Incidental Findings in Genomics

Vienna, Austria: as the cost of genome and exome1 sequencing, its use in characterizing rare diseases and personalizing cancer treatment, for example, is becoming more common. But such analyzes may yield findings unrelated to the condition for which they were requested. What to do with these secondary findings (SFs) or incidental findings (IFs) is problematic. Should they be reported to the patient and under what circumstances? How should clinical geneticists deal with the perhaps unnecessary concerns they may cause?

At the European Society of Human Genetics’ annual conference today (Saturday), Ms. Estela Carrasco, MSc, a PhD student and genetic counselor at Vall d’Hebron Hospital, Barcelona, ​​Spain, will describe how she and her colleagues wanted to look into the prevalence of SF/IFs in cancer susceptibility genes (CSGs) in patients who had undergone exome sequencing for rare diseases unrelated to cancer, and to identify CSGs with potential clinical utility unrelated to the target of the primary analysis. They then evaluated the psychological impact of disclosing SF/IFs to patients and their relatives compared to a cohort tested for their family cancer history. They analyzed exotics from 533 patients studied for non-cancer indications and monitored the psychological impact of disclosing the SF/IFs to these patients two to six months after delivery of the results.

“We found SF/IFs pathogenic (possibly disease-causing) variants in CSGs in 2% of patients who had undergone exome testing for reasons unrelated to cancer predisposition,” said Ms. Carrasco. “This allowed us to perform predictive testing on 42 family members, 18 of whom carried CSGs.”

The psychological impact was greater in those where the variant was identified as an incidental finding, but this must be weighed against the benefit of early detection and the preventive strategies that can be introduced in families who had no previous cancer diagnosis, the researchers say. “While a 2% percentage for SF/IFs may not sound very high, it is remarkable. And genetic counseling can help both communicate the results and help patients and their families adapt to the newly discovered genetic condition,” said Ms. Carrasco.

The researchers plan to continue exploring new ways to deliver genetic testing results to patients; for example, the impact of separating the timing of disclosure of primary findings from secondary findings. “We believe it is reassuring for patients to demonstrate clinical utility of the secondary findings.”

Of the 29 identified carriers (11 index cases and 18 relatives), 20 enrolled for further monitoring. The researchers were able to identify three paragangliomas (a type of neuroendocrine tumor) and one early breast cancer in a 74-year-old woman with a BRCA2 variant who had completed population-based breast cancer screening. A relative in the BRCA2 family with metastatic prostate cancer received target therapy after his BRCA2 status was revealed.

However, special problems arise in children. “The principle of a child’s autonomy can be lost if it is made public before an appropriate age, so healthcare professionals should exercise caution when asking for exome sequencing analysis in minors,” said Ms. Carrasco. “On the other hand, disclosing these results could provide an indirect benefit to these children, as it may enable their relatives to adhere to early detection and prevention programs, thereby preserving their health. To achieve this, it is important to report only clinically useful genes.

“It is important to adequately counsel individuals undergoing exome sequencing, or in the case of children, their parents or caregivers, to ensure that all potential medical applications of genetic testing are understood. And, professionally, in cases where exome sequencing is requested by clinicians who have had little training in providing information about SF/IFs, genetic counselors and clinical geneticists should be part of the multidisciplinary team delivering care.”

Professor Alexandre Reymond, chair of the conference, said: “Unlike radiologists, whose incidental findings mean there is a tumor, geneticists’ incidental discoveries are often predictive in nature. While this should not prevent us from taking action based on a useful finding, it requires dedicated and specifically trained staff to ensure that all information provided to patients and their families is clear, understandable and understood.”

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