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Table 1 Mendelian disease gene identification approaches

From: Unlocking Mendelian disease using exome sequencing

Approach Applies to Advantages Disadvantages
Candidate gene Any disease Easy to perform for one or two genes; requires no mapping, can directly identify the causative variant/mutation Relies heavily on current biological knowledge; success rate very low
Genetic mapping by karyotyping Any disease Easy to perform; no familial cases required; can detect (large) balanced events Low resolution, only detects large chromosomal aberrations; mutation detection requires second step
Genetic mapping by linkage analysis Inherited disease Easy to perform Requires large families, often identifies large loci; mutation detection requires second step
Genetic mapping by homozygosity mapping Recessive monogenic diseases Small families can be used Most useful for consanguineous families; often identifies large loci; mutation detection requires second step
Genetic mapping by CNV analysis Monogenic/monolocus disease High resolution CNV screening; no familial cases required; can potentially identify small loci Only investigates CNVs; cannot detect balanced events, no base-pair resolution; mutation detection requires second step
Whole exome sequencing (WES) Any disease Base-pair resolution exome-wide; detects most types of genomic variation; can directly identify the causative variant/mutation Unable to detect non-coding variants; limited resolution for CNVs and other structural variation; coverage variability due to enrichment process; relatively expensive
Whole genome sequencing (WGS) Any disease Base-pair resolution genome-wide; detects all types of genomic variation; can directly identify the causative variant/mutation Data analysis complex; even more expensive than exome sequencing