Family-Specific Variants and the Limits of Human Genetics

Abstract

Every single nucleotide change compatible with life is present in the human population today. Understanding these rare human variants defines an extraordinary challenge for genetics and medicine. The new clinical practice of sequencing many genes for hereditary cancer risk has illustrated the utility of clinical next-generation sequencing in adults, identifying more medically actionable variants than single gene testing. However, it has also revealed a linear relationship between length of DNA evaluated and number of rare “variants of uncertain significance” reported. We propose that careful approaches to phenotype-genotype inference, distinguishing between diagnostic and screening intent, and expanded use of family-scale genetics studies as a source of information on family-specific variants will reduce variants of uncertain significance reported to patients.

Clinical judgement in precision medicine

“…But those features, in isolation or due to complex interactions, are likely to render population‐based research of minimal value. More than half of the genetic variation in any particular individual is due to extremely rare or family‐specific variants, impossible to evaluate in the population . The combination of environmental and lifestyle factors that are potentially relevant to diagnosis and treatment decisions will likewise also preclude controlled clinical study.…”

“…More than half of the genetic variation in any particular individual is due to extremely rare or familyspecific variants, impossible to evaluate in the population. 5 The combination of environmental and lifestyle factors that are potentially relevant to diagnosis and treatment decisions will likewise also preclude con- can test multiple family members for a family-specific variant of concern and produce likelihood ratios regarding the pathogenicity or benignity of what represents strong, versus weak, mechanistic knowledge. 3 New nonepidemiologic methodologies will need to be developed to address interactions among genetics, lifestyle, and environment.…”

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

“…While there is increased clinical awareness of the potential for these germline variants to contribute to a patient's disease, there are often insufficient data in the literature to definitively classify whether a detected variant is contributing to the patient's phenotype. 6,7 For example, familial platelet disorder with predisposition to AML (FPD/AML) is an autosomal dominant disorder in which germline mutations in RUNX1 result in thrombocytopenia, platelet functional and/or ultrastructural defects, and/or susceptibility to hematologic malignancies commonly including MDS, AML, and other malignancies [8][9][10][11] ( Table 1). ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a database repository of clinically actionable genomic variants 12,13 that currently lists 325 germline RUNX1 variants deposited by clinical laboratories.…”

Patient goals, motivations, and attitudes in a patient‐driven variant reclassification study

“…The advent of clinical next‐generation sequencing has resulted in increased numbers of variants of uncertain significance (VUS) (Shirts, Pritchard, & Walsh, ). VUS can be identified in many clinical contexts for many different indications.…”

“…Patient‐driven research can also highlight patient needs and priorities in clinical settings (Xian et al, ). Given the growing number of VUS reported in genetic testing (Shirts et al, ), patient‐driven family studies for VUS reclassification, where patients are actively involved in building their pedigree, recruiting relatives for sample collection, and determining specific study goals, are an opportunity for meeting the VUS reclassification needs of patients, families, clinical genetics providers, and genetics researchers.…”