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Raising the standards of routine genetic testing

This article discusses how to ensure high quality testing in the fast changing world of genomics

Zandra Deans BSc PhD HCPC

Consultant Clinical Scientist,

Director UK NEQAS for Molecular Genetics,

Department of Laboratory Medicine,

Royal Infirmary of Edinburgh,

Little France Crescent, Edinburgh, UK

There are many factors which make genetic testing different from other routine laboratory tests but most predominately is that patients are usually tested only once in their lifetime. The results may have an impact on future life choices of the individual and affect not just immediate family members, but also more extensively across the generations. Therefore it is critical that the genetic test result is correct.

Genetic testing analyses our inherited genetic material to identify changes in chromosomes, individual genes and can even focus on single nucleotide sequence changes to help diagnose disease. Also, the testing of individuals with a family history of a genetic disorder but no apparent symptoms allows the freedom of choice whether to reinforce the ultimate fate of developing the late onset disease or confirm a disease-free status. Additionally, genetic testing bears an impact on future generations often before birth by giving couples informed choice based on prenatal diagnosis or preimplantation genetic diagnosis. All of these scenarios have considerable influence on life decisions, again stressing the importance of an accurate genetic test result.

Genetic disorders have many causative factors. For example, the inherited monogenic disease, cystic fibrosis is caused by two mutated copies of the cystic fibrosis transmembrane receptor (CFTR) gene being passed to the offspring by the parents.1 These mutations disrupt the structure and thereby the function of the CFTR protein leading to the symptoms in the patient. Other causes of genetic disease are structural and numerical chromosome mutations for example, translocations where regions of chromosomes are rearranged or extra copies of full chromosomes such as three copies of chromosome 21 in Down syndrome patients.2

Specialist knowledge

Genetic testing of inherited disorders is provided by specialist laboratories and in order to detect the scope of genetic errors the laboratories must deliver a wide range of techniques including karyotyping, microarray analysis, DNA sequencing to name only a few. Given that the interpretation of the result plus the knowledge of the disease, such as mode of inheritance and penetrance, is crucial in the accurate reporting of the results, then individuals performing the testing must be highly trained. The increasing rate of implementation of new genetic tests and techniques into laboratories highlights the essential need for ongoing training and competency assessments for staff at all levels to ensure a high standard of service is provided to patients.

Introduction of new technologies

The first generation of the next generation sequencing (NGS) technologies entered our world in the 1990s3 and has continued to evolve ever since. Massive parallel sequencing of whole genomes has moved from expensive one-off tests to being performed in diagnostic genetic laboratories for more reasonable prices. This development of full genome analysis rather than targeted mutation testing will continue to expand and roll out across many more laboratories. As seen previously with the introduction of new technologies, the NGS revolution has created problems within laboratories.

The sensitivity of testing has highlighted the importance of workflow through laboratories to minimise cross contamination of samples at different stages of the testing process. The use of appropriate gene panels and/or tailored analysis pipelines have been developed to address the ethical issues of testing for ‘other’ diseases with no relation to the current symptoms of the patient. A large number of sequence variants can be filtered out by automated calling systems but those variants detected in genes related to the patient’s phenotype, with no clear cut evidence to being the disease causing mutation, requires focused interrogation of the impact of the sequence change on the protein and subsequent interpretation of the pathogenicity of the putative ‘mutation’. All of these factors require a specialised workforce and again emphasises the need for highly trained, skilled individuals to deliver a high standard of genetic testing.


The standard of diagnostic testing has improved due to the requirement of many countries for laboratories to attain accreditation or at the very least certification or licencing. Genetics is no different to other disciplines. The implementation of quality management systems have formalised continual quality monitoring through document control, audits, staff capability checking, internal and external quality control, and error reporting, which helps to deliver and maintain a high standard of service.4

Assay validation

The ISO 15189 standard5 has stringent requirements for test validation and routine verification; therefore laboratories need to source control samples to enable the robust validation of their assays. This is not always easy as many disorders are rare and therefore the number of samples available to validate an assay is not always sufficient. The use of artificial reference material is becoming more widespread and helps to simulate the testing of samples with varying mutation levels so in-house test sensitivities can be determined and the availability of a wide range of mutations allows test specificity to be defined. However, parallel multiple gene testing has added an extra layer of complexity and laboratories are now looking to validate the testing process. This is beneficial as the platform and analysis pipeline can be validated for the set of genes rather than individual genes.

Best practice guidelines

To ensure the laboratory is providing an appropriate service by testing for the correct range of genes and applying the most up to date and relevant interpretation of the result, best practice guidelines are key. Professional bodies and quality assessment schemes facilitate the meeting of colleagues with specialist interests and consensus good practice recommendations are agreed. The fact that these are consensus-based is important to minimise the skewing of the guidance by individuals’ points of view. However, these documents must be reviewed regularly as the field of genetics is continually moving with the advancement of our understanding of the genetic changes which can now be detected.

External quality assessment

To provide laboratories with an external measure of the standard of the genetic testing they offer, participation in external quality assessment (EQA) schemes, also known as proficiency testing, is essential. The assessments involve the distribution of the same samples to all participating laboratories and require the laboratories to test according to their routine protocols and report their results back to the EQA provider. The results are peer assessed (anonymously in order to maintain the impartiality of the scoring) and individual feedback comments are given if required. These comments are based on either best practice guidelines and/or consensus of all the results submitted by all participants for that assessment. This educational element ultimately helps laboratories to remain up to date with recent developments and highlights any testing or interpretative issues that may be present within the laboratory.6–8

Any critical genotyping errors are followed up by the EQA provider and help, advice and support is offered. This can be in the form of reference samples, reporting advice, review of standard operating procedures, whichever is the best approach for the type of error detected. Therefore continual participation in EQA is a safety net for laboratories in that early detection of problems is achievable which minimises the escalation of issues into major problems.

The element that all testing laboratories are receiving the same material to test enables cross laboratory comparisons to be made and laboratories can benchmark the standard of their service against others providing similar tests. Again this promotes a high standard of testing across the genetic testing community. Laboratories acknowledge the benefits of EQA participation and often approach EQA providers for an assessment scheme during the validation process so they can be assured of the standard of their test prior to providing a clinical service.9

Error reporting

It is a widespread belief that we can all learn from mistakes. Mistakes do happen (as evidenced by EQA results and often in the press) and one of the recommendations in the Barnes Quality review in the UK10 was to use the knowledge acquired from reporting errors to help improve standards and prevent similar events reoccurring. A ‘no blame’ policy must be applied to all members of staff to help promote regular reporting of errors and ‘near misses’. Open and transparent investigations into the cause of the problem is an important learning opportunity for all levels of staff and the subsequent implementation of preventative measures help to embed good, or better, practice into the laboratory. The quality of the genetic tests performed is the responsibility of all members of the laboratory. Everyone plays his or her own role in the testing process and even the most minor step, if performed sub-optimally, will affect the quality of the end result reported to the patient.


Genetic testing often has enormous impact on the life decisions of the individual tested. The results can affect family members with unwanted news or with the opportunity to choose whether or not to test their own genetic material or other family members such as their children or unborn offspring. Therefore genetic tests must be performed with high accuracy and appropriateness. The standard of genetic testing is high but must be continually monitored and flaws acted upon in a timely manner to ensure that the developments, such as whole genome sequencing, are delivered as a high quality genetic test. However, this does not rule out the importance of the high standard of routine genetic tests performed daily in the clinical laboratories across the world. It is these tests which ultimately provide the patients with a high standard of genetic testing.


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  3. Brenner S et al. Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays. Nat Biotechnol 2000;18(10):1021.
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  5. International Organization for Standardization – ISO 15189:2012 Medical laboratories – Requirements for quality and competence.
  6. Deans ZC et al. Improvemnet in the quality of molecular analysis of EGFR in non-small cell lung cancer detecetd by three rounds of external quality assessment J Clin Pathol 2013;66(4):319–25.
  7. Deans Z et al. The experience of 3 years of external quality assessment of preimplantation genetic diagnosis for cystic fibrosis. Eur J Hum Genet 2013;21(8):800–6.
  8. Berwouts S et al. Mutation nomenclature in practice: Findings and recommendations from the cystic fibrosis external quality assessment scheme. Human Mutation, 2011;32 (11):1197–1203.
  9. Deans Z et al.  External quality assessment of BRAF molecular analysis in melanoma. J Clin Pathol 2014;67(2):120–4.
  10. Barnes D. Pathology Quality Assurance Review. (accessed 25 March 2015).