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

Rao, Aliz R.; Nelson, Stanley F.

doi:10.1186/s12920-018-0371-9

BMC Medical Genomics

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 threshold^b	f^a	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 / 10^c	LOF	Het	Exclusion	0.0020	1.51E-017	20,000	3.02E-013
complex	PBRM1	7 unrelated affecteds	4 / 7^d	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	all^d	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	all^d	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

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

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ISSN: 1755-8794

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