Genome sequencing and implications for rare disorders

Abstract

The practice of genomic medicine stands to revolutionize our approach to medical care, and to realize this goal will require discovery of the relationship between rare variation at each of the ~ 20,000 protein-coding genes and their consequent impact on individual health and expression of Mendelian disease. The step-wise evolution of broad-based, genome-wide cytogenetic and molecular genomic testing approaches (karyotyping, chromosomal microarray [CMA], exome sequencing [ES]) has driven much of the rare disease discovery to this point, with genome sequencing representing the newest member of this team. Each step has brought increased sensitivity to interrogate individual genomic variation in an unbiased method that does not require clinical prediction of the locus or loci involved. Notably, each step has also brought unique limitations in variant detection, for example, the low sensitivity of ES for detection of triploidy, and of CMA for detection of copy neutral structural variants. The utility of genome sequencing (GS) as a clinical molecular diagnostic test, and the increased sensitivity afforded by addition of long-read sequencing or other -omics technologies such as RNAseq or metabolomics, are not yet fully explored, though recent work supports improved sensitivity of variant detection, at least in a subset of cases. The utility of GS will also rely upon further elucidation of the complexities of genetic and allelic heterogeneity, multilocus rare variation, and the impact of rare and common variation at a locus, as well as advances in functional annotation of identified variants. Much discovery remains to be done before the potential utility of GS is fully appreciated.

Keywords: Diagnostic utility; Exome sequencing; Genome sequencing; Mendelian conditions; Molecular diagnoses; Rare disease; Undiagnosed diseases.

Fig. 1

Complex modes of inheritance. Digenic inheritance involves variation at 2 loci that are required for expression of a single Mendelian condition. Most often, both variants are rare, but there have been examples of one rare variant and one common variant at distinct loci leading to expression of a single Mendelian condition. Dual molecular diagnoses occur when an individual has two Mendelian conditions resulting from rare variants at two typically unlinked loci. Mendelian condition pairs can involve one or more modes of inheritance, for example, AD+AD, AD+AR, or AR + AR. Mutational burden is observed when the phenotype associated with a highly penetrant variant is modified by the presence of one or more additional variants which by themselves are not penetrant. Incomplete penetrance can be observed when disease expression requires compound inheritance of one rare and one common variant, either at the same locus, or at unlinked loci. Distinct chromosomes are represented in blue. Rare variants of high penetrance are indicated by red ovals. Common and/or low penetrance variants are indicated by grey ovals. AD – autosomal dominant; AR – autosomal recessive

Fig. 2

Disease genes can be associated with more than one Mendelian condition. Review of genes associated with disease phenotypes in OMIM (January 2019) reveal that 31% of disease genes have more than one disease phenotype association, with nearly 6% associated with more than 3 Mendelian conditions. Rare variants in LMNA are associated with a variety of both dominantly and recessively inherited phenotypes. LTD - lamin tail domain