Table 1.

Examples of Modifier Genes and Their Functional Effects

TARGET			MODIFIER
Gene(s)	Nature of Allele(s)	Condition	Gene(s)	Nature of Allele(s)	Effect Type	Modifier Effect	Refs
Examples in Humans
PRPF31	LOF mutation	retinitis pigmentosa	CNOT3	polymorphism	penetrance	reduced incidence	27, 28
KCNQ1	dominant-negative mutation	long QT syndrome	NOS1AP	polymorphism	expressivity	increased QT interval, risk of cardiac arrest, and sudden death	32
HFE	LOF mutation	hereditary hemochromatosis	HAMP	LOF mutation	dominance	heterozygote susceptibility	34
BBS1/9/10	LOF mutation	Bardet-Biedl syndrome	MKS1	LOF mutation	pleiotropy	novel seizure phenotype	38
SMAD6	LOF mutation	non-syndromic craniosynostosis	BMP2	polymorphism	penetrance	increased incidence	63
SMN1	LOF mutation	spinal muscular atrophy	PLS3	polymorphism	penetrance	prevention of disease	64
CFTR	LOF mutation	cystic fibrosis	MUC4/20, SLC9A3, HLA-DRA, EHF/APIP, AGTR2/SLC6A14	polymorphism	expressivity	altered severity of lung disease	65
CFTR	LOF mutation	cystic fibrosis	DCTN4	polymorphism	expressivity	altered time to initial lung infection	66
MYH7	LOF mutation	hypertrophic cardiomyopathy	MYBPH	polymorphism	expressivity	altered severity of cardiac hypertrophy	67
HBB	LOF mutation	sickle cell disease	BCL11A, HBS1L-MYB	polymorphism	expressivity	increased levels of fetal hemoglobin, decreased rate of pain crisis	96
Examples in Mice
Grhl3	spontaneous LOF mutation (curly tail)	spina bifida	Lmnb1	polymorphism	penetrance	reduced incidence	30
Pkd1	engineered LOF mutation	polycystic kidney disease	Nedd9	engineered LOF mutation	expressivity	increased kidney size and cyst number	33
Atp2b2	spontaneous LOF mutation (deaf waddler)	deafness	Cdh23	polymorphism	dominance	heterozygote susceptibility	36
Bcl2	engineered LOF mutation	overactive apoptosis	Bid	engineered LOF mutation	pleiotropy	improved lymphocyte count and survival with no effect on hypopigmentation or kidney disease	40
129/Sv background	inbred strain genetic background	testicular germ cell tumors	Kitl, Dnd1, Stra8, Eif2s2, Apobed1, A1cf, Ago2, Trp53	engineered LOF mutation	penetrance	altered incidence	45, 46, 47, 48, 49
Apoe	engineered LOF mutation	atherosclerosis	Raet1e	polymorphism	expressivity	decreased aortic root lesion area	69, 70, 71
Mpl	engineered LOF mutation	thrombocytopenia	Myb	ENU-induced hypomorphic mutation	expressivity	increased platelet count	72
Mecp2	engineered LOF mutation	Rett syndrome	Sqle	ENU-induced LOF mutation	pleiotropy	increased motor function and lifespan with no effect on malocclusion or inflammation	73
Nr2e3	spontaneous LOF mutation	enhanced S cone syndrome	Nr1d1	polymorphism	penetrance	reduced incidence	92, 93
Gars	ENU-induced novel function mutation	Charcot-Marie Tooth disease type 2D	Nrp1	engineered LOF mutation	expressivity	increased loss of motor function	75

Abbreviations are as follows: LOF, loss-of-function; ENU, ethylnitrosourea.