Genetics of inflammatory bowel disease from multifactorial to monogenic forms

Table 1 Genes involved in the phenotype of monogenic very early onset of inflammatory bowel disease

Gene	Inheritance	Chr	OMIM	Disease	Clinical Features IBD-like	Treatment	Ref.
Hyper and autoinflammatory disorders
MVK	AR	12q24	#260920	Mevalonate kinase deficiency	Abdominal pain, Diarrhea, vomiting	Anakinra	[28,30-32]
MEFV	AR	16p13	#134610 #249100	Familial Mediterranean Fever	Diarrhea, abdominal pain, mucus in the stool, peritonitis	Colchicine	[33,34]
PLCG2	AD	16q23	#614878	Autoinflammation, antibody deficiency, and immune dysregulation syndrome	Bloody diarrhoea, UC, enterocolitis		[35]
NLRP12	AD	19q13	#611762	Familial cold autoinflammatory syndrome 2	Abdominal pain	Anakinra	[37]
NLRC4	AD	2p22	#616050	Autoinflammation with infantile enterocolitis	Neonatal-onset enterocolitis	Anakinra	[38-40]
Immune regulation and dysregulation disorders (innate and adaptive immune responses)
XIAP	XL	Xq25	#300635	X-linked lymphoproliferative syndrome 2	Perianal abscesses	HSCT	[41-44]
STXBP2	AR	19p13	#613101	Familial haemophagocytic lymphohistiocytosis type 5	IDB-like colitis	HSCT	[45]
HPS1	AR	10q23	#203300	Hermansky Pudlak syndrome (type 1, 4 and 6)	IBD, UC, Granulomatous colitis	Platelet transfusion Anakinra	[46-50]
HPS4		22q12	#614073		Granulomatous colitis	Infliximab
HPS6		10q24	#614075		Gastrointestinal symptoms, granulomatous colitis, imperforate anus, gluteal flap repairs	Subtotal colectomy
FOXP3	XL	Xp11	#304790	Immunodysregulation, polyendocrinopathy and enteropathy	Intractable diarrhea, total or subtotal intestinal villous atrophy, enteropathy	HSCT	[51]
AIRE	AR/AD	21q22	#240300	Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy	Malabsorption, diarrhea, chronic atrophic gastritis	No specific treatment is available	[52]
IL10		1q32	*124092	IL-10 Signaling defects	Severe early-onset enterocolitis
IL10RA	AR	11q23	#613148	Inflammatory Bowel Disease-28, early onset	Early onset enterocolitis, enteric fistula, perianal abscesses	HSCT	[53-63]
IL10RB	AR	21q22	#612567	Inflammatory Bowel Disease-25, early onset	Early onset enterocolitis, perianal abscesses, enterocutaneous and rectovaginal fistula
Defects in phagocyte bacterial killing and neutropenia
SLC37A4GSD-1b	AR	11q23	#232220	Glycogen storage disease 1b	Perioral and perianal lesions, ileitis, colitis, CD-like, protuberant abdomen	Granulocyte colony stimulating factor, prophylactic oral iron	[64-66]
G6PC3	AR	17q21	#612541	Severe Congenital neutropenia 4	Diarrhea, colitis, abdominal pain, perianal fistula or abscess, CD-like, oral aphthous ulceration	Granulocyte colony stimulating factor	[67]
ITGB2	AR	21q22	#116920	Leucocyte adhesion deficiency 1	CD-like with discontinuous stomatitis, ileocolitis, perianal and rectal abscess, fistulas, adhesion, strictures	HSCT	[70,71]
NCF1	AR	7q11	#233700	Chronic granulomatous	Colitis, perirectal abscess	HSCT	[70-75]
NCF2	AR	1q25	#233710	disease	Perirectal abscesses due to immunodeficiency
NCF4	AR	22q12	#613960		Chronic granulomatous colitis, diarrhea perianal infections, erosions and ulceration of the gastric fundus and colonic mucosa, multiple small granulomata on colonic biopsy.
CYBA	AR	16q24	#233690		Perirectal abscesses due to immunodeficiency
CYBB	XL	Xp11	#306400		Gastrointestinal perirectal abscesses due to immunodeficiency, enteritis and colitis
T and B lymphocyte selection activation defects
WAS	XL	Xp11	#301000	Wiskott-Aldrich Syndrome	Diarrhea, hematemesis and melena IBD, UC like, colonic inflammation with crypt abscess	HSCT/transfusion of autologous genetically modified	[77-79]
DCLRE1C	AR	10p13	#603554 #602450	Omenn Syndrome; Athabascan-type severe combined immunodeficiency	Chronic diarrhea	HSCT	[25,80-82,85,86]
RAG1	AR	11p12	4	Omenn Syndrome
RAG2	AR		#603554
LIG4	AR	13q33	#606593	LIG4 Syndrome	Protracted diarrhea	HSCT
ADA	AR	20q13	#102700	Partial adenosine deaminase deficiency	Enzyme replacement therapy using frozen irradiated red blood cells/HSCT	HSCT
IL2RG	XL	Xq13	#300400 #312863	Severe Combined Immunodeficiency; Moderate Immunodeficiency
CD3G	AR	11q23	#615607	Immunodeficiency 17	Diarrhea autoimune, gastroenteritis, recurrent, enteropathy	HSCT
ZAP70	AR	2q11	#269840	Selective T-cell defect	Diarrhea	HSCT
LCK	AR	1p35	#615758	Immunodeficiency 22	Darrhea autoimmune, panniculite	HSCT	[83,84]
LRBA	AR	4q31	#614700	Common variable immunodeficiency 8	Colitis, IBD	Ig replacement therapy/HSCT	[88,90,91]
ICOS	AR	2q33	#607594	Common variable immunodeficiency 1	Early onset gastrointestinal tract infections, enteritis, recurrent diarrhea	Ig replacement therapy/ HSCT	[92]
IL21	AR	4q27	# 615767	IL-21 deficiency	Early onset IBD	Ig replacement therapy/HSCT	[93]
CTLA-4	AD	2q33	#616100	Autoimmune lymphoproliferative syndrome type V	Early onset IBD and autoimmunity	No specific treatment is available	[122]
TNFRSF13B	AR/AD	17p11	#240500	TACI deficiency	Enteritis, recurrent diarrhea	Ig replacement therapy/HSCT	[94]
COG6	AR	13q14	#614576	Congenital disorder of glycosylation, type III	Anal anteposition, recurrent diarrhea, IBD	No specific treatment is available	[123]
BTK	XL	Xq22	#300755 #307200	Agammaglobulinemia Isolates growth hormone deficiency type III	Diarrhea	Ig replacement therapy/HSCT	[99,100]
PIK3R1	AR	5q13	#615214	Agammaglobulinemia 7	Recurrent gastroenteritis		[101]
CD40LG	XL	Xq26	#308230	Immunodeficiency with hyper-IgM type I	Diarrhea		[96,97]
AICDA	AR	12p13	#605258	Immunodeficiency with hyper-IgM type II	Gastrointestinal tract infections		[98]
Disorder of apoptosis
CASP8	AR	2q33	#607271	Caspase 8 deficiency	chronic diarrhea	No specific treatment is available	[102]
ITCH	AR	20q11	#613385	Autoimmune disease, multisystem with facial dysmorphism	Enteropathy, chronic diarrhea, malabsorption, gastrostomy tube feeding	Immunosuppressive treatment	[112]
MASP2	AR	1p36	#613791	MASP2 deficiency	IBD, UC-like		[113]
WELL defined syndromes associated with EO-IBD
TTC7A	AR	2p21	#243150	Multiple intestinal atresia	Multiple areas of atresia along the small and large intestines, Intestinal malrotation Intraluminal calcification, bowel distention Mucous membrane ulceration	Surgery	[103-105]
TTC37	AR	5q15	#222470	Trico hepato enteric syndrome	Diarrhea, severe villous atrophy	Parenteral nutrition	[107,108]
SKIV2L	AR	6p21	#614602	Trico hepato enteric syndrome 2	Diarrhea, colitis, severe and intractable villous atrophy	Ig supplementation	[106]
NEMO/IKBKG	XL	Xq28	*300248	X-linked ectodermal dysplasia and immunodeficiency	CD-like colitis, villous atrophy, recurrent digestive tract infections, intractable diarrhea and recurrent ulcerations	HSCT	[109,110]
GUCY2C	AD	12p13	#614616	Familial Diarrhea	Early onset chronic diarrhea, IBD, CD, small-bowel obstruction, esophagitis, irritable bowel syndrome, ileal inflammation, abdominal pain	Parenteral nutrition	[111]
Defects affecting the integrity of intestinal barrier
COL7A1	AR	3p21	#226600	Dystrophic epidermolysis bullosa	Gastrointestinal complications, diarrhea, colitis, esophageal blisters strictures, anal blisters, constipation	Immuno myeloablative chemotherapy and allogenic HSCT	[114]
ADAM17	AR	2p25	#614328	Neonatal inflammatory skin and bowel disease 1	Perioral and perianal erythemas with fissuring, diarrhea, malabsorption, plasma cell duodenitis crypt hyperplasia, villous atrophy	EGFR Ligands	[115]
FERMT1/KIND1	AR	20p12	#173650	Kindley syndrome	Intestinal involvement with haemorrhagic diarrhoea, UC	No specific treatment is available	[116]
EGFR	AR	7p11	#616069	Neonatal inflammatory skin and bowel disease 2	Diarrhea	No specific treatment is available	[117,118]
TGFBR1	AD	9q22	#609192	Loeys-Dietz syndrome, type 1	Gastrointestinal disorders,	Medication and preventative surgery	[119]
TGFBR2	AD	3p24	#610168	Loeys-Dietz syndrome, type 2

IBD: Inflammatory bowel disease; UC: Ulcerative colitis; HSCT: Hematopoietic stem cell transplantation; CD: Crohn's disease.