New approaches to establish genetic causality

Abstract

Cardiovascular medicine has evolved rapidly in the era of genomics with many diseases having primary genetic origins becoming the subject of intense investigation. The resulting avalanche of information on the molecular causes of these disorders has prompted a revolution in our understanding of disease mechanisms and provided new avenues for diagnoses. At the heart of this revolution is the need to correctly classify genetic variants discovered during the course of research or reported from clinical genetic testing. This review will address current concepts related to establishing the cause and effect relationship between genomic variants and heart diseases. A survey of general approaches used for functional annotation of variants will also be presented.

Fig. 1. Example pedigrees illustrating Mendelian inheritance and co-segregation

(A) A pedigree illustrating autosomal dominant transmission of a trait. Red symbols represent family members with the trait ("affected"). Genotypes are given beneath each pedigree symbol to indicate presence of wildtype (WT) or mutant (Mut) alleles. (B) Same pedigree as in (A) modified to illustrate incomplete penetrance (e.g., presence of mutant allele in a phenotypically unaffected person) and decreased expressivity (e.g., presence of mutation but with less severe disease). (C) Pedigree illustrating autosomal recessive inheritance. Open symbols with a central red dot represent unaffected heterozygous mutation carriers. (D) Pedigree illustrating X-linked inheritance. Genotypes are given beneath each pedigree symbol to indicate presence of wildtype (black X, blue Y) or mutant (red X) sex chromosomes. (E) Pedigree illustrating occurrence of a de novo mutation.

Fig. 2. Classification scheme for genetic variants

The likelihood of pathogenicity according to a scheme proposed by the American Board of Medical Genetics is illustrated as a spectrum from most likely (pathogenic) to least likely (benign) pathogenic. A large category in the center ("variants of unknown significance) represents variants that cannot be easily classified.

Fig. 3. Common types of nucleotide sequence variants

Three common types of single nucleotide variants that occur within protein coding regions of genes are illustrated. Missense or nonsynonymous variants are those predicted to result in an amino acid change in the encoded protein. Nonsense variants induce premature "stop" codons predicted to result in a truncated protein product. Frameshift variants in which there is an insertion or deletion of a number nucleotides that is not a multiple of 3 will cause disruption of the protein coding sequence and often lead to a premature stop codon.