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Table 2 Statistical significance of variants found to be causal in selected previous studies

From: Calculating the statistical significance of rare variants causal for Mendelian and complex disorders

Inheritance Gene Individuals sequenced Indivs w/ var in gene Variant consequence Zygosity filter MAF thresholdb fa P-val Approximate # of genes targeted Corrected P-value
AR ISPD 1 full-sibling doubleton and 5 unrelated affecteds all LOF CHet/Hom Exclusion 0 4.16E-008 7200 3.00E-004
AD CDKN1C 1 third-cousin doubleton and 4 unrelated affecteds all nonsyn Het Exclusion 0.0044 5.24E-015 2500 1.31E-011
AD MLL2 10 unrelated affecteds 7 / 10c LOF Het Exclusion 0.0020 1.51E-017 20,000 3.02E-013
complex PBRM1 7 unrelated affecteds 4 / 7d LOF Hom none stated 0 5.56E-014 20,000 1.11E-009
complex WDR62 2 affecteds in consanguineous family% all LOF Hom Exclusion 0 9.75E-008 20,000 1.95E-003
AR C5orf42 6 unrelated affecteds alld nonsyn Het 0.1% 0.0779 2.23E-007 20,000 4.46E-003
AR C5orf42 2 affecteds in consanguineous family all nonsyn Hom none stated 0 4.88E-008 20,000 9.75E-004
complex AP4E1 6 affecteds in a single, large family all nonsyn Het 1% 0.0459 1.44E-003 530 0.76
AR ANTXR1 2 unrelated affecteds from consanguineous families all nonsyn Hom 0.1% 0 3.04E-013 144 4.38E-011
AR ITGB6 2 unrelated affecteds all nonsyn CHet/Hom none stated 0.0012 1.44E-006 20,000 2.87E-002
AR CSPP1 1 proband sequenced in region of homozygosity all LOF Hom 1% 0 2.00E-004 40 7.99E-003
AR GMPPB 3 unrelated affecteds and 3 sibs in consanguineous family sequenced in single candidate gene alld nonsyn CHet/Hom 1% 0.0032 2.15E-014 1 2.15E-014
AR DHODH 1 full-sibling doubleton and 2 unrelated affecteds all nonsyn CHet/Hom Exclusion 0.0004 1.35E-007 20,000 2.69E-003
AR SCN5A Gene screened in 10 affecteds from 7 families 5 / 10 nonsyn CHet/Hom none stated 0.0012 9.25E-010 1 9.25E-010
AD MAX 3 unrelated affecteds all nonsyn Het Exclusion 0.0064 2.61E-007 20,000 5.22E-003
AR GPSM2 1 proband sequenced in region of homozygosity all LOF Hom Exclusion 0.0000 2.00E-004 66 1.32E-002
AR TBC1D24 15 unrelated affecteds 6 / 15 nonsyn CHet/Hom 1.00% 0.0004 2.02E-017 20,000 4.05E-013
AR PGM3 3 unrelated affecteds all nonsyn CHet/Hom 0.3% 0.0004 6.37E-011 20,000 1.27E-006
  1. Applying our methods to previous NGS findings, in which researchers filtered variants using various criteria, would have statistically validated findings in silico. See Additional file 7 for more details. aThe parameter f denotes the proportion of individuals in the 1000 Genomes Project dataset who have a rare variant at least as severe as the identified variants. bWe used a threshold of MAF < 0.1% for studies with no specific MAF threshold. A MAF threshold labeled exclusion refers to studies where variants were not filtered for a given threshold and variants were excluded based on their presence in public databases such as dbSNP. cFollow-up Sanger sequencing identified mutations in 2 out of 3 exome-negative cases. dFollow-up sequencing of the given gene identified further mutations in multiple additional cases. Abbreviations: MAF minor allele frequency, AD autosomal dominant, AR autosomal recessive, XL X-linked, nonsyn nonsynonymous variant, LOF loss-of-function variant, Het heterozygous, Hom homozygous, CHet/Hom compound heterozygous or homozygous