Pathogenicity of De Novo Rare Variants
Challenges and Opportunities
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Human molecular genetics has played a critical role in the discovery of novel disease pathways and identification of new targets for therapeutic development. The most significant advantage of this scientific field is its unique potentials to establish causal links between germline mutations and human diseases. This in turn has led to the identification of most relevant targets in humans for development of potent therapeutics. This general concept pertains mainly to single gene or so-called Mendelian disorders, which are largely caused by mutations that alter a protein structure or function and have sufficient power to independently cause disease. Before the advent of high-throughput sequencing, these variants were largely identified by positional cloning. Regardless of the tools used for their discovery, disease causality of Mendelian variants is primarily established by close to perfect segregation of the disease alleles with the trait in family-based studies. A major benefit of family-based studies is the common genetic background of the studied subjects, which allows circumventing the problem of population stratification. Selective pressures in direct relationship to the effect size and severity of disease alleles determine the allele frequencies. For instance, fitness-related traits are highly subjected to natural selection and are caused by variants with much lower allele frequencies compared with those that underlie late-onset diseases.1 In general, disease allele frequencies of Mendelian traits are low and at a fraction of their prevalence. With the advent of high-throughput sequencing, the ability to identify rare Mendelian variants has dramatically increased. The reducing cost of sequencing and its increased throughput have turned whole-exome sequencing and whole-genome sequencing to increasingly attractive genetic tools for Mendelian traits. The modern tools of whole-exome sequencing or whole-genome sequencing have facilitated discovery of novel rare variants for Mendelian disorders with previously unknown genetic causes. These, in turn, have led to the discovery …