Genetic interactions and modifier genes in Hirschsprung's disease

Table 1 Genes associated with Hirschsprung's disease

Locus	Gene	Associated syndrome	Incidence	Penetrance	Inheritance	Ref.
10q11	RET	Non-syndromic HSCR	50% familial	70% male	Dominant	82-84
			30% sporadic	50% female
5p13	GDNF	Non-syndromic HSCR	5 cases	Low	Dominant	85-89
13q22	EDNRB	Shah-Waardenburg	5%	Low	Dominant or recessive	44,90
		Non-syndromic HSCR
20q13	ET3	Shah-Waardenburg	1 case	N/A	Dominant or recessive	91
		Non-syndromic HSCR
1p36	ECE1	Cardiac and autonomic nervous system defects with HSCR	1 case	N/A	Dominant	40
22q13	SOX10	Shah-Waardenburg	> 5%	~80%	Dominant	47,49,50,92
		Non-syndromic HSCR
2q22	ZFHX1B	Mowat-Wilson	< 5%	60%	Dominant	62,93-95
4p12	PHOX2B	CCHS–Ondines Curse	< 5%	20%	Dominant	96
19p13	NTN	Non-syndromic HSCR	1 case		Dominant	97
18q21	TCF4	Epileptic encephalopathy	1 case		Dominant	98
10q21.1	KIAA1279	Goldberg-Shprintzen	Rare		Recessive	21

HSCR: Hirschsprung's disease; CCHS: Congenital central hypoventilation syndrome.

Table 2 Phenotypes of mouse models of enteric nervous system defects

	Wild-type	Colonic aganglionosis	Total intestinal aganglionosis	Hypoganglionosis
Ret	+/-	51/51	-/-	C620R/+
	9/9	S697A/S697A	Y1062F/Y1062F
	Y162F/+		C620R/C620R
Ednb	sl/+	sl/sl
		Ednrbtm1Ywa/Ednrbtm1Ywa
Et3	ls/+	ls/ls
		Et3tm1Ywa/ Et3tm1Ywa
Sox10	Dom/+ (~80%)	Dom/+ (~20%)	Dom/Dom
	LacZ/+ (~80%)	LacZ/+ (~20%)	LacZ/LacZ
Interactions		Ret+/-; Ednrbs/s	Ret51/51; Et3ls/ls
		Ret51/+; Et3ls/ls	Sox10Dom/+; Et3ls/ls
			Sox10Dom/+; Edrnbsl/sl
Other genotypes		Sall4-/-	Gdnf-/-	Gdnf+/-
		B1Intergrin-/-	Gfra1-/-	Hlx1-/-
		Ece1-/-	Phox2b-/-
			Pax3-/-