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Clinical guidelines

Guidelines for preventive activities in general practice 9th edition

2. Genetic counselling and testing

Age 0-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-79 > 80

Genetic testing can be used for various purposes, from preconception planning (refer to Chapter 1. Preventive activities prior to pregnancy), during pregnancy, for neonates (newborn screening), during childhood and right through to adult-onset familial diseases (eg cancer, cardiac and neurodegenerative diseases).

In order to identify patients who may be at risk of a genetic disorder, a comprehensive family history must be taken from all patients, and this should be regularly updated. A family history should include first-degree and second-degree relatives on both sides of the family and ethnic background. Age of onset of disease and age of death should be recorded where available.

Increased frequency and early onset of cancers in families, premature ischaemic heart disease or sudden cardiac death, intellectual disability, multiple pregnancy losses, stillbirth or early death, and children with congenital abnormalities may suggest the presence of genetically determined disease. Patients of particular ethnic backgrounds may be at increased risk and may benefit from genetic testing for specific conditions. Possible consanguinity (eg cousins married to each other) should be explored, for example, by asking, ‘Is there any chance that a relative of yours might be related to someone in your partner’s family?’ General Practitioners (GPs) should consider referral to, or consultation with, a genetic service (general or cancer genetics) for testing because test results, which rely on sensitivity, specificity and positive predictive value, are not straightforward. Testing often involves complex ethical, social and legal issues. The time on waiting lists for genetic services is usually longer than one month, so direct consultation and liaison by telephone are necessary when the genetic advice could affect a current pregnancy. On the basis of current evidence, whole genome sequencing is not recommended in low-risk general practice populations (refer to Chapter 15. Screening tests of unproven benefit).

Clinical genetic services provide testing, diagnosis, management and counselling for a wide range of genetic conditions. Reasons for referral include:

  • diagnosis of a genetic condition
  • family history of a genetic condition
  • recurrence risk counselling (eg risk of recurrence in a future pregnancy)
  • pregnancy counselling (eg preconception, consanguinity)
  • prenatal screening and testing
  • presymptomatic and predictive testing for adult-onset disorders (eg cancer)
  • discussions surrounding genetic testing
  • arranging of genetic testing.

Services such as paternity testing or genetic testing/management of very common genetic conditions (eg haemochromatosis) are not provided by clinical genetic services.

Use of a simple family history screening questionnaire (FHSQ) can help identify individuals who may require a more detailed assessment of their family history of cancer, heart disease or diabetes (refer to Appendix 2A. Family history screening questionnaire for a published and validated FHSQ).1 This tool can be used as part of the patient assessment at their first visit to a practice. If a patient is uncertain about their family history, they can be asked to discuss the FHSQ with their relatives prior to completing the questionnaire. For patients with low literacy, the FHSQ may need to be completed with the support of a healthcare professional. A positive response to any question requires follow-up with a more detailed assessment of the family history. As family history can change, it is recommended that the FHSQ be repeated at least every years.

Table 2.1. Genetic testing: Identifying risks
Who is at risk?What should be done?How often?
Cystic fibrosis (CF)
Increased probability:
  • Northern European or Ashkenazi Jewish ancestry
  • Family history of CF or a relative with a known CF mutation
  • Where partner is affected or a known carrier of CF
  • Partners from Northern European or Ashkenazi Jewish backgrounds who are consanguineous (eg cousins married to each other)
  • Men with infertility suspected or due to congenital absence of the vas deferens
Offer referral for genetic counselling and carrier testing (III, B) 2–5

If patient is pregnant, contact genetic services to organise screening in first trimester
Test couple for carrier status if planning pregnancy or in first trimester
Down syndrome
Probability:
  • All pregnant women
Combined maternal serum and ultrasound screening in first trimester* 3, 6–11

Maternal serum screening in second trimester† (C)

Non-invasive prenatal test (NIPT)‡
First or second trimester
Significantly increased probability:
  • Women who had a previous Down syndrome pregnancy
  • Women with positive maternal serum screening/nuchal translucency ultrasound, NIPT in first trimester or maternal serum screening in second trimester
  • Parent with a chromosomal rearrangement (eg balanced translocation of chromosome 21)
Fetal diagnostic genetic testing (C) 10

Offer referral for genetic counselling
First or second trimester
Fragile X syndrome
Increased probability

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 (ADHD)
  • speech and language problems
  • social and emotional problems, such as aggression or shyness
  • relative with a fragile X mutation
Deoxyribonucleic acid (DNA) test for fragile X and karyotype/comparative genomic hybridisation by microarray for other possible causes of developmental delay 3, 12, 13

Refer to genetic services for genetic counselling and testing at-risk family (I, A)
Any age for diagnosis

Prior to pregnancy to ascertain carrier status and reproductive risk
  • a female with a history of primary ovarian insufficiency or premature menopause (aged <40 years) 14–16
(IV, B)
  • adults with ataxia, balance problems and parkinsonism 17
(IV, A)
Haemoglobinopathies and thalassaemias
Increased probability
  • People from any of the following ethnic backgrounds: Southern European, African, Middle Eastern, Chinese, Indian subcontinent, Central and South-east Asian, Pacific Islander, New Zealand Maori, South American, Caribbean, and some northern Western Australian and Northern Territory Aboriginal and Torres Strait Islander communities
Test for mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and ferritin 3, 18–20

Haemoglobin electrophoresis (III, B)

Blood for deoxyribonucleic acid (DNA) studies

Arrange partner testing if: MCV ≤80 fL and/or MCH ≤27 pg and/or abnormal haemoglobin (Hb) electrophoresis
Test couple for carrier status prior to pregnancy or in first trimester
Breast and ovarian cancer
Refer to Section 9.3. Breast cancer
Colon cancer
Refer to Section 9.2. Colorectal cancer
Familial hypercholesterolaemia (FH)
Increased probability
  • Premature ischaemic heart disease (ie ischaemic heart disease in men aged <55 years and women aged <60 years)
  • First-degree relative with premature ischaemic heart disease (men aged <55 years and women aged <60 years)
  • Total cholesterol >7.5 mmol/L or low density lipoprotein-cholesterol (LDL-C) >4.9 mmol/L
  • First-degree relative with a total cholesterol >7.5 mmol/L or LDL-C >4.9 mmol/L
  • Tendon xanthomata or arcus cornealis at <45 years of age
Assess their probability of having FH using the Dutch Lipid Clinic Network (DLCN) criteria or Modified UK Simon Broome (MUKSB) criteria (III, B) (Appendix 2B. Dutch Lipid Clinic Network Criteria for making a diagnosis of Familial Hypercholestroloaemia in adults) 21, 22

Offer referral to a lipid disorders clinic if DLCN score ≥3 or the MUKSB suggests possible FH
First presentation
Hereditary haemochromatosis (HHC)
Increased probability
  • All first-degree relatives of patients with HHC who are C282Y homozygous or C282Y/H63D compound heterozygous
Positive family history – asymptomatic and symptomatic 9, 23–29

For patients aged >18 years, test for HFE mutations, transferrin saturation and serum ferritin to simultaneously assess future and current risk of iron overload (C). Medicare Benefits Schedule (MBS) rebate applies if affected relative is first-degree relative; no MBS rebate applies for more distant relatives

If HFE mutation tests show C282Y homozygous or C282Y/H63D compound heterozygous result, arrange for all of that patient’s first degree relatives aged >18 years to have tests for HFE mutations and transferrin saturation and serum ferritin (C). MBS rebate applies
Aged >18 years at first presentation

Although abnormalities in transferrin saturation and serum ferritin may occur at <18 years of age in patients with HHC, morbidity from significant iron overload is exceedingly rare before the age of 18 years
Consider in these patients:
  • Patients with conditions that could be a complication of haemochromatosis (eg arthritis, chronic fatigue, erectile dysfunction, early menopause, cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes mellitus)
  • Patients with liver disease of unknown cause, including those with suspected alcoholic liver disease
  • Patients with a family history of haemochromatosis, liver cancer, unexplained early death from liver or heart failure
  • Patients with porphyria cutanea tarda and chondrocalcinosis (‘pseudogout’)
Other patients – asymptomatic and symptomatic

For patients aged >18 years, test transferrin saturation and serum ferritin

If transferrin saturation >45% or serum ferritin >250 µg/L on repeated testing, test for HFE mutations. MBS rebate applies

The ideal sample for testing transferrin saturation and serum ferritin is early morning fasting blood test with iron supplements withheld for 24 hours
*First trimester Down syndrome screening:
  • free beta human chorionic gonadotrophin (HCG), pregnancy associated plasma protein at 10–12 weeks (this also provides risk for trisomy 18 and Edwards syndrome)
  • nuchal translucency screen at 11 weeks, 3 days to 13 weeks, 6 days
  • NIPT‡ from 10 weeks for trisomy 21, 18 and 13; not available for MBS rebate. Tests for fetal DNA in maternal blood
†Second trimester serum screening:
  • beta HCG, unconjugated oestriol, alpha-fetoprotein and inhibin A, ideally at 15–17 weeks; also gives risk for Edward syndrome and neural tube defects (NTDs)
ADHD, attention deficit hyperactivity disorder; CF, cystic fibrosis; DLCN, Dutch Lipid Clinic Network; DNA, deoxyribonucleic acid; FH, familial hypercholesterolaemia; Hb, haemoglobin; HCG, human chorionic gonadotrophin; HHC, hereditary haemochromatosis; LDL-C, low density lipoprotein-cholesterol; MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume; MUKSB, Modified UK Simon Broome; NIPT, non-invasive prenatal test; NTD, neural tube defect

References

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  2. Southern KW, Merelle MM, Dankert-Roelse JE, Nagelkerke AD. Newborn screening for cystic fibrosis. Cochrane Database Syst Rev 2009;1:CD001402.
  3. RANZCOG - College statements and guidelines [Accessed 19 April 2016].
  4. Ioannou L, McClaren BJ, Massie J, et al. Population-based carrier screening for cystic fibrosis: A systematic review of 23 years of research. Genet Med 2014;16(3):207–16.
  5. Delatycki M, Burke J, Christie L, et al. Population based carrier screening for cystic fibrosis. Position statement. Alexandria, New South Wales: Human Genetics Society of Australasia, 2013.
  6. The American College of Obstetricians and Gynecologists Committee on Genetics and The Society for Maternal-Fetal Medicine Publications Committee. Committee opinion no. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol 2012;120(6):1532–34.
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  8. Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370(9):799–808.
  9. Genetics in Family Medicine: Guidebook for General Practitioners [Accessed 15 April 2016].
  10. Facher J, Robin N. Genetic counselling in primary care. What questions are patients likely to ask, and how should they be answered. Postgrad Med 2000;107(3):59–66.
  11. Dick P. Periodic health examination, 1996 update. 1. Prenatal screening for and diagnosis of Down syndrome. Canadian Task Force on the Periodic Health Examination. CMAJ 1996;154(4):465–79.
  12. Cohen J, Lennox N. Fragile X syndrome. In: Lennox N, Diggens J, editors. Management guidelines: People with developmental and intellectual disabilities. Melbourne: Therapeutic Guidelines Limited, 1999.
  13. Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. N Engl J Med 2012;366(8):733–43.
  14. Murray A, Schoemaker MJ, Bennett CE, et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. Genet Med 2014;16(1):19–24.
  15. Laml T, Preyer O, Umek W, Hengstschlager M. Genetic disorders in premature ovarian failure. Hum Reprod Update 2002;8(5):483–91.
  16. Premature and early menopause [Accessed 15 April 2016].
  17. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA. Penetrance of the fragile X–associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291(4):460–69.
  18. Dormandy E, Bryan S, Gulliford MC, et al. Antenatal screening for haemoglobinopathies in primary care: A cohort study and cluster randomised trial to inform a simulation model. The Screening for Haemoglobinopathies in First Trimester (SHIFT) trial. Health Technol Assess 2010;14(20):1–160.
  19. Cunningham F, Bowden D. Suggested protocol for pre-conceptual and antenatal carrier testing for haemoglobinopathies. Clayton, Vic: Monash Medical Centre, 2013.
  20. Pagon RA, Bird TD, Dolan CR, Stephens K AM, editors. GeneReviews. Seattle: University of Washington, 2010.
  21. Sullivan D, Watts G, Hamilton-Craig I, and members of the Cardiovascular Genetic Diseases Writing Group. Guidelines for the diagnosis and management of familial hypercholesterolaemia. Sydney: Cardiac Society of Australia and New Zealand, 2013.
  22. Watts GF, Sullivan DR, Poplawski N, et al. Familial hypercholesterolaemia: A model of care for Australasia. Atheroscler Suppl 2011;12(2):221–63.
  23. Crawford D, Macdonald D. Haemochromatosis. 3rd edn. Mount Waverley, Vic: Digestive Health Foundation and the Gastroenterological Society of Australia, 2007.
  24. Powell LW, Dixon JL, Ramm GA, Purdie DM.
    Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Int Med 2006;166(3):294–303.
  25. Delatycki MB, Powell LW, Allen KJ. Hereditary hemochromatosis genetic testing of at-risk children: What is the appropriate age? Genet Test 2004;8(2):98–103.
  26. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: A systematic review for the US Preventive Services Task Force. Ann Intern Med 2006 Aug 1;145(3):209–23.
  27. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010;53(1):3–22.
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