Grant Blashki

Sylvia Metcalfe

Jon Emery

Background Our improved understanding of the human genome and the genetic contributions to disease have been looming over the horizon for some decades now with great promise of improvements in prevention, prediction and treatment of diseases. Yet, as with many technological revolutions, the real gains on the ground have been much slower to emerge. Objective/s The aim of this paper is to outline some of the common genetic issues that arise in general practice clinical consultations, and the clinical scenarios in which general practitioners (GPs) may suggest genetic testing for patients or referral to one of the various specialist genetics services. Discussion GPs will notice that more consultations now involve some discussion of genetic issues and, indeed, there is a range of genetic tests that GPs can request. These issues and tests require detailed explanation to patients and their families.

With the rapid developments in human genetics in recent years, there have been high expectations about how these scientific discoveries will translate into real benefits for patients.1,2 It is clear that these advances are going to filter down to primary care settings and become a significant element of day-to-day clinical care – indeed, there is already a variety of genetic investigations that GPs can request. These genetic tests require detailed explanation to patients and their families to assist them in interpreting what they mean and making informed decisions.3,4 The humble family history, often a cursory entry into the medical records, is in fact a powerful tool when undertaken diligently and systematically, and there now exists a validated tool to assist with this process.5 Specific genetic tests also now come into play in a wide range of clinical settings: pre-pregnancy and pregnancy counselling in the context of couple carrier screening6 or screening the fetus,7 newborn screening,8 cancer screening,9 cardiovascular screening,10 clotting and bleeding problems,11 and neurological and developmental problems such as fragile X syndrome.12

As with so many complex clinical presentations in primary care, there is always tension between those that the GP can manage and those needing specialist management. Over time, clinical practice tends to evolve that defines the line in the sand. There is a level of complexity for many genetics consultations that does require specialised expertise and it is timely, as more genetic testing becomes available, to reflect on how GPs may work with genetics services and genetics counsellors and patients.13–16 The aim of this paper is to outline some of the common genetics issues that arise in GP clinical consultations, and the clinical scenarios in which GPs may suggest genetic testing for patients or referral to one of the various specialist genetic services. Prenatal testing is also a rapidly developing field and is dealt with in a separate article17 in this edition of AFP and not addressed specifically in this paper.

The role of GPs

General practitioners are potentially well placed to integrate many genetics issues into routine consultations, although training to date has been limited.5,18–20 Much of the day-to-day work of general practice already involves the management of chronic diseases, the prevention of cancer and the management of patients within the context of their families.21 Indeed, much of the interaction between GPs and patients, especially in regard to preventive care, is already fundamentally about risk assessment and management. In addition, as families share genes, GPs working with families are well placed for long term follow up of genetics-based risks.

GPs are also accustomed to communicating test results to patients and managing the subsequent implications of a test.22 But there are significant differences regarding genetic information, compared with the sorts of routine test results that GPs are accustomed to communicating to their patients.23 Public understanding of genetics is often clouded by overhyped media reports or internet misinformation and there are many common misunderstandings.16 For example, the presence of a cancer gene often leads some patients to believe that disease is inevitable rather than an increased probability. In addition, genetics tests can have more broad reaching impact than routine investigations for the individual’s identity, for their family members and, potentially, for employment and the costs of obtaining life insurance.3 In this context, confidentiality and informed consent are especially pertinent, and particular care is needed in preparing patients for genetic information, to ensure accurate understanding, interpretation and appreciation of the implications.

Raising genetics issues in general practice

GPs are well positioned to determine whether a patient/family might consider pursuing genetic investigation. In considering the value of genetic tests, the GP should be mindful of the possibility of raising anxiety levels unnecessarily, or raising concerns about a disease for which there is no possibility to improve the prognosis.24 There are also familial diseases for which we do not yet have routine genetic tests, for example schizophrenia or type 2 diabetes, so GPs needs to manage patients’ expectations.

A systematic approach to family history is more accurate than an ad hoc approach. One tool, the Family History Questionnaire (Table 1) is a validated questionnaire for primary care assessment of some of the common diseases: diabetes, ischaemic heart disease, melanoma, breast, ovarian, colorectal and prostate cancer.25 It can be used as a paper-based questionnaire for patients or integrated as a template into medical software, or undertaken with the GP or in the practice waiting room.

Table 1. Family health questionnaire: 9 items This risk assessment focuses on your close relatives including parents, children, brothers and sisters who are either living or dead. Yes No Have any of your close relatives had heart disease before the age of 60?

‘Heart disease’ includes cardiovascular disease, heart attack, angina and bypass surgery. Have any of your close relatives had diabetes?

‘Diabetes’ is also known as type 2 diabetes or non-insulin dependent diabetes Do you have any close relatives who have had melanoma? Have any of your close relatives had bowel cancer before the age of 55? Do you have more than one relative on the same side of the family who has had bowel cancer at any age?

Please think about your parents, children, brothers, sisters, grandparents, aunts, uncles, nieces, nephews and grandchildren. Have any of your close male relatives had prostate cancer before the age of 60? Have any of your close female relatives had ovarian cancer? Have any of your close relatives had breast cancer before the age of 50? Do you have more than one relative on the same side of your family who has had breast cancer at any age?

Please think about your parents, children, brothers, sisters, grandparents, aunts, uncles, nieces, nephews and grandchildren. Reproduced with permission from the American Academy of Family Physicians from Emery D, Reid G, Prevost AT, Ravine D, Walter FM. Ann Fam Med 2014;12:241–4925

There are some particular clinical scenarios that may prompt the GP to consider genetic testing. These scenarios and the sorts of tests that might be considered are listed in Table 2 (available online only). This table has been developed using the NHMRC’s Genetics at a Glance summary,26 which is underpinned by an extensive resource, Genetics in Family Medicine: The Australian Handbook for General Practitioners.3 Although published in 2007 and requiring updating in parts, it is still relevant to general practice and the GP’s role in genetics medicine. The table has also been heavily informed by the Guidelines for preventive activities in general practice (the Red book).27 It presents the common genetics issues encountered in general practice including: hereditary haemochromatosis, neurofibromatosis, skin cancer, prostate cancer, breast cancer, colorectal cancer, type 2 diabetes, familial hypercholesterolaemia, fragile x and other causes of developmental delay, hereditary thrombophilias and haemoglobinopathies.

There are some important clinical and ethical considerations that should be addressed before offering patients genetic tests.26 The patient should be fully informed about the purpose and personal/family implications of a genetic test before obtaining consent. One key issue is to explain to patients who have had a predictive or pre-symptomatic genetic test, that they have a duty to inform life insurers of the test result when applying for a new policy or altering an existing policy.26 Also, although the GP has no duty per se to inform the relatives of a patient about a positive genetic test result, the patient should be encouraged and supported to share the information with their relatives, and it may be worth discussing in advance how the test results are to be communicated.

Some genetic tests may be available in Australia at no cost to the patient through genetics services funded by state or territory governments, whereas other genetic tests may be available only at out-of-pocket costs to the patient, sometimes at a cost of hundreds to thousands of dollars. In Australia, the following DNA tests are available on the federal Medicare Benefits Schedule (MBS) for specific indications: haemochromatosis (HFE), fragile X syndrome, Factor V Leiden and some other inherited thrombophilias.26 In addition, various tests for chromosomal analysis are also available on the MBS, for example, karyotyping and chromosomal microarrays for investigation of developmental delay.

Table 2. Overview of common familial diseases in family medicine26,28 Clinical scenario Investigations/referral Comments All patients Where possible, take a three-generational family history including: First-degree relatives (children, siblings, parents) on both sides of the family

Second-degree relatives (aunts, uncles and grandparents) on both sides of the family Consider using the Family History Questionnaire as part of the medical history Key information in the family history: Ethnic background (ancestry and culture)

Adoption

Age at diagnosis

Age and cause of death

Birth defects

Stillbirths and miscarriages Hereditary haemochromatosis (HH)

Patients with one or more of: Liver disease of unknown cause, including those with suspected alcoholic liver disease

all first degree relatives with haemochromatosis or with a known mutation in the HFE gene

gene Patients with conditions that could be a complication of HFE (diabetes mellitus, atypical arthritis, cardiomyopathy, erectile dysfunction or chronic fatigue) Test for fasting transferrin saturation and serum ferritin concentration.

If fasting transferrin saturation >45% or fasting ferritin >250 µg/L on more than one occasion, test for HFE mutations

If a HFE mutation is identified, discuss options for genetic testing and referral for genetic counselling of at-risk family

Children of C282Y heterozygotes should only be tested if the other parent has the C282Y mutation. Testing children in affected families is generally not recommended until age 18 years unless symptomatic.

Other first-degree relatives of C282Y heterozygotes should be tested with iron studies. If these are positive, discuss genetic testing and referral for genetics counselling In Australia, the MBS covers HFE gene testing for patients with: Raised ferritin or transferrin saturation levels on more than 1 occasion; or

First-degree relative diagnosed with HH or with two HFE mutations. Neurofibromatosis (NF)

Patients with:

NF1: multiple café au lait spots,

inguinal/axillary freckling

multiple neurofibromas NF2: bilateral vestibular schwannomas;

gradual hearing loss,

balance problems

tinnitus Genetic testing NF1

Not necessary for diagnosis after birth

Prenatal genetic testing possible only when the family specific gene mutation is known

Genetic testing NF2

Pre-symptomatic genetic testing is available to blood relatives of individuals in whom a mutation has been identified. Autosomal dominant pattern of inheritance

50% of cases due to sporadic mutation Skin cancer increased risk family history of melanoma in first-degree relative

fair complexion

a tendency to burn rather than tan

presence of freckles, light eye colour, light or red hair colour

age >30 years (>50 years most at risk)

presence of solar lentigines

past history of non melanoma skin cancers (age <40 years higher risk)

people with childhood high levels of ultraviolet exposure

episodes of sunburn in childhood Annual skin examination

Advice on self examination Genetic testing in research phase Skin cancer – high risk multiple atypical or dysplastic naevi and who have a history of melanoma in themselves or in a first degree relative Preventive advice,

Examination of skin (with or without photography)

Advice on self examination Review every 3–12 months Prostate cancer – high risk Men with one or more first-degree relatives diagnosed under age 65 years

Men with a first-degree relative with familial breast cancer (BRCA1 or BRCA2) Respond to requests for screening by informing patients of risks and benefits of screening Note that routine screening of the general population for prostate cancer is not recommended28 unless: the man specifically asks for it; and

he is fully counselled on the pros and cons Breast cancer – moderately increased risk One first-degree relative diagnosed with breast cancer before the age of 50 (without the additional features of the potentially high-risk group)

Two first-degree relatives, on the same side of the family, diagnosed with breast cancer (without the additional features of the potentially high-risk group)

Two second-degree relatives, on the same side of the family, diagnosed with breast cancer, at least one before age 50 years (without the additional features of the potentially high-risk group) Clarify risk at http://canceraustralia.gov.au/clinical-best-practice/ gynaecological-cancers/familial-risk-assessment-fra-boc

Breast awareness

Consider referral to or consultation with a family cancer clinic for further assessment and management

Mammogram at least every 2 years from age 50–69 years

Annual mammograms from age 40 may be recommended if the woman has a first-degree relative <age 50 years diagnosed with breast cancer In this increased risk group the relative risk of breast cancer up to age 75 years is between 1:8 and 1:4. (<4% of the female population)



Note that for routine screening in the general population mammography is recommended every 2 years for women 50–69 years old Breast cancer – potentially high risk Women who are at potentially high risk of ovarian cancer

Two first- or second-degree relatives on one side of the family diagnosed with breast or ovarian cancer plus one or more of the following features on the same side of the family:

additional relative(s) with breast or ovarian cancer

breast cancer diagnosed before age 40 years

bilateral breast cancer

breast and ovarian cancer in the same woman

Ashkenazi Jewish ancestry

breast cancer in a male relative.

One first or second degree relative diagnosed with breast cancer at age 45 years or younger plus another first or second degree relative on the same side of the family with sarcoma (bone/soft tissue) at age 45 years or younger

Member of a family in which the presence of a high-risk breast cancer gene mutation has been established Clarify risk at www. nbocc.org.au/fraboc

Advise referral to a cancer specialist or family cancer clinic for risk assessment, possible genetic testing and management

Ongoing surveillance strategies may include regular clinical breast examination, breast imaging with mammography, magnetic resonance imaging (MRI) or ultrasound and consideration of ovarian cancer risk In this group, the relative risk of breast cancer up to age 75 years is between 1:8 and 1:4. (<1% of the female population) Ovarian cancer – higher risk

Family history of ovarian cancer, especially first-degree relatives and more than one relative (risk of about 3 times the population average)

Presence of the breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) Based on current evidence no screening is recommended



Consider increased frequency of screening for breast and colorectal cancer in higher risk groups Routinely screening for ovarian cancer using blood tests for cancer antigen (CA) 125, or transabdominal or transvaginal ultrasound provides no benefit.



Note that those who have used the oral contraception, or carried a pregnancy to term have a lower (about half) the risk of the population average. Colorectal cancer (CRC) category 1: average or slightly increased riskAsymptomatic people with: no personal history of bowel cancer, colorectal adenomas or ulcerative colitis and no confirmed family history of CRC, or one first- or second-degree relative with CRC diagnosed at age 55 years or older FOBT every 2 years from 50 years of age CRC category 2: moderately increased riskAsymptomatic people with: one first-degree relative with CRC diagnosed before age 55 years, or two first-degree or one first- and one second degree relative/s on the same side of the family with CRC diagnosed at any age (without potentially high-risk features as in Category 3) Colonoscopy every 5 years from age 50 years, or at an age 10 years younger than the age of first diagnosis of CRC in the family, whichever comes first

Sigmoidoscopy plus double-contrast barium enema or

CT colonography (performed by an experienced operator) is acceptable if colonoscopy is contraindicated

Consider offering FOBT This group comprises about 1–2% of the population CRC category 3: High riskAsymptomatic people with: three or more first- or second-degree relatives on the same side of the family diagnosed with colorectal cancer (suspected Lynch syndrome, also known as hereditary non-polyposis CRC or HNPCC) or other Lynch syndrome-related cancers or two or more first- or second-degree relatives on the same side of the family diagnosed with CRC including any of the following high-risk features; multiple CRC in the one person CRC before age 50 years a family member who has or had Lynch syndrome-related cancer

or at least one first or second degree relative with CRC, with a large number of adenomas throughout the large bowel (suspected familial adenomatous polyposis (FAP)) or somebody in the family in whom the presence of a high risk mutation in the adenomatous polyposis coli (APC) or one of the mismatch repair genes has been identified Refer to bowel cancer specialist to plan appropriate surveillance

Refer for genetic screening of affected relatives

FAP: flexible sigmoidoscopy or Colonoscopy in attenuated FAP

Recommended screening schedules are as follows;

Familial adenomatous polyposis (APC mutation status unknown): every 12 months from age 12–15 years to age 30–35 years and every 3 years after age 35 years

Lynch syndrome: 1–2 yearly from age 25 years or 5 years earlier than the youngest affected member of the family (whichever is earliest). Aspirin 100 mg/day is effective prophylaxis31 This group with a relative risk of 4–20, make up <1% of the population

Note that members of proven FAP and Lynch syndrome families who are shown not to carry the family mutation are no longer at high risk and revert to the average-risk group and still require population based screening. Type 2 diabetes – increased risk Age >40 years

Aboriginal and Torres Strait Islander peoples AUSDRISK every 3 years Diabetes risk may be calculated using AUSDRISK.28 This calculates a score related to the risk of developing diabetes over a 5-year period Type 2 diabetes – high risk

Any one of following risk factors: AUSDRISK score of 12 or more

all people with a history of a previous cardiovascular event (acute myocardial infarction or stroke)

women with a history of gestational diabetes mellitus

women with polycystic ovary syndrome

patients on antipsychotic drugs Fasting blood sugar every 3 years Familial hypercholesterolaemia Premature ischaemic heart disease (men aged <55 years, women aged <60 years)

First-degree relative with premature ischaemic heart disease (men aged <55 years, women aged <60 years)

Total cholesterol >7.5 or LDL-C >4.9

First-degree relative with a total cholesterol >7.5 or LDL-C >4.9

Tendon xanthomata or arcus cornealis at age <45 years Genetic testing is available through specialist cardiac or Genetics Services Assess their probability of having family history using the Dutch Lipid Clinic Network criteria or Modified UK Simon Broome criteria (28)



Offer referral to a lipid disorders clinic if DLCN score >3 or the MUKSB suggests a possible family history Fragile X and other causes of developmental delay

Children or adults of either sex with one or more of the following features: developmental delay including intellectual disability of unknown cause

autistic-like features

attention deficit hyperactivity disorder

speech and language problems

social and emotional problems, such as aggression or shyness

a female with a history of primary ovarian insufficiency or premature menopause (age <40 years)

adults with ataxia, balance problems and Parkinsonism

a relative with a fragile X mutation Chromosomal analysis (chromosomal array or karyotype if array not available) and DNA test for fragile X syndrome (available on the MBS) in children and adults.

Refer to Genetics Services for cascade testing of relatives There is no known single gene that causes autism; genetic testing is not currently available.

Diagnosis of Fragile X Syndrome can be made at any age. GPs ought to be aware of the risk of adult-onset conditions for carriers of Fragile X syndrome – Fragile X associated tremor ataxia (more so in males than females) and primary ovarian insufficiency in females – which can have a wide-ranging impact, not just on the child with Fragile X syndrome Hereditary thrombophilias DVT <50 yrs

Spontaneous thrombosis in absence of recognised risk factors

Recurrent thrombosis

Family history of thrombosis

Thrombosis in unusual sites e.g. CNS, abdominal veins, upper limb

Stillbirth or fetal death in utero Consider screening for thrombophilia A thrombophilia screen (factor V Leiden, prothrombin variants, antithrombin III deficiency, protein C deficiency, protein S deficiency and activated protein C resistance) is available on the MBS only if the patient has: A personal history of proven venous thromboembolism or pulmonary embolism, or

A 1˚ relative who has a proven defect of any of the above Carrier screening for haemoglobinopathiesPeople have increased risk if have ancestry/ethnic background from; Southern European, African (including Americas and Caribbean), Middle Eastern, Chinese, Indian subcontinent, Central and South East Asian, Pacific Islander, New Zealand Maori, South American and some northern Western Australian and Northern Territory Indigenous communities Mean corpuscular volume, mean corpuscular haemoglobin, ferritin, haemoglobin electrophoresis and iron levels



Seek advice from haematology or genetic services about DNA testing especially for alpha-thalassaemia carriers Test couple prior to pregnancy or in first trimester Adapted with permission from from Barlow-Stewart, K., et al. (2007). Genetics at a Glance, The Australian Government Agency, Biotechnology Australia: 1-6.

# Many of the recommendations have been sourced from The Red Book- Guidelines for preventive activities in general practice, 8th edition, East Melbourne: Royal Australian College of General Practitioners, 2012.

Case 1. Breast cancer risk

A woman aged 25 years comes in for her routine Pap smear in a country town in rural Western Australia. In discussion with the GP she mentions that two of her aunts, her father’s sisters, had breast cancer at the ages of 38 and 42 years respectively. She wonders if it is actually possible ‘to get the cancer gene through her dad’s side’. She is otherwise well and healthy and is wondering if she should be having some further tests to see if she has an increased risk of breast cancer. The GP explains that it is indeed possible to have increased breast cancer risk through the paternal side of the family and that her family history puts her in a potentially high risk category for breast cancer. Given her complex history, the GP suggests referral to a familial cancer clinic or genetics service to further explore her risk of breast cancer.

Case 2. Thrombophilia

Jane is a 32 years of age and goes to the GP complaining of a left lower leg pain, which seems to have come on spontaneously. The GP examines her and notices that the calf is warm and tender and suspects a deep venous thrombosis (DVT), which is confirmed on Doppler ultrasound later that day. Looking back through Jane’s medical history on the medical software summary, the GP also notices that Jane had an unexplained late miscarriage at the age of 28 years. On further questioning about her family, Jane explains that her father had an unusual arm thrombosis during his university days and spent some time in hospital on a blood thinning medication. The GP suggests that although the immediate issue is to manage the DVT, it would be a good idea to be screened for thrombophilia.

Case 3. Fragile X syndrome

Justin is 5 years of age and is brought in by his mother Cynthia for a routine vaccination. During the consultation, Cynthia explains that Justin has been having a very hard time since starting school, struggling to keep up with the other children. Indeed, the teacher has raised the possibility of a learning disability. Cynthia also mentions that her 8-year-old daughter is only just coping at school as she is very shy and finds mathematics really challenging. The GP is aware that Cynthia has recently had her intrauterine device removed and is planning to have a third child. The family is well known to the GP, who is aware that Cynthia’s father, Michael, has a recent history of intention tremor of the hands, two recent unexplained falls, and had been referred to a neurologist. The GP explains that it would be a good idea to get Justin assessed by a paediatrician in the first instance, and advises that it might be worthwhile for Cynthia and her husband to come and have a chat about their plans to get pregnant again, and consider seeing a genetics counsellor. The GP also makes a note to book an appointment for Michael, to discuss the possibility of fragile X tremor ataxia syndrome (FXTAS), which is a possible explanation for his neurological presentation.

Genetic services in Australia

There are state- and territory-based clinical genetics services throughout Australia. These services provide specialist risk assessment, diagnosis, testing and counselling services, which might include outreach services in some regions. Familial cancer and prenatal testing services may be offered through these clinics or through separate specialist centres. GPs can refer patients directly to clinical genetics services or may wish to contact the service themselves first to discuss genetic issues, risk assessment and management.

A recent phenomenon for GPs to be aware of is the marketing of direct-to-consumer genetic testing (also known as genetic profiling). A number of companies have been offering testing where the consumer mails in a sample, for example a saliva sample, and receives a detailed report outlining their personal genetic risks for a long list of diseases. At this stage, however, the accuracy and interpretation of these reports is uncertain and the NHMRC has warned consumers to carefully consider the unintended consequences for insurance, privacy and emotional health from such tests.28 Direct-to-consumer genetic testing is dealt with in more detail in a separate article in this edition of AFP.29

Over time genome-wide sequencing will become increasingly available for patients with suspected genetic conditions, but as yet this is not offered routinely in diagnostics. This type of sequencing uses technology known as ‘next generation’ or ‘massively parallel’ sequencing, which involves very fast, high-throughput sequencing of DNA fragments generating millions of ‘reads’. Using this technology it is possible to sequence a panel of selected or targeted genes, whole exomes (all of the protein coding sequences in a genome) or whole genomes (the entire 6 billion base pairs of DNA in a person’s 46 chromosomes), at much reduced costs, compared with sequencing each gene separately. Note that the new noninvasive prenatal tests (NIPT) now available for prenatal screening are based on this technology. However, one of the challenges associated with these genome-wide technologies is interpreting the enormous amount of information generated, particularly when the sequence variants identified are not clearly pathogenic, a challenge already faced with the introduction of chromosomal microarrays.30 It remains to be seen how this new sequencing technology will become integrated into diagnostics and influence GP practice but, given the pace at which these technologies develop and how quickly they can enter healthcare (such as has happened with chromosomal microarrays and NIPT), GPs need to be aware of these developments.

Conclusion

Genetic testing offers patients the opportunity to better understand their health risks. At the same time the sensitive new information that can be obtained from genetic testing has broad implications for emotional wellbeing, privacy and insurance. The GP can assist patients by being informed about the genetic testing that is available and being alert for clinical scenarios where genetic testing may be appropriate. As with other fields in primary healthcare, GPs can work with specialist health professionals such as geneticists and genetics counsellors to ensure patients receive the best advice and care.

Competing interests: None.

Provenance and peer review: Commissioned, externally peer reviewed.

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Correspondence afp@racgp.org.au