Clinical genomics and contextualizing genome variation in the diagnostic laboratory

Abstract

Introduction: The human genome contains the instructions for the development and biological homeostasis of the human organism and the genetic transmission of traits. Genome variation in human populations is the basis of evolution; individual or personal genomes vary tremendously, making each of us truly unique.

Areas covered: Assaying this individual variation using genomic technologies has many applications in clinical medicine, from elucidating the biology of disease to designing strategies to ameliorate perturbations from homeostasis. Detecting pathogenic rare variation in a genome may provide a molecular diagnosis that can be informative for patient management and family healthcare.

Expert opinion: Despite the increasing clinical use of unbiased genomic testing, including chromosome microarray analysis (CMA) with array comparative genomic hybridization (aCGH) or SNP arrays, clinical exome sequencing (cES), and whole-genome sequencing (WGS), to survey genome-wide for molecular aberrations, clinical acumen paired with an understanding of the limitations of each testing type will be needed to achieve molecular diagnoses. Potential opportunities for improving case solved rates, functionally annotating the majority of genes in the human genome, and further understanding genetic contributions to disease will empower clinical genomics and the precision medicine initiative.

Keywords: Molecular diagnosis; genomic instability; multilocus pathogenic variation; mutation; precision medicine.

Figure 1.

Multilocus pathogenic variation and de novo mutation Standard pedigree symbols are used with squares representing males and circles females; filled squares and circles depict an individual with a clinical disease phenotype. Below these pedigree symbols are shown representative X chromosome and 1 representative of the 22 autosomes each with 5 different gene loci A through J. The plus (+) symbol refers to wild type and variant alleles at the gene locus. Rare variant pathogenic alleles are represented as red minus signs and new mutation depicted by a lightning bolt. AD, autosomal dominant; XL, X-linked.

Figure 2.

Multilocus pathogenic variation and biallelic AR disease traits Filled diamond indicates affected individual of either sex. Two representative autosomes from the 22 are shown. Four different ways to obtain a homozygous disease gene locus are shown: (a) Mendelian segregation from carrier unrelated parents, (b) uniparental isodisomy (UPD), (c) deletion CNV, and d) identity-by-descent from consanguineous parentage. Rare variant pathogenic alleles are represented as red minus signs and new mutation depicted by a lightning bolt.