Resources: DNA in medicine and research

Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation  BMJ (2021) 372 https://www.bmj.com/content/372/bmj.n214 (Open access) 

A new study from the University of Exeter College of Medicine and Health, UK has found that common genetic screening methods used in commercial DNA kits and research projects are “extremely poor” at correctly detecting rare genetic variants linked to diseases such as breast and ovarian cancer. For an individual person, they conclude that “such screening methods are more likely to be wrong than right”. 

The researchers recommend that such screening methods, called ‘SNP chips’, are not relied upon by doctors, and instead, that such test results be validated with standard diagnostic methods. The use of ‘SNP chip’ data has implications for healthcare, as people are being increasingly screened for rare disease variants via consumer tests, for which they seek medical advice and medical interventions. Some research projects may also return results from SNP chips to research participants, or are considering doing so in future.  If people are given incorrect results based on a ‘SNP chip’ alone, this could be very serious. For example, many women have surgery to remove their breasts and/or ovaries if they believe they have a mutation in the BRCA1 or BRCA2 gene that gives them a high risk of developing breast or ovarian cancer.

Direct-to-consumer tests usually do not sequence the whole genome. Instead, they typically use ‘SNP-chip’ genotyping methods, which check for the presence or absence of specific small genetic variants, e.g. single nucleotide polymorphisms (SNPs) or small deletions or insertions.  These methods were originally developed to look at common genetic variation in human populations, but are now being increasingly developed to detect rare genetic variants in people, despite the difficulties in accurately screening for rare variants with such techniques. This is because with very rare variants where they may be only a single or handful of carriers, they become difficult to distinguish over the background experimental noise of reference data sets from the wider population. 

In order to perform a systematic evaluation of the accuracy of SNP chip methods in detecting rare genetic variants, researchers compared more accurate sequencing data of almost 50,000 DNA samples from the UK Biobank project with ‘SNP chip’ data. They also analysed SNP chip data sets from 21 direct-to-consumer test participants. 

Of the 21 data sets from consumer tests, 100 % of all known disease-causing or risk enhancing single nucleotide polymorphisms (SNPs) were incorrect when compared with the actual sequence data. 74 % of small known disease-causing deletions or insertions  were also incorrect. Moreover, 20 of the 21 people investigated had at least one false positive result for a rare disease variant when compared with sequencing – meaning that these people were told that they had a problem that they do not have. 

Of the 49,908 UK biobank participants data, similarly low levels of correct genotyping were observed. This part of the study looked at rare mutations in the BRCA1 and BRCA2 genes, that increase a person’s risk of breast and/or ovarian cancer. The researchers compared the results of sequencing with two different SNP chips. Across both SNP chips, 425 BRCA variants thought to increase cancer risk were detected in 889 UK Biobank participants. Of these, just 17 variants in 37 participants were present in the sequencing data, and the others were false positives – meaning they identified a problem that did not exist. Even the most common true positive (present in 10 participants) had conflicting and uncertain interpretations. A further 43 BRCA variants associated with increased cancer risk were present in the sequencing data of 70 participants but were not detected by either SNP chip, meaning that these people’s increased risk of cancer would not have been identified. The authors concluded that the performance of both chips for genotyping BRCA variants was very poor.

How to design a national genomic project—a systematic review of active projects Human Genomics (2021) 15:20 https://humgenomics.biomedcentral.com/articles/10.1186/s40246-021-00315-6 (open access)

This study provides a summary of various genomic research projects being undertaken in countries across the globe. They identify 41 national projects that are currently active. The major aims of these projects vary, but they also share some common goals including attempting to determine the genetic variation that exists in healthy individuals, searching  for disease-susceptibility variants, increasing the required infrastructure for future research and translation to the clinic, as well as enabling the idea of personalised medicine. 

The study raises some challenges of these projects, including in understanding genetic variation in the healthy population, due to the difficulties in defining who is healthy at any given time point, with implications determining which variants increase risk of disease.

Projects vary in scope, with Estonia for example, planning to sequence over 30 % of the population, while others are focusing on many fewer people. The design of projects was also observed to be influenced by whether or not projects are privately or publicly funded, resulting in different priorities with regard to what diseases are assessed, and the scope of assessment. Differences in data sharing are also apparent, with some making data available to commercial companies, while others do not. Most projects are however, committed to some form of data sharing with researchers and the public.

Opportunistic genomic screening. Recommendations of the European Society of Human GeneticsEuropean Journal of Human Genetics (2021) 29:365–377 https://www.nature.com/articles/s41431-020-00758-w (open access)

The European Society of Human Genetics has published recommendations on the use of genomic screening to look for genetic variants that are unrelated to the original health problem being assessed in a patient. This additional form of screening, called ‘opportunistic genomic screening’, is being suggested for roll out as part of genomics services that are in the midst of expansion in various countries, including in the US, France and the UK. This means that screening for completely unrelated disorders to the health problem being assessed for, may form part of routine healthcare approaches. 

The Society argues that a cautious approach should be applied to any form of opportunistic screening, suggesting that pilot programs could be used to compare any potential benefits to other, more cost effective alternatives such as cascade testing, where family members of someone carrying a disease-causing mutation are also offered screening. 

Their cautious approach is based on a number of ethical and health complexities raised by opportunistic genomic screening. Moving from the original genetic test for a specified health problem, to screening programs as part of an ‘active search’ for other unrelated genetic variants comes with both risks and benefits, and thus careful analysis is needed to ensure it is a proportional intervention. While genetic variants may be found that could be mitigated by medical interventions, risks can also arise from insufficient evidence regarding the health impact of a genetic variant. The interpretation of variants in unaffected people is hindered by the lack of validation of such tests at the population level when a family history of disease is lacking. The society thus recommends any screening to prioritise only well known, and highly penetrant genetic risk factors. Further, additional psychological burdens would be associated with an unfavourable test result, which would also raise costs in the form of required genetic counselling, if such services were to become routine. Identifying genetic ‘risk’ factors also has the potential for turning everyone who gets opportunistic screening  into a “patient-in-waiting”, affecting people’s ability to get a job or a form of insurance, especially in nations with privatised healthcare systems.

Proposals to “opt-out” of opportunistic screening, rather than “opting in”, would also challenge the human right to fully informed consent over the access and handling of personal genetic data. Such a procedure would go against the norm for patient screening programs, which usually require the full and explicit consent of those being offered the tests. People should have also the right to decline information, or restrict the types of testing being performed. It is possible that someone may want to know about certain genetic variants but not others. Consent issues are further exacerbated by the increasing merging of health and research programs that may violate respect for autonomy. For example, if someone was offered a combined research and healthcare screening package, they may feel coerced into offering access for research in order to gain healthcare information. The society recommends that informed consent should be central to any such screening programs. A wider debate is also recommended, to prevent patients being reduced into objects of well-intentioned medical deliberations and interventions.  

Finally, with regard to children, the society recommends a highly cautious approach that restricts screening to childhood diseases that are fully ‘actionable’, i.e. can be properly treated or prevented whilst still in childhood. Proposals to routinely perform pre-natal sequencing, or sequencing of new-borns, requires urgent debate with regard to such programs. 


LawSeq. Mapping and Shaping the Law of Genomics: https://lawseq.umn.edu