, affected families and clinicians in the field have little voice. Understanding and developing care for people with inherited disease depends on setting up and maintaining databases with information on the incidence, phenotype, penetrance, treatment strategies, and prognosis of these conditions. Gene mutation databases are labour intensive to develop, populate and maintain, but are essential if we are to realise the benefits of the vast amount of genetic data on individuals and populations, both healthy and unhealthy, embedded in the human genome. At present, there is a lack of funds for critical inherited disease registries or databases in Australia and around the world. Without adequate and sustained funding for database set-up and curation, these databases will inevitably harbour data deficiencies and even inaccuracies, which may have serious health consequences. So, what is being done, and what more can be done, to address this deficiency. Several specific databases already exist: Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim) is a public database of bibliographic information about human genes and genetic disorders;2 the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php) collects data on published germline mutations in nuclear genes underlying human inherited disease;3 the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/) provides access to biomedical and genomic information;4 and there are over a thousand genes in locus-specific databases (http://www.hgvs.org/dblist/glsdb.html).5 However, all these excellent activities are insufficient to meet the rapidly emerging need to document all mutations in all genes, which would allow interpretation of the human genomic sequences available from diagnostic, research and, increasingly, commercial sources. At a gathering of experts in human genetics in 2006, the Human Variome Project (www.humanvariomeproject.org) was created to fulfil this need.6-8 This project aims to facilitate “the establishment and maintenance of standards, systems and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease”. It is working towards the comprehensive collection of genetic information from all sources, ensuring data accuracy, making the information freely available and, at the same time, developing standards to achieve these goals. Critical collaborative projects are underway to define protocols that can be readily extended to all genes and to all countries. The Human Variome Project has initiated two pilot studies that will act as models for global collection of all gene mutations and their effects. The first involves the International Society for Gastrointestinal Hereditary Tumours (InSiGHT; http://www.insight-group.org), the peak international body of health care professionals caring for families with inherited gastrointestinal cancer. InSiGHT maintains a database of mutations in the mismatch repair genes responsible for Lynch syndrome (hereditary non-polyposis colorectal cancer syndrome). InSiGHT has established governance, curation, interpretation, phenotype, functional assay, and histopathology subcommittees to support its database, aiding in ensuring integrity of the data, controlling access for bona fide use, and encouraging submissions of variants from individual laboratories and national data collections. Since engaging with the Human Variome Project, and learning of its experience in locus-specific database management, InSiGHT has increased its variant submissions from 550 to over 11 000, and attracts over 20 000 website “hits” per month, strongly affirming its value to the scientific community. Obtaining funding for this critically important database has been difficult, but full credit needs to go to the Cancer Council Victoria, the Victorian Cancer Agency and, most importantly, to the George Hicks Foundation, for grasping an important leadership opportunity. The second pilot study is being conducted by the Australian Node of the Human Variome Project, which is developing a country-specific system as a model for other countries, where possible using freely available software and data management systems.9 While several countries have collected mutation data for their population, there are no unified collection standards and no links to other international efforts. This project, funded by the Australian Government’s National eResearch Architecture Taskforce (NeAT) (https://www.pfc.org.au/bin/view/Main/NeAT), will address this deficiency. It is in the early- to mid-phase of its work, and trials in two laboratories are expected to take place by the end of 2010. Examples of the potential future uses of a complete list of mutations causing human disease are given in the Box. In brief, the possibilities for preventing or otherwise reducing suffering from disease opened up by the Human Variome Project will benefit individuals, as well as reduce the burden of global health care budgets. The main limitations to achieving the aims of the Human Variome Project are the speed of development and the spread of systems for countries, genes and disease groups; capitalising on these developments is, and will be, dependent on funding. Funding is needed for efforts to collect disease- or gene-specific data and data for individual countries, but the benefits for each country’s health care budget should more than offset the necessary initial outlay. The fact that genetic data are not in a single repository means that expensive professional time is spent “surfing” the web to look for previous examples of a particular mutation, or proper care cannot be given because vital data are buried in hospital files. Funding and recognition of the global Human Variome Project’s key coordinating role has been problematic due to it “falling through the cracks” of existing funding mechanisms. However, this situation is changing, with recognition by the World Health Organization in 2006, and UNESCO in 2010, which hosted the third Human Variome Project meeting at its headquarters in Paris, 10–14 May 2010. The pilot studies and the clear clinical need support the case for funding. It should be remembered that genetics has allowed medical testing to predict outcomes for patients and families contributing to prevention. Past, current and future support will ensure cost-effective, translational and preventive personal genetic health care worldwide, which will benefit millions of families. Future uses of a complete list of mutations causing human disease, as envisaged by the Human Variome Project Individuals (or their advisers) will be able to search their genome sequence for variations. If a variation is found, it can be compared with the complete catalogue of mutations to determine whether it is harmful. Examples include: a variation in a colon cancer gene — if harmful, preventive screening can be instituted; or a variation in the glaucoma gene in a person whose grandfather went blind at age 57 — preventive therapy can be instituted. When two individuals are planning to have children, they will be able to compare their genome sequences with the complete catalogue of mutations and their effects. They might be told that they both have a serious defect in, for example, the gene locus responsible for maple syrup urine disease, and advised to consult a genetic counsellor. This type of use has precedents in the premarital testing for the globin gene causing thalassaemia in the Mediterranean area, particularly in Cyprus. This has resulted in almost complete elimination of this disease through family planning. The ethnic-specific mutations in the Ashkenazi Jewish population are well known. When an individual has a specific disease, defining the mutation in a number of specific genes costs around $50, compared with several thousand dollars when the whole gene in question has to be sequenced. Lists of mutations in genes in all ethnic groups will allow definition of the most common mutations in each group.

Richard G H Cotton AM, BAgSc, PhD, DSc · Finlay A Macrae MB BS(Hons), MD, FRACP

The challenge of convincing governments of the value of a nationally comprehensive data collection Congenital anomalies are worth bothering about — they affect around one in 20 births in Australia.1-3 They are the second most common cause of perinatal and infant mortality and the fourth commonest cause of mortality in 1–14-year-olds in Australia.4,5 They are major contributors to hospital admissions6 and often result in lifetime disability. They are costly to our health system, including the considerable expense of providing programs to screen for, diagnose and terminate pregnancies affected by major congenital anomalies (Down syndrome and neural tube defects in particular). Importantly, some anomalies are preventable, including neural tube defects (70% preventable with adequate periconceptional folic acid7) and anomalies resulting from exposure to teratogens (eg, by avoiding alcohol during pregnancy). For many congenital anomalies, early identification allows interventions to decrease the risk of secondary disabilities. We need good data to monitor trends in congenital anomalies, to identify clusters of cases that may require investigation for possible environmental causes, and to evaluate the effectiveness of interventions for screening, treatment and prevention. Nationally, the Australian Institute of Health and Welfare (AIHW) National Perinatal Statistics Unit (NPSU) collates information on congenital anomalies that is supplied voluntarily by health departments in the states and territories. However, there remains considerable variability between jurisdictions in the scope and quality of the data collected. This variability — which includes the sources of case ascertainment, the upper age limit for inclusion, definitions and classifications used, methods of operation, and resources available for collecting, updating, validating and using the information — limits the utility of the collection. National data published by the NPSU can only be as complete as the data provided by individual states and territories. Lack of completeness is evident in two recent AIHW reports. The first, Congenital anomalies in Australia 2002–2003,8 does not include data from the Northern Territory, because data were not available. This may change, as the NT is reviewing its perinatal data needs. In addition, data were only available from four states on terminations of pregnancy at less than 20 weeks’ gestation for congenital anomalies.8 The absence of information on early terminations is also evident in the second report, Neural tube defects in Australia.9 The prevalence of neural tube defects at birth for the period 1998–2005 was similar for all states included in the report, at around 5 per 10 000 births, but the total prevalence (including early terminations of pregnancy from the four states collecting such information) was more than twice as high, at 10.1 per 10 000 pregnancies. Furthermore, of the four states collecting data on early terminations, the total prevalence in 2005 in South Australia, Victoria and Western Australia was 13.3 per 10 000, double that in New South Wales (6.2 per 10 000), suggesting incomplete ascertainment of terminations in NSW. One of the purposes of the report on neural tube defects9 was to provide baseline data against which to monitor the effect of the introduction of mandatory fortification of bread-making wheat flour with folic acid, in place nationally by 13 September 2009. Because such a high proportion of neural tube defects are diagnosed prenatally and affected pregnancies terminated, post-intervention monitoring in Australia will be restricted to the three states where there is complete ascertainment of such terminations. The inclusion of terminations of pregnancy is essential for a national data collection on congenital anomalies — not only for evaluating interventions such as folic acid fortification, but also for evaluating and monitoring the safety and quality of prenatal screening programs and diagnostic tests, and the associated health and psychosocial impacts. In response to the limitations in national data collection, a program was commenced in 2007 to develop a national minimum dataset on congenital anomalies. Members of a committee representative of the states and territories reached consensus on collecting good data on a limited number of conditions, particularly those with important clinical, social or health care impacts; and on the use of internationally agreed definitions for congenital anomalies. However, because of existing data limitations in some jurisdictions, commitment to a national minimum dataset is not currently possible. In addition, the scope of the proposed national collection has been limited to the perinatal period, which means terminations of pregnancy for congenital anomalies before 20 weeks’ gestation will not be included. These decisions are very disappointing and suggest that Australian policymakers and governments are still to be convinced of the value of monitoring congenital anomalies, which, despite their magnitude and importance as a cause of mortality and morbidity, are clearly not seen as a public health priority. Historically, data collection for congenital anomalies has been unfunded or under-resourced in Australia. Apart from mandatory folic acid fortification, there has been no national policy on the surveillance, prevention and management of congenital anomalies. There has also been no consumer involvement in deliberations on the societal impact of these anomalies, the need to collect national data, and the ways in which these data should be collected and used. The challenge remains to convince governments of the value of a nationally comprehensive collection that can be used to monitor trends, identify clusters that may require investigation, evaluate the effectiveness of screening and interventions for treatment and prevention, and allow research into the prevention of congenital anomalies.

Carol I Bower MB BS, PhD, FAFPHM · David Lester-Smith BM BS, FRACP, MPH · Elizabeth J Elliott MD, MPhil, FRACP

To the Editor: Two recent publications have described programs of carrier testing for cystic fibrosis (CF) gene mutations.1,2 The authors conclude that CF carrier testing of women in early pregnancy and their partners, as well as couples contemplating pregnancy, can successfully identify those who are at risk of having a child with CF and provide them with reproductive choices. The authors use these proof-of-concept studies, in the absence of Australian economic data, to call for all couples to be offered CF carrier testing that is supported by government funding. Although reproductive choice is clearly an individual’s right, what obligation does the community have regarding government funding of specific services to generate information that might assist such couples? Genetic screening policies have often been determined on the basis of technological capability, rather than through a rigorous evidence-based review process.3 Decision making should also take into account evidence of clinically effective screening programs, ethical principles, and opportunity costs, given the limited resources available in the health sector. A simple economic analysis of these publications highlights some issues that need to be addressed. Massie and colleagues identified nine carrier couples by screening 3200 individuals (3000 females) before conception or during early pregnancy (CF carrier frequency, one in 30). Two of the nine carrier couples had affected pregnancies, which equates to a cost of $300 000 per CF case. In Christie and colleagues’ dataset of 1000 individuals, 73% had no family history of CF; 27 of these individuals carried CF mutations, and two carrier couples but no affected pregnancies were identified. Based on population gene frequency statistics (CF carrier frequency, one in 25; 75% of CF gene mutations being p. F508del),1 Massie et al’s screening model2 would, on average, require 3585 women to be screened to detect one affected pregnancy, costing about $740 000. Christie et al’s expanded one-step model1 would require about 3763 couples to be screened to detect one affected pregnancy, at a cost of more than $430 000. Among the 270 individuals with a family history of CF who were screened in the latter model, 126 were carriers of CF mutations (carrier frequency, one in two). It is clear that cascade screening of those with a family history would be a more effective strategy. There is an ethical argument that projected economic benefits from the termination of affected fetuses should not play a role in decisions to offer testing.4 Nevertheless, technological capability needs to be considered together with evidence of cost-effectiveness and community acceptance before public funding of community CF carrier screening can be justified.

Peter C O’Leary · Susannah J Maxwell · Leanne M Youngs · Kate J Brameld · Ian R Walpole

In reply: Our aims in publishing the outcomes of offering cystic fibrosis (CF) carrier testing to couples were to demonstrate the high acceptability rate and report the reproductive choices made by high-risk couples. Not all decisions resulted in termination. O’Leary and colleagues rightly raise the question of screening costs. Laboratory costs will reduce with economies of scale and centralisation of testing. The recent release of a position paper on population screening for CF by the Human Genetics Society of Australasia1 will influence the demand for testing. It recommends that all couples intending to have children, and women in early pregnancy and their partners, be made aware of the availability of CF carrier testing, and that couples should be offered testing for 10 CF transmembrane conductance regulator gene mutations using an expanded one-step or two-step model. O’Leary and colleagues suggest that cascade testing of those with a family history of CF would be a more effective strategy. However, only 10% of children born with CF have a family history.2 Studies have demonstrated that costs of CF screening are less than the averted medical care costs associated with fewer births of infants with CF.3-5 Although economic considerations are important, these should not form the primary goal of any screening program.

Louise M Christie · Angela J Ingrey · Gillian M Turner · Anne L Proos · Gloria E Watts

To the Editor: The research article by Keogh and colleagues1 on uptake of genetic testing and insurance implications highlights the need to ensure that Australian insurance industry policy in relation to genetic testing does not increase the risk of adverse health outcomes. The authors called upon the insurance industry and the Human Genetics Advisory Committee (HGAC) of the National Health and Medical Research Council (NHMRC) to reconsider the use of genetic information in relation to insurance.1 Another recently published study has also raised concerns about the way genetic information is used in the insurance industry.2 The HGAC has had initial discussions with the insurance industry about: avoiding genetic discrimination in the insurance setting; developing policies and guidelines to ensure appropriate use of genetic test results in insurance underwriting; promoting genetic education and training in the financial industry; and providing support for consumers and health professionals wanting to challenge adverse decisions. Through the HGAC, the NHMRC will encourage the development of an evidence-based process for assessment of genetic tests for use by the insurance industry, to ensure that it meets the required standard for underwriting. This will, in turn, support appropriate, equitable consumer access to optimal health care.

Warwick P Anderson

Charles Darwin visited New Zealand in December 1835, and Australia from January until March 1836, on the return portion of his voyage around the world in HMS Beagle. Despite the shortness of these visits, he retained an interest in these countries throughout his life, maintaining correspondence and receiving many biological specimens. His experiences in these places influenced his thinking on evolution, particularly on the evolution of man. Aspects of his health recorded during this part of the voyage support a new hypothesis for the diagnosis of the illness that Darwin endured for most of his life.

John A Hayman MB BS, MD, FRCPA

Some years ago, a woman in her late 30s was referred to me for consideration for an amniocentesis on the basis of advanced maternal age. She had had three previous pregnancies, all resulting in healthy babies. An ultrasound confirmed a single, viable intrauterine pregnancy, and a fetal size consistent with dates. The amniocentesis was performed without complications. However, the results of the chromosome culture showed there was a balanced 2 on 17 translocation (Box). This was of concern to me — if this was a new mutation, there would be a significant risk that the fetus could have a neurological disorder, ranging from mild cerebral dysfunction, through to severe intellectual disability. However, most cases that I see with a translocation are not new mutations; they are a reflection of the chromosome makeup of one of the parents. I contacted the patient, and told her of the result, and requested that her blood and her husband’s blood be analysed for evidence of a translocation. After 72 hours, the laboratory issued the report showing that neither the patient nor her husband had the translocation. This did alarm me, but when I told the patient about the results, she asked whether it would be reasonable for her boyfriend to have chromosome analysis done as well. I assured her that this would be very useful, and contacted her boyfriend. He supplied blood and, sure enough, it showed that he had a balanced 2 on 17 translocation. I explained to the patient that, under these circumstances, the fetus was very unlikely to have an intellectual disability, and she seemed quite relaxed about this information. I discussed the result further with the patient’s boyfriend, pointing out to him that it may be possible that his siblings could also have a balanced translocation. If he or his siblings had any further children, these children could be affected. The patient’s boyfriend told me categorically that he was not going to be having any more children. He had a sister who had three children, and she was not going to have any further pregnancies. Nevertheless, his sister agreed to have a chromosome analysis done, which confirmed that she had a normal chromosome complement. The boyfriend also told me that he had a brother who lived on a farm. When I asked if it was likely that he would have children, he said that his brother was 28 years old and had been damaged by obstetric forceps during a difficult delivery, leaving him with an intellectual disability. This brother agreed to have chromosome analysis, and surprise, surprise, it showed that he had an unbalanced translocation. This then would explain his intellectual disability. I doubt very much whether the obstetric forceps played any role in his condition. When my patient’s baby was born, a physical examination showed that the baby was normal. I recount this history to reinforce that sometimes the obvious is not as clear cut as one may first think. The country general practitioner who delivered the boyfriend’s brother 28 years ago has probably laboured under the weight of blame being ascribed to him for the poor outcome in this young man. Chromosome translocations If two chromosomes break, genetic material can be exchanged between the chromosomes. This is called a translocation. If the person with the translocation has lost or gained no genetic material, and is phenotypically normal, the rearrangement of the genetic material is said to be balanced — a balanced translocation. If the person has an excessive or decreased amount of genetic material after the breakage, the rearrangement of the genetic material is said to be unbalanced — an unbalanced translocation.

Francis V Carmody FRCOG, FRANZCOG, DDU

Objective: To review the outcomes of offering carrier testing for cystic fibrosis (CF) to couples considering pregnancy, and to women in early pregnancy and their partners.Methods: An after-hours clinic was established in Newcastle for discussion of issues related to prenatal testing. Couples were offered CF carrier testing by extracting DNA from a mouthwash sample. An expanded one-step model was used with both partners being tested initially for the p.F508del cystic fibrosis transmembrane conductance regulator gene (CFTR) mutation. If one partner was a p.F508del carrier, the other partner was tested for an additional 28 CFTR mutations.Results: Of 1000 individuals who were offered CF carrier testing, none declined. No re-collections of mouthwash samples were required, and results were available within 14 days. There were 730 individuals who had no family history of CF (73%); 27 were carriers (4%; 95% CI, 2.4%–5.3%), and there were two high-risk couples where both partners were carriers of p.F508del. There were 270 individuals who had an affected family member with CF or a child identified as a CF carrier through newborn screening; 126 were carriers (46%; 95% CI, 40.6%–52.8%), and there were two high-risk couples — one couple where both partners were carriers of p.F508del, and another couple where the woman was homozygous for p.F508del and the man was a p.F508del carrier. The information on carrier status led the four high-risk couples to change their reproductive decisions to avoid having a child with CF.Conclusion: CF carrier testing for couples using an expanded one-step model will detect about 80% of high-risk couples and enables various reproductive choices. We believe that all couples considering pregnancy, and women in early pregnancy and their partners, should be offered CF carrier testing.

Louise M Christie RN, CM, GradDipGenCouns · Angela J Ingrey BSc, GradDipGenCouns · Gillian M Turner MB ChB, DSc, FHGSA · Anne L Proos MSc · Gloria E Watts BSc, MSc

To the Editor: The introduction of non-invasive prenatal testing will revolutionise the practice of prenatal diagnosis. One of the many potential applications of non-invasive prenatal diagnosis (NIPD) is to determine fetal RHD status in pregnant Rhesus (Rh) D-negative women, and the feasibility of such testing was aptly demonstrated by Hyland and colleagues1 and commented on by Cole and Savoia.2 It is clear that once the technical problems of indeterminate results and gene variants are resolved, NIPD for RHD status will have improved clinical utility over current invasive testing, thus reducing the need for invasive procedures and prophylactic treatment of all RhD-negative women. The assay developed by Hyland et al can also be used to determine fetal sex, indicating a potential additional use in women at risk of carrying a fetus with a sex-linked disorder, so as to halve the number of chorionic villus sampling (CVS) tests being performed. However, it is worth noting that the number of CVS tests currently performed for this indication is extremely small. In Victoria, the complete population-based dataset on prenatal diagnosis for 2007 shows that there were only eight invasive tests for sex-linked disorders.3 The most significant impact of NIPD technology will be for pregnant women who request prenatal testing for Down syndrome. If NIPD testing for Down syndrome becomes available, it is anticipated that current testing based on chromosome analysis (karyotyping) of a sample obtained by CVS or amniocentesis will become redundant. However, replacing karyotyping — a genome-wide test — with a targeted NIPD test for Down syndrome will mean that many of the other chromosome abnormalities currently detected by CVS or amniocentesis will no longer be detected.4 We do not know whether this is important to women or not. Before implementing any NIPD test, we suggest that each application needs a separate investigation, including a careful comparison of clinical utility between current tests and the proposed replacement technology.

Marleen R Susman · David J Amor · Jane L Halliday