Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?

Jamuar, Saumya Shekhar; Kuan, Jyn Ling; Brett, Maggie; Tiang, Zenia; Tan, Wilson Lek Wen; Lim, Jiin Ying; Liew, Wendy; Javed, Asif; Liew, Woei Kang; Law, Hai Yang; Tan, Ee Shien; Lai, Angeline; Ng, Ivy; Teo, Yik Ying; Venkatesh, Byrappa; Reversade, Bruno; Tan, Ene Choo; Foo, Roger

doi:10.1016/j.ebiom.2016.01.030

Cited by 25 publications

(37 citation statements)

References 43 publications

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“…To foster such discussions, knowledge on the prevalence of secondary findings in medically actionable genes in the general population is required. Recently, multiple studies have reported frequencies of secondary findings ranging from 1 to 9% in various populations [5][6][7][8][9][10][11][12][13]. This broad range of reported frequencies is largely explained by the cohorts tested (e.g., inclusion of individuals more prone to have a pathogenic variant) in combination with differences in sequence technology (e.g., whole-exome sequencing (WES) of inferior quality), classification of variants, and amount of genes for which pathogenic variants are taken into account.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…The prevalence of ACMG cancer gene LP/P variants in our increased FH risk group was also considerably higher than other reported studies that assessed the presence of pathogenic variants in the 59 ACMG gene list of unselected populations ranging from 1.5% 27 to 2.7% 7 and 1.6% in an ethnically similar cohort. 28 Large scale population screening programs have been initiated globally to optimise the utility of genomic data. The analysis of genomic data has unquestionably led to a greater understanding of the genetic basis of health and disease.…”

Section: Discussionmentioning

confidence: 99%

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

Bylstra

Lim²,

Kam

et al. 2020

Preprint

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Background Family history has traditionally been an essential part of clinical care to assess health risks.However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs, with less emphasis on family history assessment. We evaluated the utility of family history for genomic sequencing selection. MethodsWe analysed whole genome sequences of 1750 healthy research participants, with and without preselection based on standardised family history collection, screening 95 cancer genes. ResultsThe frequency of likely pathogenic/ pathogenic (LP/P) variants in 884 participants with no family history available (FH not available group) (2%) versus 866 participants with family history available (FH available group) (3.1%) was not significant (p=0.158). However, within the FH available group, amongst 73 participants with an increased family history cancer risk (increased FH risk), 1 in 7 participants carried a LP/P variant inferring a six-fold increase compared with 1 in 47 participants assessed at average family history cancer risk (average FH risk) and a seven-fold increase compared to the FH not available group.The enrichment was further pronounced (up to 18-fold) when assessing the 25 cancer genes in the ACMG 59-gene panel. Furthermore, 63 participants had an increased family history cancer risk in absence of an apparent LP/P variant. ConclusionOur findings show that systematic family history collection remains critical for health risk assessment, providing important actionable data and augmenting the yield from genomic data. Family history also highlights the potential impact of additional hereditary, environmental and behavioural influences not reflected by genomic sequencing.

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“…Accuracy of the finding from GWASs needs to be replicated and confirmed. This is partly due to high prevalence of incidental findings or incidentalome, referring to identifying variants in genes that are unrelated to the patient's primary condition (Brothers et al, 2013;Jamuar et al, 2016).…”

Section: Looking Ahead and Future Perspectivesmentioning

confidence: 99%

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

Petros

Makonnen

Aklillu

2017

OMICS: A Journal of Integrative Biology

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Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 b-galactosamide a-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

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Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?

Cited by 25 publications

References 43 publications

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

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

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

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

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