Making Genetics a Family Affair

When it comes to defining what family means, it’s all relative. Around the world, familial relationships can have different connotations. Consider the case of Singapore, where the terms ‘aunty’ and ‘uncle’ do not simply refer to the siblings of one’s parents, as in most Western cultures, but are also used to respectfully address elders in the community. In medicine, however, ‘family’ universally refers to individuals related by blood, with whom you share your genes—and, thus, your propensity for disease.

Family history has long been used by clinicians to assess health risk, and forms a major component of risk assessment guidelines for many conditions. Recently, its value has been questioned and its use minimised in screening populations as genomic sequencing has evolved to become the go-to screening method. Further fuelling this change is the fact that in some studies 48 to 75 percent of individuals found to harbour a disease-related genetic variant have no family history of the disease in question.

Taking History Online

Today, the decision to note down family history largely depends on how the data is collected. Traditionally, the process could be laborious and time-consuming, involving emailing questionnaires to participants, who are entrusted to collect the relevant information from their family members. Given the self-reporting nature of the process, information is often incomplete or non-specific, posing difficulties in interpretation.

Fortunately, interactive web-based tools that can simplify this process are becoming widely available. One example is MeTree, a web-based, patient-facing family history collection and clinical decision support tool developed by Lori Orlando and Geoffrey Ginsburg of Duke University, US. MeTree creates a pedigree of at least three generations for a range of health conditions, and its interactive platform prompts participants to enter additional details should there be any key questions they may have missed.

These features can improve the quality of data and produce more comprehensive health history records. “A study in which our group was involved found that using a web-based family history collection tool such as MeTree increased the level of detail of data collected, thereby increasing the detection of inherited health risks for participants,” said Patrick Tan, Executive Director of the Institute of Precision Medicine (PRISM) and Precision Health Research Singapore (PRECISE).

Complementing Cancer Genetics

Despite these improvements, the question remains: does family history remain relevant in the genomics era? To address this, Tan and his colleagues at PRISM collaborated with Duke University researchers to assess the value of using family history collected through MeTree to identify individuals most likely to benefit from genomic screening. Since certain types of cancer run in families and several genes already have established links to the disease, the team explored the relationship between cancer risk—as determined through family history—and the presence of clinically significant genomic variants.

Specifically, the study compared the detection of pathogenic variants in 95 cancer genes in 1,750 Singaporean participants with and without a family history available through MeTree. “Our study found that participants who had an increased risk of cancer according to their family history were six times more likely to carry a genetic variant associated with a cancer syndrome in comparison to those who did not report a significant family history of cancer,” said first author Yasmin Bylstra, Principal Genetic Counsellor at PRISM.

Sometimes, however, the data didn’t add up. In less than 10 percent of cases, family history and genetic results were inconsistent  —with no detectable cancer variant despite a family history indicating increased risk. Consequently, these patients still require cancer surveillance recommendations according to their family history findings, which may have been missed if only genomic sequencing had been performed.

This means that family history may in fact complement genetic testing by identifying people who are more likely to benefit from genomic sequencing, noted Bylstra. Given that a genetic test can cost over S$1,000 per patient for whole genome sequencing, using family history as a triaging method to select at-risk individuals may be cost-effective.

Population-level impact

Within their study cohort, the researchers found that 8.4 percent of individuals with family history data had an increased risk of developing cancer. While it may seem like a small number, such a statistic should not be overlooked by Singapore’s 5.7 million residents. “Extrapolated to the population-level, this would equate to a significant proportion of Singaporeans at increased risk of developing cancer who could potentially be unaware,” Tan said.

While their initial research focused on cancer, the team wants to include more participants and assess the risk of other inheritable conditions, such as cardiac, metabolic and haematological diseases, noted Tan. Similar to the current study, the family history for these conditions can be assessed through MeTree.

Despite the increasing adoption of genomic sequencing in clinical care, it is apparent that family histories remain a critical component of health risk assessment. Not only can they inform individuals of their risk of developing inherited medical conditions, but family histories also allows clinicians to recommend optimal screening methods for patients—advancing national strategies for precision and prevention medicine in Singapore and around the world.

References:

1. Bylstra, Y., Lim, W.K., Kam, S., Tham, K.W., Wu, R.R, et al. Family history assessment significantly enhances delivery of precision medicine in the genomics era. Genome Medicine 13, 1-11 (2021).

2. Wu, R.R., Sultana, R., Bylstra, Y., Jamuar, S., Davila, S., et al. Evaluation of family health history collection methods impact on data and risk assessment outcomes. Preventive medicine reports 18, 101072 (2020).