Incidental findings: current opinions of professionals and patients

Last update: April 12, 2016

What are incidental findings?

indian female doctor and patientThe more exome and genome sequencing spread, the more the ascertainment and return of incidental findings becomes of crucial importance and ethical relevance. Incidental findings which are sometimes referred to as “secondary” findings or more common among researchers “incidentalome”, are defined as the counterpoint to the primarily sought after diagnostic results or as additional findings unrelated to the primary test indication. In other words, patients undergoing clinical exome or genome sequencing to find the causative mutation of their disorder or to participate in a research study may be discovered to harbour a disease-causing mutation for an unrelated/unexpected condition. The scientific and medical community has long discussed about this multifaceted topic, not rarely falling into controversy.

Of note, despite that incidental findings are widespread all over the genome, they must be actively sought after to be detected, requiring an extra load of work and affecting turnaround times and test costs.

Current guidelines of the ACMG

The milestone publication on the reporting of incidental findings is the 2013 paper “ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing” released by the American College of Medical Genetics (PMID: 23788249). These recommendations point to a list of 56 genes of which mutations are associated with severe and highly penetrant yet medically actionable conditions. For these genes the ACMG recommends reporting pathogenic and likely pathogenic mutations, but not variants of uncertain clinical significance. It is estimated that the likelihood for any individual undergoing clinical exome or genome sequencing to be found carrier of a medically actionable mutation is about 1-3%.

The right to know and not to know

A crucial aspect of the reporting of incidental findings is surely the right of the patient to know but also not to know. In fact most genetic clinics luckily adopt a patient-centered vision about the reporting of incidental findings. Some clinics have also developed articulated incidental-specific consent forms, where the patient can pick and choose just some diseases/conditions, leaving out all the others.

Carrier status and non-actionable variants

Further evolutions of the SOPs (Standard Operating Procedures) on the reporting of incidental findings, which may be general or just study-specific, may regard the reporting about the carrier status for a list of autosomal recessively inherited disorders (e.g. cystic fibrosis, cystinuria, hearing loss, etc.) or the reporting of non-actionable variants. Whereas the first may be well accepted and welcomed by the patient, the latter is actually not recommended by the good medical practice.

The patients’ point of view

It is interesting to shed some light on the preferences of the patients, who may often opt for “knowing everything” when not appropriately counselled. A good counselling on each and every clinical condition included in the list of possible incidental findings may take up to several hours, so professionals have agreed on a more streamlined approach, considering appropriate to spend no more than 30 minutes on incidental findings. It is interesting to highlight how the patients consent may considerably change after having received good counselling. In particular for medically non-actionable variants, only a minority of fully informed patients choose to have them. Other interesting aspects may concern the patient’s cultural/spiritual background. For example, when coming to the carrier status for certain recessive diseases which may be transmitted to the progeny, some patients may oppose issues of religious beliefs, which would prevent them from acting based on the results of incidental findings (pregnancy planning/contraceptive measures).

Common patient misconceptions

Overall, it is important to give the probands adequate explanations about the following sensitive issues, which may bias the patient’s perception and choices about incidental findings:

Opting-in or opting-out of incidental findings will not affect the sensibility and sensitivity of the test in regard to its primary clinical indication; i.e.: reporting or not reporting incidental findings won’t affect the diagnostic yield of the test.

– Incidental findings may also be available later in time, so it is not necessary to make a decision immediately.

– The patient may choose which incidental findings may be reported and which not.

Pleiotropy

There’s another aspect that professionals should take into account when providing the patients with counselling on incidental findings: the concept of a single gene or variant associating to multiple phenotypes. Such phenomenon is known as pleiotropy. Some examples: mutations in the BRCA1 and BRCA2 gene can increase susceptibility not only to breast-ovarian cancer, but also to a multitude of other cancer types; mutations in the PAH gene may cause phenylketonuria, eczema, light pigmentation, or even mental retardation; CFTR mutations may cause from cystic fibrosis to azoospermia.

Breda Genetics srl standing point on incidental findings

Breda Genetics has decided to stick to ACMG guidelines on the reporting of incidental findings, giving in parallel a big emphasis to the right of the patient to know or not to know. Particularly for patients of minor age we never report incidental findings about conditions with late onset and for which no therapeutic/preventative option of proved efficacy is available. We don’t report non-medically actionable variants. As an exception to the ACMG guidelines, we may occasionally decide to report about variants of uncertain significance whenever we think this might be of significant relevance for the patient. At Breda Genetics we also positively rate the possibility for the patient to choose for which conditions they want to receive incidental findings.

References: PMID: 26566463, 26478737, 24481117, 23788249

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