Incidental findings in genomic testing for diabetes

The benefit of using next generation sequencing (NGS) to provide a single test for all known genetic subtypes for patients with genetically heterogeneous conditions such as MODY is obvious – a faster genetic diagnosis leading to a beneficial change of treatment. But does a “targeted” NGS test have the potential to uncover genetic information that may not be so welcome? The answer is that potentially, yes it does. Genetic analysis of a gene that is known to cause a disease other than the one for which the patient is being tested could reveal additional unexpected information unrelated to the initial clinical question that was being addressed, and is popularly referred to as an ‘incidental finding’.

Most of the genes included in the targeted NGS MODY test have only been linked to diabetes-causing mutations. But there are exceptions. For example the gene panel includes LMNA, a gene in which mutations cause insulin-resistant diabetes due to partial lipodystrophy, but also a range of other phenotypes including Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth disease type 2B, limb girdle muscular dystrophy type 1b, Hutchinson-Gifford Progeria syndrome and dilated cardiomyopathy. What is the likelihood of finding a mutation that predicts risk of one of these phenotypes? Our historical data includes more than 200 patients with partial lipodystrophy in whom the LMNA gene had been analysed by Sanger sequencing and no mutations causing other phenotypes had been identified. This suggests that the likelihood of finding a mutation that predisposes to, for example, dilated cardiomyopathy is low.

Similarly, the targeted NGS MODY test also screens the ABCC8 and KCNJ11 genes, which sometimes contain activating mutations that cause sulphonylurea responsive diabetes. However, this test is equally capable of detecting recessive inactivating ABCC8 and KCNJ11 mutations, unexpectedly revealing the patient’s carrier status for the autosomal recessive condition, congenital hyperinsulinism. The laboratory policy is not to report an incidental finding of carrier status, but to focus solely on the clinical reason for referral.

The very nature of testing the whole exome or genome provides ample opportunity for detecting incidental findings. Indeed, if all 20,000 genes are intentionally analysed then these findings are no longer incidental, but might be better described as “additional” to the primary reason for testing. The risk of incidental or additional findings can be reduced by using testing strategies such as trio sequencing for de novo mutations or looking for mutations in shared genes in a cohort approach (as described earlier this week). When developing a new diagnostic test using next generation sequencing or planning a research strategy to find new genetic aetiologies by exome or genome sequencing it is essential to consider the likelihood of revealing incidental findings and to formulate a policy for reporting. If the plan is to feedback incidental or additional findings then this should be discussed with patients (or their parents) during the consent process.

Whilst there is growing evidence that many patients are keen to receive information about additional, clinically actionable findings, the results of studies such as the 100,000 Genomes Project are eagerly awaited in order to aid the understanding of the overall risks and benefits of receiving such information.