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

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, 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.

Impact of Genetic Counseling on Patient-Reported Electronic Cancer Family History Collection

“…This factor makes an accurate family history especially important for those who may be more likely to have variants of uncertain significance identified, which is more frequent in patients who belong to racially and/or ethnically underrepresented groups. 22 We found that CGC modifications of family history were most frequent to third-degree relatives (44%). This finding is consistent with prior studies.…”

Genotype-Phenotype Dissociation in Two Taiwanese Children with Molybdenum Cofactor Deficiency Caused by MOCS2 Mutation

“…9 The MOCS2 c.16C > T gene mutation has been reported in the literature. 10,11 The two reported MoCoD patients harbored the same genotypes, MOCS2 homozygous c.16C > T mutation, but developed diverse clinical neuroimaging features. Patient 1 exhibited a severe disease course soon after birth, followed by subsequent myoclonic seizures and movement disorder, and the brain MRI showed diffuse cystic encephalomalacia including involvement in the bilateral globus pallidi, while patient 2 had a mild phenotype with prominent movement disorder after intercurrent illness, and the brain MRI showed selective injury of the bilateral globus pallidi and the cerebellum.…”

Current and future applications of biomarkers in samples collected through minimally invasive methods for cancer medicine and population‐based research

“…There are two ways DNA can be used in cancer research: (1) detection of cancer based on detection of tumor cells or DNA released by the tumor into the circulation and (2) detection of familial tendency and/or genetic propensity for certain cancer based on germline DNA. The second is beyond the scope of this article (for review see Bylstra et al, 2021; Chanock & Ostrander, 2020; Chatrath et al, 2020; Gayther et al, 1995; Rotunno et al, 2020). Examples of minimally invasive samples that can be used to obtain DNA for biomarker analysis are fluids containing tumor cells or cell‐free tumor DNA (Peng et al, 2017).…”