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A clinical approach to genetic testing for non-specialists

BMJ 2017; 358 doi: (Published 28 September 2017) Cite this as: BMJ 2017;358:j4101
  1. Christopher Semsarian, professor1 2 3,
  2. Jodie Ingles, researcher1 3
  1. 1Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia
  2. 2Central Clinical School, Sydney Medical School, University of Sydney, Australia
  3. 3Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia;
  1. Correspondence to Chris Semsarian c.semsarian{at}
  • Accepted 8 August 2017

What you need to know

  • Gene tests give probabilistic information to determine whether a variant is disease causing or benign

  • A genetic counsellor is best equipped to convey genetic results to the patient, including explaining all possible genetic outcomes and implications of testing for the family, life insurance, etc

  • There might be secondary genetic findings—ie, a variant considered clinically important which was not the indication for the test. The chance of secondary genetic findings should be discussed during the consent process

A 32 year old mother of two presents to her general practitioner after the sudden death of her previously healthy 29 year old brother. Postmortem examination identified an underlying inherited cardiomyopathy, and subsequent genetic analysis of postmortem DNA found the Arg502Trp variant in the MYBPC3 gene, a common cause of hypertrophic cardiomyopathy.1 Given the familial risk, relatives were advised to seek medical attention. The woman raises questions, including what the disease risk is for herself, her two children, siblings, and parents, what the gene result means, and whether the family should pursue genetic testing. She is concerned about preventing any further sudden deaths in her family. Here we provide an overview of the basic principles of genetic testing and how these can be applied in a general clinical setting.

Genetics revision

Inheritance of traits hails from Mendel’s pea experiments in the 1800s, where he showed that parents contribute an allele each to their offspring, with one “dominating” the other. This principle is the basis of modern medical genetics, where Mendelian diseases are inherited in families as autosomal dominant, recessive, or X linked traits (box 1). Adding to the complexity in humans, we also see incomplete penetrance—ie, the non-expression of a trait, and clinical heterogeneity, where variability in clinical characteristics due to environmental and other genetic factors occurs. While Mendelian inheritance refers to the inheritance of …

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