Figure 1

A timeline illustrating technological breakthroughs and hallmark publications for Mendelian disease gene identification. (a) The main historical events leading up to the introduction of whole exome sequencing (WES). The vast majority of all Mendelian disease genes known so far have been identified using conventional methods, including linkage analysis [6, 57–59], homozygosity mapping [7], karyotyping [60] and copy number variation (CNV) detection [8, 61, 62]. Many studies following the initial descriptions have been based on technical achievements, such as the first human linkage map [63] or the first draft of the human genome [11, 64]. The next generation sequencing (NGS) era was accelerated by the first commercial release of an NGS instrument [65], and using the same technology the first individual human genome was sequenced by NGS [66]. (b) The main exome sequencing events and landmark publications. More than 30 Mendelian disease genes have been identified by exome sequencing so far. Exome sequencing is now the tool of choice for Mendelian disease gene identification, starting with the proof of concept [67] and identification of the first recessive [14] and dominant disease genes [29]. It has been shown that linkage and homozygosity information can be retrieved directly from exome sequencing data, allowing the application for traditional mapping approaches [53, 68]. Abbreviations: ID, intellectual disability; RFLP, restriction fragment length polymorphism; STS, sequence-tagged site; WGS, whole genome sequencing.