Table 1 Chromosomal loci with risks of Hirschsprung disease, modified [6, 7]
Cytogenetic location/gene | Relative risk | Prevalence in HSCR | Mode of inheritance | Phenotype |
|---|---|---|---|---|
1p36.12/ECE1 | rare | AD | HSCR, cardiac defects, autonomic dysfunctions | |
1q43-q44/SDCCAG8 | AR | Bardet-Biedl syndrome-16 (like Bardet-Biedl syndrome-1)/Senior-Loken syndrome-7 | ||
2q22.3/ZFHX1B (ZEB2) | 3000-fold | 6% | AD | HSCR/Mowat-Wilson syndrome (MR, craniofacial dysmorphisms) |
2q31.1/BBS5 | AR | Bardet-Biedl syndrome-5 (like Bardet-Biedl syndrome-1) | ||
3p21 | 4-fold | HSCR6 | ||
3p21.32/CELSR3 (EGFL1) | Encephalopathy | |||
3p21.31/LZTFL1 | AR | Bardet-Biedl syndrome-17 (like Bardet-Biedl syndrome-1) | ||
3q11.2/ARL6 | AR | Bardet-Biedl syndrome-3 (like Bardet-Biedl syndrome-1) | ||
4p13/PHOX2B | 1000-fold | 0.5% | AD | Ondine syndrome (hypoventilation, autonomic dysfunctions) |
4q27/BBS7 | AR | Bardet-Biedl syndrome-7 (like Bardet-Biedl syndrome-1) | ||
4q27/BBS12 | AR | Bardet-Biedl syndrome-12 (like Bardet-Biedl syndrome-1) | ||
4q31.3-q32.3 | HSCR9 | |||
5p13.2/GDNF | rare | AD | HSCR3/Ondine syndrome (hypoventilation, autonomic dysfunctions) | |
7p14.3/PTHB1 | AR | Bardet-Biedl syndrome-9 (like Bardet-Biedl syndrome-1) | ||
7q21.11/SEMA3A/SEMA3D | 1.5-fold | AD | Hypogonadism, anosmia, altered axon branching | |
8p12/NRG1 | 1.2-fold | AD | Schizoaffective disorders | |
8q22.1/C8orf37 | AR | Bardet-Biedl syndrome-21 (like Bardet-Biedl syndrome-1) | ||
8q24.3/DENND3 | neurological involvement | |||
9p13.3/RMRP | 25-fold | 0.5% | AR | Cartilage-hair hypoplasia (short limb dwarfism, hypotrichosis, immunodeficiency) |
9p21.2/IFT74 | AR | Bardet-Biedl syndrome-20 (like Bardet-Biedl syndrome-1) | ||
9p24.1 | ||||
9q31/IKBKAP | AD; AR | HSCR5; Riley-Day syndrome (sensory and autonomic dysfunction) | ||
9q33.1/TRIM32 | AR | Bardet-Biedl syndrome-11 (like Bardet-Biedl syndrome-1) | ||
10q11.21/RET | 3000-fold | 48% of familial 20% of sporadic | AD | HSCR1 classical; HSCR/medullary thyroid carcinoma/multiple endocrine neoplasia syndrome-2A/−2B/ Ondine syndrome (hypoventilation, autonomic dysfunctions) |
10q22.1/C10orf27 (TBATA) | Thymus, brain and testes associated (TBATA) alterations | |||
10q22.1/KIAA1279 (KIF1BP) | AR | Goldberg-Shprintzen megacolon syndrome (MR, craniofacial dysmorphisms, nervous system anomalies) | ||
10q22.2/VCL | AD | Myopathy | ||
10q23.1/NRG3 | Schizoaffective disorders | |||
10q25.2/BBIP1 | AR | Bardet-Biedl syndrome-18 (like Bardet-Biedl syndrome-1) | ||
10q25.3/GFRA1 | rare | HSCR | ||
11p15.4/NUP98 | myelodysplastic syndrome | |||
11q13.2/BBS1 | AR, DR | Bardet-Biedl syndrome-1 (MR, obesity, retinal degeneration, genitourinary anomalies, HSCR, polydactyly and other laterality defects) | ||
11q13.4/DHCR7 | 50-fold | 1% | AR | Smith-Lemli-Opitz syndrome (MR, craniofacial dysmorphisms, 2–3 toe syndactyly, multiple malformations, hypogonadism) |
12q21.2/BBS10 | AR | Bardet-Biedl syndrome-10 (like Bardet-Biedl syndrome-1) | ||
12q21.32/CEP290 | AR | Bardet-Biedl syndrome-14 (like Bardet-Biedl syndrome-1)/Joubert-syndrome/Meckel syndrome/Leber congenital amaurosis-10 | ||
12q23.2/ASCL1 | AD | Ondine syndrome (hypoventilation, autonomic dysfunctions) | ||
13q22.3/EDNRB | 1000-3700-fold | 5% | AD, AR | HSCR2/ABCD syndrome/ Waardenburg-syndrome-4A (deafness, pigmentation defects) |
14q13.3/NKX2–1 | AD | Nonmedullary thyroid carcinoma, brain-lung-thyroid syndrome, chorea | ||
14q31.3/TTC8 | AR | Bardet-Biedl syndrome-8 (like Bardet-Biedl syndrome-1) | ||
15q24.1/BBS4 | AR | Bardet-Biedl syndrome-4 (like Bardet-Biedl syndrome-1) | ||
16q13/BBS2 | AR | Bardet-Biedl syndrome-2 (like Bardet-Biedl syndrome-1) | ||
16q23 | HSCR8 | |||
17q11.2/NF1 | AD | Neurofibromatosis 1 (Cafè-au-lait macules, neurofibromas, Lisch nodules) | ||
17q21/HOXB5 (HOX2A) | ||||
17q22/MKS1 | Bardet-Biedl syndrome-13 (like Bardet-Biedl syndrome-1)/Joubert-syndrome/Meckel syndrome | |||
19p13.3/NRTN | rare | HSCR | ||
19p13.3/NCLN | neurological involvement | |||
19q12 | 5-fold | HSCR7 | ||
20p11.22-p11.23 | ||||
20p12.2/MKKS | AR | McKusick-Kaufman/Bardet-Biedl syndrome-6 (like Bardet-Biedl syndrome-1) | ||
20q13.32/EDN3 | rare | AD, AR | HSCR4/Waardenburg-syndrome-4B (deafness, pigmentation defects); Ondine syndrome (hypoventilation, autonomic dysfunctions) | |
Trisomy 21 (21q22) | 50–100-fold | 8% | Down syndrome (MR, craniofacial dysmorphisms, gastrointestinal and cardiac malformations) | |
Partial tetrasomy 22q11 | AD | Cat eye syndrome (coloboma, craniofacial dysmorphisms, anorectal and cardiac malformations) | ||
22q12.3/IFT27 | AR | Bardet-Biedl syndrome-19 (like Bardet-Biedl syndrome-1) | ||
22q13.1/SOX10 | > 4000-fold | 4% | AD | HSCR/Waardenburg syndrome-4C or -2E (deafness, anosmia, pigmentation defects, hypogonadism, neurological involvement) |
Xq28/L1CAM | 40-fold | 1% | XLR | L1 syndrome (MR, hydrocephalus due to congenital stenosis of aqueduct of Sylvius, adducted thumbs) |
Male sex | 4-fold | 80% short-segment 65% long-segment | - SRY competes for SOX10 binding site - Males have less ECE1 and EDN3 expression in bowel |