TABLE 1.
Inflammatory bowel disease cohort studies to investigate a spectrum of monogenic Inflammatory bowel disease using next-generation sequencing
| Publication | Year | Cohort description Study setup Patient selection Ethnicity | Age-at-IBD diagnosis—median or mean (range; in years) | Sequencing technology / Number of candidate genes | Number of patients Total (n)/monogenic IBD (n) / Functional validation, yes/no | Therapeutic consequences of genetic findings and Comment |
|---|---|---|---|---|---|---|
| Taylor et al (21) | 2015 | Single centre, UK IBD-onset <7 years | WGS 40 genes | Total 15 Monogenic IBD 0 |
N/A | |
| Kammermeier et al (47) | 2014 | Single tertiary referral centre; UK Extensive disease (pancolitis or panenteritis) Diagnosis within the first 36 months of life Caucasian n =11, Asian n =14 |
Median 0.58 years (0.1–1.6) | Sanger sequencing TGPS n = 25 WES n = 20 40 genes | Total 25 Monogenic IBD 7/25 IO-IBD 19% (4/21) |
HSCT assessment initiated and performed |
| Kelsen et al (48) | 2015 | Single tertiary referral centre; USA IBD-onset under 5 years of age |
Range 0.06 to 5 | WES 400 genes |
Total 125 Monogenic 0 Hypomorphic variants Yes |
N/A |
| Ashton et al (49) | 2016 | Single tertiary centre; UK Age <18 years | Median age at diagnosis 12.2 years Median age at onset 11.04 years |
WES n =147 51 genes |
Total 147 Unclear† No |
|
| Ostrowski et al (50) | 2016 | Multicentre; Poland Paediatric IBD No family history of IBD | 88 patients with IBD, 43 under 6 years of age, and 45 more than 40 years of age VEO-IBD: age range 1 to 5; median 3 |
WES n = 43 VEO-IBD and n = 45 after 40 years old 40 genes |
Total 88 Unclear† 2 homozygote variants (NCF4 and WAS) were found in 2 affected adults and one child, no functional validation |
|
| Xiao et al (51) | 2016 | Single tertiary centre, China VEO-IBD Chinese n = 13 |
mean age 0.5 range: 0 to 3 years | TGPS 10 genes, including susceptibility genes | Total 13 Monogenic IBD 3 Others not clear IO-IBD 23% (3/13) No |
|
| Petersen et al (52) | 2017 | Multicentre; international Early-onset IBD or chronic diarrhea Age at diagnosis <10 years of life Caucasian n = 47, Arab n = 9, Turkish n = 5, Other n = 10 |
Average 3 years | Total 71 TGPS n = 46 TGPS+WES n = 25 28 genes, including 5 susceptibility genes |
Total 71 Monogenic IBD 5 IO-IBD 13% (4/31) VEOIBD 9.26% (5/54) Yes |
HSCT initiated and performed |
| Suzuki et al (53) | 2017 | Multicentre; Japan 35 patients age <16 years, among whom 27 patients under the age of 6 Japanese n = 33, Japanese-Chinese n = 1, Japanese-Brazilian n = 1 |
Mean 4.50 years | TGPS n = 35 55 genes |
Total 35 Monogenic IBD 5, IO-IBD 22% (2/9) Paris A1a 13.3% (4/30) Paris A1b 20% (1/5) Yes |
HSCT initiated and performed |
| Kammermeier et al (16) | 2017 | Single centre, tertiary referral, UK IBD-onset <2 years 52% were White Europeans, 16% were Middle Eastern/Arab States, 8% Pakistani, 8% Indian, 6% Bangladeshi, 5% African, and 5% of mixed ethnic origin; 29% were offspring from consanguineous unions; 18% had a positive family history of IBD |
Median 0.25 years (0.1–0.9) | TGPS only n = 17 WES only n = 37 Sanger only n = 8 40 genes |
Total 62 Monogenic IBD 19, IO-IBD 31% (19/62) Partial |
HSCT initiated and performed |
| Quaranta et al (37) | 2018 | Single centre, tertiary referral, UK Age at IBD diagnosis 7–40 years Severe disease (need for intestinal surgery and/or therapy progression to biologics) |
WES 59 genes |
Total 503 Monogenic IBD 1, Paris A1a/b 0.19% (1/503) Yes |
HSCT initiated and performed | |
| Charbit-Henrion et al (31) | 2018 | Multicentre, international Clinical presentation of severe VEO-IBD (n = 185) and congenital diarrhea; History suggestive of monogenic disorder (n = 22) European n = 200, Asian n = 2 African n = 3, Australia n = 2 |
<2 years n = 144; > 6 years n = 22 | TNGS n = 167 WES n = 51 66 genes |
Total 207 Monogenic IBD 66, IO-IBD 41% (59/144) VEO-IBD 33.5% (62/185) 6 years 18% (4/22) Yes | |
| Amininejad et al (38) | 2018 | 660 early-onset/familial cases among the 2390 cases with Crohn’s disease | NGS 23 PID-genes | Hypomorphic variant in XIAP | no | |
| Fang et al (34) | 2018 | Single centre, China IBD-onset before 6 months of age or VEO-IBD accompanied with severe perianal disease, severe malnutrition or growth failure, or resistance to conventional treatment median age of disease-onset was 14 mo (IQR: 0–72 mo) among 54 patients with VEO-IBD Chinese n = 54 |
Median 2.9 years (0.25–14.4) |
TGPS n = 12 WES n = 6 TGPS and WES n = 2 4503 genes |
Total Monogenic IBD 9 IO-IBD 19.3% (6/31) VEOIBD 16.6% (9/54) Yes |
HSCT assessment initiated |
| Lega et al (35) | 2019 | Multicentre, Italy VEO-IBD and patients with early-onset IBD with severe/atypical phenotypes* | Median Monogenic IBD 2.25 years (0.83–4); Nonmonogenic IBD 2 years (0.66–4) | Candidate gene n = 47 TGPS n = 69 WES n = 16 TrioWES n = 5 Candidate genes: WES n = 400 TGPS A n = 30 TGPS A n = 43 | Total 93 Monogenic IBD 12; IO-IBD 14.5% (8/55) VEO-IBD 11.5% (10/87) > 6 years 17% (2/6) Yes | HSCT n = 7 Liver transplant n = 1 |
| Crowley et al (36) | 2020 | Single tertiary centre IBD-onset Canada under 18 years IBD-onset European/Caucasian 566, East Asia n = 19, South Asia n = 104, Africa n = 29, Mixed n = 63, American n = 65, Asian n = 35, West Asian n = 21, Unclassified n = 103 | Median 12.0 years (0–18) | WES (trio analysis) 67 genes | Total 1005 Monogenic IBD 31 Yes IO-IBD 13.8% (4/29) VEO-IBD 6.2% (7/112) 6 to 9.9 year 1.7% (3/179) 10 to 17.9 year 2.5% (17/ 684) | HSCT initiated and performed |
| Ashton et al (54) | 2020 | Single tertiary centre; UK Age <18 years | Median 11.9 years (1.3–17.4) | WES n = 401 68 genes | Total 401 Unclear† No |
|
| Serra et al (8) | 2020 | Multicentre, international Severe IBD disease course (previous surgery or need for biological therapy) no suspicion of monogenic IBD Caucasian n = 99 African n = 2, Asian n = 21 Jewish n = 1 Others/unknown n = 22 |
Median 3.5 years (4–6.8) | WES 67 genes | Total 145 Monogenic IBD 4 VEO-IBD 2.75% (4/145) Mosaicism n = 1 (CYBB) Yes |
HSCT assessment initiated in several patients |
| Uchida et al JPGN | 2020 | Multicentre, Japan Age <17 years, early-onset diarrhea, refractory to conventional therapies Japanese n = 107, Japanese- Laotian n = 1 |
Median age at onset 3.82 (IQR 2.50) years | TGPS 193 genes | Total 108 Monogenic IBD 15 VEO-IBD 9.9% (8/81) IO-IBD 17.1% (7/41) 6 to 10 years 38.4% (5/13) 10 to 17 years 14.3% (2/14) Yes |
HSCT = hematopoietic stem cell transplantation;TPS = Targeted panel sequencing, WES = Exome sequencing; WGS = genome sequencing.
*
Severe perianal disease, recurrent/atypical infections, skin/annexes abnormalities, abnormal immune status, associated multiple/severe autoimmunity,
history of macrophage activation syndrome or hemophagocytic lymphohistiocytosis, intestinal atresia, or early development of tumors.
†
In these articles, no functional validation of novel variants was performed. Many variants are found at unexpectedly high allele frequencies (ExAC and gnomAD databases), thus pathogenicity and inheritance pattern is unclear.