Exome sequencing is revolutionizing Mendelian disease gene identification. disease has received a increase in the last year or two by the launch of new technology that enable the sequencing of DNA at a higher throughput and at lower costs than previously feasible [4]. Although traditional gene mapping approaches (such as for example karyotyping [5], linkage evaluation [6] homozygosity mapping [7] and duplicate amount variation (CNV) evaluation [8]) have resulted in great insights into Mendelian disease in the last few decades (Body ?(Figure1),1), they cannot detect all types of genomic variation (Desk ?(Desk1).1). The strategy applied would depend on if the disease is certainly, for instance, caused by one nucleotide mutations or by CNVs, which is certainly challenging to predict beforehand. Furthermore, mapping techniques would often not really reduce the amount of applicant genes sufficiently for simple follow-up by Sanger sequencing [9]. For instance, genome-wide one nucleotide polymorphism evaluation in a big Dutch pedigree with autosomal-dominant familial exudative vitreoretinopathy (FEVR, MIM 613310), a retinal disorder, determined a linkage peak around 40 Mb on chromosome 7, that contains a lot more than 300 genes [10]. Also after adding linkage data from another FEVR Paclitaxel pontent inhibitor family members the spot was still too large for straightforward disease-gene identification, and Sanger sequencing of a few candidate genes did not identify causative mutations. Next generation sequencing (NGS) has the potential to identify all kinds of genetic variation at base-pair resolution throughout the human genome in a single experiment. This can be performed much faster and more cost efficiently than with traditional techniques (the sequencing of a genome by traditional techniques needed many years and cost millions of dollars, whereas NGS technology can sequence a genome for less than $7,000 and within a week [11]). This enables the detailed genomic analysis of large numbers of patients [12]. In the case of the two families with FEVR, we [10] used next generation sequencing to investigate the entire coding sequence of the 40-Mb region in a single affected individual from the first family and identified mutations in tetraspanin 12 ( em TSPAN12 /em ) to be the cause of FEVR in both families and in three additional families. For most Mendelian disorders, however, there is no disease locus known and an unbiased approach is required. Table 1 Mendelian disease gene identification approaches thead th align=”left” rowspan=”1″ colspan=”1″ Approach /th th align=”left” rowspan=”1″ colspan=”1″ Applies to /th th align=”left” rowspan=”1″ colspan=”1″ Advantages /th th align=”left” rowspan=”1″ colspan=”1″ Disadvantages /th /thead Candidate geneAny diseaseEasy to perform Paclitaxel pontent inhibitor for one or two genes; requires no mapping, can directly identify the causative variant/mutationRelies heavily on current biological knowledge; success rate very lowGenetic mapping by karyotypingAny diseaseEasy to perform; no familial cases required; can detect (large) balanced eventsLow resolution, only detects large chromosomal aberrations; mutation detection requires second stepGenetic mapping by linkage analysisInherited diseaseEasy to performRequires large families, often identifies large loci; mutation detection requires second stepGenetic mapping by homozygosity mappingRecessive monogenic diseasesSmall families can be usedMost useful for consanguineous families; often identifies large loci; mutation detection requires second stepGenetic mapping by CNV analysisMonogenic/monolocus diseaseHigh resolution CNV screening; no familial cases required; can potentially identify small lociOnly investigates CNVs; cannot detect balanced events, no base-pair resolution; mutation detection requires second stepWhole exome sequencing (WES)Any diseaseBase-pair resolution exome-wide; detects most types of genomic variation; can directly identify the causative variant/mutationUnable to detect non-coding variants; limited resolution for CNVs and other structural variation; coverage variability due to enrichment process; relatively expensiveWhole genome sequencing (WGS)Any diseaseBase-pair resolution genome-wide; detects all types of Paclitaxel pontent inhibitor genomic variation; can directly identify the causative variant/mutationData analysis complex; even more expensive than exome sequencing POLD4 Open in a separate window Open in a separate window Figure 1 A timeline illustrating technological breakthroughs and hallmark publications for Mendelian disease gene identification. (a) The main historical.