Valuable clinical indicators for identifying infantile-onset inflammatory bowel disease patients with monogenic diseases

doi:10.3748/wjg.v27.i1.92

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World Journal of Gastroenterology

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Retrospective Study

World J Gastroenterol. Jan 7, 2021; 27(1): 92-106
Published online Jan 7, 2021. doi: 10.3748/wjg.v27.i1.92

Table 1 Genotypes of 49 infantile-onset inflammatory bowel disease patients

Patient	Gene	Variant (allele 1)	Amino acid	ACMG (P/LP)	Variant (allele 2)	Amino acid	ACMG (P/LP)
Patient	Gene	Variant (allele 1)	Amino acid	ACMG (P/LP)	Variant (allele 2)	Amino acid	ACMG (P/LP)
1	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
2	IL10RA	c.299T>G	V100G	P (PS1+PS3+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
3	IL10RA	c.191A>G	Y64C	LP (PM1+PM2+PM3+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
4	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
5	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
6	IL10RA	c.493C>T	R165X	P (PVS1+PS1+PM2+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
7	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
8	IL10RA	c.350G>A	R117H	P (PS1+PM1+PM2+PP3+PP4)	c.493C>T	R165X	P (PVS1+PS1+PM2+PP4)
9	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.436delC	P146fs	P (PVS1+PS1+PM2+PP4)
10	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
11	IL10RA	c.421G>A	G141R	P (PS1+PM2+PM3+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
12	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
13	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.350G>A	R117H	P (PS1+PM1+PM2+PP3+PP4)
14	IL10RA	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
15	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
16	IL10RA	c.99G>A	W33X	P (PVS1+PS1+PM2+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
17	IL10RA	c.493C>T	R165X	P (PVS1+PS1+PM2+PP4)	c.493C>T	R165X	P (PVS1+PS1+PM2+PP4)
18	IL10RA	c.109G>T	E37X	LP (PVS1+PM2+PM3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
19	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
20	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
21	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
22	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.350G>A	R117H	P (PS1+PM1+PM2+PP3+PP4)
23	IL10RA	c.99G>A	W33X	P (PVS1+PS1+PM2+PP4)	c.299T>G	V100G	P (PS1+PS3+PM2+PP3+PP4)
24	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
25	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
26	IL10RA	c.301C>T	R101W	P(PS1+PS3+PM1+PM2+PP3+PP4)	c.493C>T	R165X	P (PVS1+PS1+PM2+PP4)
27	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
28	IL10RA	c.493C>T	R165X	P (PVS1+PS1+PM2+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
29	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
30	IL10RA	c.302G>A	R101Q	LP (PM1+PM2+PM3+PM5+PP3+PP4)	c.349C>T	R117C	P (PS1+PM1+PM2+PP3+PP4)
31	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
32	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
33	IL10RA	c.299T>G	V100G	P (PS1+PS3+PM2+PP3+PP4)	c.569T>G	F190C	LP (PS1+PM2+PM3_VeryStrong+PP3+PP4)
34	IL10RA	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
35	IL10RA	c.299T>G	V100G	P (PS1+PS3+PM2+PP3+PP4)	c.299T>G	V100G	P (PS1+PS3+PM2+PP3+PP4)
36	WAS	IVS8: +3- +6 GAGT del		LP (PS1+PM2+PP3+PP4)
37	IKBKG	c.1217A>T	D406V	P (PS1+PM1+PM2+PP3+PP4)
38	SLC37A4	c.310 ins T		P (PVS1+PM2+PP4)	c.1014-1120 del107		P (PVS1+PM2+PP4)
39	CYBB	c.674+2T>C		P (PVS1+PM2+PP4)
40	CYBB	c.1272G>A	W424X	P (PVS1+PS1+PM2+PP4)
41	CD40LG	c.267delC	Q90Sfs*6	LP (PVS1+PM2+PP4)
42	LIG4	c.833G>T	R278L	LP (PM1+PM2+PM3+PM5+PP3+PP4)	c.1144_1145delCT	L382Efs*5	LP (PVS1+PS1+PM2+PP4)
43	CARD11	c.155T>C	I52T	LP (PS2+PM2+PP4)
44	PIK3CD	c.3061G>A	E1021K	P (PS1+PS3+PM2+PP3+PP4)
45	IL10RA	c.350G>A	R117H	P (PS1+PM1+PM2+PP3+PP4)
46	IL10RA	c.537G>A	T179T	P (PS1+PS3+PM2+PP3+PP4)
47	IL10RA	c.787C>T	R263X	LP (PVS1+PM2+PP4)
48	IL10RA	c.301C>T	R101W	P (PS1+PS3+PM1+PM2+PP3+PP4)
49	CXCR4	c.1001G>A	R334Q	VUS (PM2+PP3+PP4:BS4)

ACMG: American College of Medical Genetics and Genomics; P/LP: Pathogenic/likely pathogenic; VUS: Variants of uncertain significance.

Table 2 Clinical features and growth parameters among three groups of patients

	AP	M-IBD	NM-IBD	P value
Total number	40	44	29
Male (%)	25 (62.50)	27 (61.36)	21 (72.41)	0.591
Median onset age (mo, IQR)	4.44 (1.25,11.76)	0.51 (0.04,1.79)¹	3.99 (3.00,9.00)	< 0.001
Diarrhea (≥ 8 times/d, %)	10 (25.00)¹	38 (86.40)¹	17 (58.60)	< 0.001
Diarrhea with blood (%)	30 (75.00)	29 (65.90)	24 (82.80)	0.320
Perianal disease (%)	0 (0)	35 (79.54)¹	7 (24.14)	0.005
Fever (%)	2 (5.00)¹	28 (63.63)	12 (41.38)	< 0.001
Death (%)	0 (0.00)	9 (20.45)	1 (3.45)²	0.001
Z scores for weight (mean ± SD)	-0.05 ± 0.21¹	-1.95 ± 0.26	-1.15 ± 0.29	< 0.001
Z scores for height (mean ± SD)	0.19 ± 0.19¹	-1.95 ± 0.25	-1.32 ± 0.31	< 0.001
Z scores for BMI (mean ± SD)	-0.21 ± 0.24²	-1.30 ± 0.28	-0.52 ± 0.27	0.026

¹Compared with the other two groups, adjusted P value < 0.05.

²Compared with the monogenic inflammatory bowel disease (M-IBD) group, adjusted P value < 0.05. AP: Allergic proctocolitis; M-IBD: Monogenic inflammatory bowel disease; NM-IBD: Non-monogenic inflammatory bowel disease; IQR: Interquartile range; SD: Standard deviation; BMI: Body mass index.

Table 3 Results of blood test and inflammatory factors among three groups of patients (median, interquartile range)

	AP	M-IBD	NM-IBD	P value
WBC (× 10⁹)	8.77 (6.78, 10.75)¹	14.88 (9.84, 19.37)	13.77 (8.87,18.51)	< 0.001
Hemoglobin (mg/L)	119 (115, 126)¹	98 (90, 113)	100 (80.50,116)	< 0.001
PLT (× 10⁹)	304 (254, 383)¹	447 (306.75, 591.50)	477 (323.50, 601.50)	0.002
CRP (mg/L)	1 (0.20, 1.00)¹	48 (7.98, 75.23)¹	21 (1.00, 44.35)	< 0.001
ESR (mm/h)	6 (4, 8)¹	18.50 (8, 39)	21 (6, 42)	< 0.001
TNF-α (pg/mL)	14.60 (10.68, 17.03)¹	21.50 (17.58, 27.88)	22.90 (14.48, 61.28)	< 0.001
IL-6 (pg/mL)	2.85 (2.00, 3.35)¹	21.00 (10.20, 50.30)	14.55 (6.81, 30.00)	< 0.001
IL-10 (pg/mL)	500 (5, 5)	85.50 (42.75, 127.25)¹	6.37 (5.00, 14.80)	< 0.001
Ferritin (ng/mL)	22.90 (14.90, 37.05)	55.90 (36.10, 231.20)¹	15.50 (10.60, 27.72)	< 0.001
Albumin (g/L)	41 (38, 43)¹	31 (27, 35)	33 (27.00, 36.50)	< 0.001
Serum iron (μmol/L)	8.00 (5.90, 10.20)	3.90 (2.60, 6.88)	5.70 (4.35, 11.38)	0.069

¹Compared with the other two groups, adjusted P value < 0.05. AP: Allergic proctocolitis; M-IBD: Monogenic inflammatory bowel disease; NM-IBD: Non-monogenic inflammatory bowel disease; WBC: White blood cells; PLT: Platelets; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; TNF: Tumor necrosis factor; IL: Interleukin.

Table 4 Binary logistic analysis for identifying risk factors for infantile-onset inflammatory bowel disease

	AP (median, IQR)	IO-IBD (median, IQR)	Adjusted OR (95%CI)	P value
WBC (× 10⁹)	8.77 (6.78, 10.75)	14.12 (8.85, 18.27)	1.19 (1.01, 1.40)	0.040
ESR (mm/h)	6 (4, 8)	19.00 (8.00, 39.00)	1.10 (1.01, 1.20)	0.037
TNF-α (pg/mL)	14.60 (10.68, 17.03)	21.65 (17.33, 29.45)	1.25 (1.05, 1.50)	0.013
Albumin (g/L)	41 (38, 43)	32 (27, 36)	0.86 (0.74, 1.00)	0.048

Binary logistic analysis showed that white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), tumor necrosis factor (TNF)-α, and albumin in peripheral blood could be used to identify the infantile-onset inflammatory bowel disease from AP if a child had diarrhea and hematochezia in early childhood. Higher WBC, ESR, and TNF-α, as well as lower level of albumin suggested a higher probability of inflammatory bowel disease. AP: Allergic proctocolitis; IO-IBD: Infantile-onset inflammatory bowel disease; IQR: Interquartile range; OR: Odds ratio; CI: Confidence interval; WBC: White blood cells; ESR: Erythrocyte sedimentation rate; TNF: Tumor necrosis factor.

Table 5 Binary logistic analysis for identifying risk factors for monogenic inflammatory bowel disease

	M-IBD (median, IQR)	NM-IBD (median, IQR)	Ajusted OR (95%CI)	P value
Ferritin (ng/mL)	55.90 (36.10, 231.20)	15.30 (9.40, 27.60)	1.14 (1.06, 1.24)	0.001
IL-10 (pg/mL)	85.20 (43.30, 126.50)	5.00 (5.00, 9.11)	1.04 (1.01, 1.08)	0.005
Median onset age (mo)	0.51 (0.04, 1.79)	3.99 (3.00, 9.00)	3.47 (1.29, 9.29)	0.013
Perianal disease (%)	35 (79.50)	7 (24.10)	11.42 (1.71, 76.23)	0.012

Binary logistic analysis showed that higher levels of ferritin and interleukin (IL)-10 in peripheral blood, earlier onset age, and presence of perianal disease suggested that inflammatory bowel disease children may have the gene mutation. However, most of the mutations (79.6%) in this study occurred in IL-10RA, and in order to avoid the bias, we did further analyses as showed in Table 6. M-IBD: Monogenic inflammatory bowel disease; NM-IBD: Non-monogenic inflammatory bowel disease; IL: Interleukin; IQR: Interquartile range; OR: Odds ratio; CI: Confidence interval.

Table 6 Comparison of risk factors among infantile-onset inflammatory bowel disease patients with or without IL-10RA mutation and non-monogenic inflammatory bowel disease (median, interquartile range)

	*IL-10RA* M-IBD	*Non-IL-10RA* M-IBD**	NM-IBD	P value
Ferritin (ng/mL)	55.90 (53.12, 74.73)	45.25 (16.58, 68.70)	15.30 (14.55, 17.95)¹	< 0.001
IL-10 (pg/mL)	85.20 (66.20, 125.00)¹	8.90 (5.00, 85.20)	5.00 (5.00, 9.11)	< 0.001
Median onset age (mo)	0.04 (0.00, 0.08)¹	2 (0.41, 4.08)	3.99 (3, 9)	< 0.001
Perianal disease (%)	32 (91.43)¹	3 (33.33)	7 (24.14)	0.002

¹Compared with the other two groups, adjusted P value < 0.01. M-IBD: Monogenic inflammatory bowel disease; NM-IBD: Non-monogenic inflammatory bowel disease; IL: Interleukin.

Citation: Su W, Yu Y, Xu X, Wang XQ, Huang JB, Xu CD, Xiao Y. Valuable clinical indicators for identifying infantile-onset inflammatory bowel disease patients with monogenic diseases. World J Gastroenterol 2021; 27(1): 92-106
URL: https://www.wjgnet.com/1007-9327/full/v27/i1/92.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i1.92