Opportunities and challenges of whole-genome and -exome sequencing

Abstract

Recent advances in the development of sequencing technologies provide researchers with unprecedented possibilities for genetic analyses. In this review, we will discuss the history of genetic studies and the progress driven by next-generation sequencing (NGS), using complex inflammatory bowel diseases as an example. We focus on the opportunities, but also challenges that researchers are facing when working with NGS data to unravel the genetic causes underlying diseases.

Keywords: Complex diseases; Inflammatory bowel diseases; NGS; Next-generation sequencing; Variant priorization; Variants of unknown significance (VUS); WES; WGS; Whole-exome sequencing; Whole-genome sequencing.

Fig. 1

Number of PubMed citations for ATG16L1, NOD2, IL23R, HLA/MHC, GWAS and autophagy in combination with “inflammatory bowel disease”, “Crohn’s disease” OR “ulcerative colitis” from the years 1997–2015 depicting a steep increase of follow-up studies for genes and pathways after discovery. Interestingly, the HLA/MHC association signal in IBD has been known for a long time, however, studies for this locus in IBD are rarer and no increase can be observed. We think that this region is understudied, given its importance in disease etiology (in particular in ulcerative colitis), calling for more IBD immunogenetics studies in the future

Fig. 2

a Top: Range of IBD-relevant variants based on genetic complexity underlying the disease and variant penetrance. Bottom: Overview of identified IBD genes ranging from monogenic to complex forms based on the highest known penetrance for each gene. For both NOD2 and PRDM1, for example, both common and rare variants have been identified as disease-relevant in patients [110, 111]. b Timeline of gene discovery for IBD [–137]. Top graph shows cumulative number of genes separated by technology (log scale)

Fig. 3

Course of a typical trio exome project yielding several VUS and benefit of MME for variant selection. Filter by mode of inheritance: recessive or dominant; by variant consequence: missense, nonsense, splice-site, start-loss or stop-loss; by frequency: maximum minor allele frequency of 1% in various databases (ExAC, EVS, in-house controls)