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Comput Math Methods Med. 2013;2013:179761. doi: 10.1155/2013/179761. Epub 2013 May 14.

The number of candidate variants in exome sequencing for Mendelian disease under no genetic heterogeneity.

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  • 1Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, Research Organization of Information and Systems, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.


There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs) in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of "no genetic heterogeneity." All variants were assumed to be under the "null model," and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N = 20, 50), filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no "genetic heterogeneity" is appropriate and could provide general guidelines for sample size determination.

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