Table 1 Mendelian disease gene identification approaches

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