1 in 38 individuals at risk of a dominant medically actionable disease

Abstract

Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging from 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.

Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

“…The rate of secondary findings in our cohort is 3.4% (2/58), comparable to the rate of previously published as 1.8% to 4.6%. [23][24][25][26]…”

Direct-to-consumer genetic testing with third party interpretation: beware of spurious results

“…Each person has around 100 000 rare genomic variants [5], and working out what they might mean is far from easy. Over 2% of people have a (likely) disease-causing variant in one of the 59 'medically actionable' disease genes which the American College of Medical Genetics and Genomics (ACMG) recommends are opportunistically examined when people have clinical sequencing [22], but the ACMG recently stressed that this gene list was not developed with population screening in mind [23]. Whilst exome and genome sequencing may be highly useful in finding explanations for people affected by rare conditions [24], there is currently limited evidence that this technology would lead to clinical benefit if offered to the population at large [25].…”

Family History Assessment Significantly Enhances Delivery of Precision Medicine in the Genomics Era

“…Several screening programs are initiating genomic sequencing for healthy or unselected populations, irrespective of health status or family history. [3][4][5][6][7][8][9] Amongst these population screening programs there is consensus to return genomic results which are medically significant however there is less concordance regarding which genes fall into this category.…”