Clinical Interpretation and Management of Genetic Variants

Abstract

Highlights The human genome contains approximately 4 million variants, whose population frequencies vary according to the ethnic backgrounds. Genetic diversity of humans in part determines interindividual variability in susceptibility to diseases, response to therapy, and the clinical outcomes. Genetic variants exert a gradient of biological and clinical effect sizes. In general, variants with the largest effect sizes are responsible for the single-gene disorders, whereas those with moderate and modest effect sizes are responsible for oligogenic and polygenic diseases, respectively. A phenotype is the consequence of nonlinear stochastic interactions among multiple genetic and nongenetic determinants. Discerning pathogenicity of the genetic variants, identified through genetic testing, in the clinical phenotype is challenging and requires complementary expertise in human molecular genetics and clinical medicine.

A combinatorial oligogenic basis for the phenotypic plasticity between late-onset dilated and arrhythmogenic cardiomyopathy in a single family

“…The modifier roles of the PVs or LPVs in the PKP2 , DSP , SCN10A , and others identified in the family members benefit from biological plausibility and the well-established roles of these genes in cardiomyopathies and/or arrhythmias [ 17 , 18 , 19 ] . Nevertheless, the observations are also in accord with the notion that the ensuing phenotype, even in single-gene disorders, is influenced by a number of genetic and non-genetic factors, exerting a gradient of phenotypic effects with the final phenotype being the outcome of stochastic, multilayer, and nonlinear interactions among numerous genetic and non-genetic determinants [ 21 , 26 , 27 ] . Despite the plausibility, the role of the PVs and LPVs as the modifiers of the phenotype caused by the PVs in TTN gene in the family members could not be discerned unambiguously.…”

“…The findings, overall, suggest an age-dependent penetrance of the TTN variants, typically presenting in the 6th decade of life, whereby expression of the phenotype is partially conditional to the presence of concomitant LPVs in other genes associated with cardiomyopathies and cardiac arrhythmias or the presence of external factors, such as alcohol consumption. These findings illustrate the complexity of genotype-phenotype correlation in hereditary cardiomyopathies and advocate for an oligogenic basis of the phenotype and the need for a comprehensive genetic analysis to identify all PVs and LPVs in each genome in the clinical genetic testing [ 21 ] .…”

Network-based pathogenicity prediction for variants of uncertain significance

“…On the other hand, recent large-scale germline analyses have identified clinically significant variants in the populations that do not exhibit the classic hereditary tumor phenotype. These analyses revealed the need to discuss moderate risk variants, modifier genes, and oligogenic diseases ( 30, 31 ). However, the clinical utility for these variants is still undetermined, and are most of them are annotated as VUS.…”

Facilitations and Hurdles of Genetic Testing in Neuromuscular Disorders

“…Quickly, thanks to the introduction of automated DNA sequencers, the manual method was improved and replaced by the automated one [ 18 , 21 ]. All such technological advances were useful in launching of the Human Genome Project in 1990; the draft of the human genome, first released in 2001, was then completed in 2003, leading to the release of the sequence of the entire human genome, the illustration of the vast genetic diversity in humans, and the identification of a large number of disease genes [ 6 , 22 ]. Such a project also contributed to the improvement of sequencing technology, up to the development in 2005 of next generation sequencing (NGS).…”