Family history assessment significantly enhances delivery of precision medicine in the genomics era

Yasmin Bylstra, Weng Khong Lim, Sylvia Kam, Koei Wan Tham, R Ryanne Wu, Jing Xian Teo, Sonia Davila, Jyn Ling Kuan, Sock Hoai Chan, Nicolas Bertin, Cheng Xi Yang, Steve Rozen, Bin Tean Teh, Khung Keong Yeo, Stuart Alexander Cook, Saumya Shekhar Jamuar, Geoffrey S Ginsburg, Lori A Orlando, Patrick Tan, Yasmin Bylstra, Weng Khong Lim, Sylvia Kam, Koei Wan Tham, R Ryanne Wu, Jing Xian Teo, Sonia Davila, Jyn Ling Kuan, Sock Hoai Chan, Nicolas Bertin, Cheng Xi Yang, Steve Rozen, Bin Tean Teh, Khung Keong Yeo, Stuart Alexander Cook, Saumya Shekhar Jamuar, Geoffrey S Ginsburg, Lori A Orlando, Patrick Tan

Abstract

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 rendering the value of family history unknown. We evaluated the utility of incorporating family history information for genomic sequencing selection.

Methods: To ascertain the relationship between family histories on such population-level initiatives, we analysed whole genome sequences of 1750 research participants with no known pre-existing conditions, of which half received comprehensive family history assessment of up to four generations, focusing on 95 cancer genes.

Results: Amongst the 1750 participants, 866 (49.5%) had high-quality standardised family history available. Within this group, 73 (8.4%) participants had an increased family history risk of cancer (increased FH risk cohort) and 1 in 7 participants (n = 10/73) carried a clinically actionable variant inferring a sixfold increase compared with 1 in 47 participants (n = 17/793) assessed at average family history cancer risk (average FH risk cohort) (p = 0.00001) and a sevenfold increase compared to 1 in 52 participants (n = 17/884) where family history was not available (FH not available cohort) (p = 0.00001). The enrichment was further pronounced (up to 18-fold) when assessing only the 25 cancer genes in the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes. Furthermore, 63 (7.3%) participants had an increased family history cancer risk in the absence of an apparent clinically actionable variant.

Conclusions: These findings demonstrate that the collection and analysis of comprehensive family history and genomic data are complementary and in combination can prioritise individuals for genomic analysis. Thus, family history remains a critical component of health risk assessment, providing important actionable data when implementing genomics screening programs.

Trial registration: ClinicalTrials.gov NCT02791152 . Retrospectively registered on May 31, 2016.

Keywords: Cancer; Clinically actionable variants; Family history; Population genomics screening.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Family history assessment and clinically actionable variant detection overview

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