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Table 1 Chromosomal loci with risks of Hirschsprung disease, modified [6, 7]

From: Total colonic aganglionosis and cleft palate in a newborn with Janus-cysteine 618 mutation of RET proto-oncogene: a case report

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)
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
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
  1. Other genes (ABCC9, ARID1B, ARVCF, BACE2, COMT, CREBBP, DLL3, DNMT3B, DSCAM, ELP1,FZD3, GABRG2, GAL, GAP43, GHRL, IL11, INMT, MAPK10, MBTPS2, MED12, MIR146A, MIR369, NRSN1, NTRK3, PIGV, PSPN, PTCH1, RELN, RORA, SAMD9, SLC6A20, SOX2, TCF4, TUBA1A, VAMP5, WNT3A) without direct evidence for role in HSCR are actually classified as red/research gene only (
  2. Abbreviations: AD Autosomal dominant, AR Autosomal recessive, ARL6 ADP-ribosylation factor-like protein 6 gene, ASCL1 Achaete-scute homolog 1, BBIP1 BBSome interacting protein 1 gene, BBS Bardet Biedl syndrome gene, CELSR3 Cadherin EGF LAG seve-pass G-type receptor 3 gene, CEP290 Centrosomal protein gene, C8orf37 Chromosome 8 open reading frame 37, C10orf 27 Chromosome 10 open reading frame 27, DENND3 DENN domain-containing protein 3 gene, DHCR7 7-dehydrocholesterol reductase gene, DR Digenic recessive, EDNRB Endothelin receptor type b gene, EDN3 Endothelin 3 gene, GDNF Glial cell line-derived neurotrophic factor gene, GFRA1 GDNF family receptor alpha-1, HSCR Hirschsprung disease, IFT Intraflagellar transport, IKBKAP Inhibitor of kappa light polypeptide gene enhancer gene, KIAA1279 Kinesin binding protein, LZTFL1 Leucine zipper transcription factor like 1, L1CAM L1 cell adhesion molecule gene, MKKS McKusick-Kaufman syndrome gene, MKS1 Meckel syndrome-1 gene, MR Mental retardation, NCLN Nicalin, NF1 Neurofibromin 1 gene, NKX2–1 NK1 Homebox 1, NRG1 Neuregulin 1, NRTN Neurturin, NUP98 Nucleoporin 98, PHOX2B Paired-like homeobox 2B gene, PTHB1 Parathyroid hormon-responsive B1 gene, RET Rearranged during transfection protooncogene, RMRP RNAse mitochondrial RNA processing gene, SDCCAG8 Serologically defined colon cancer antigen 8 gene, SEMA Semaphorin, SOX10 Sry-box 10 gene, TTC8 Tetratricopeptide repeat domain 8, TRIM32 Tripartite motif containing 32, VCL Vinculin, XLR X-linked recessive, ZFHX1B Zinc finger homeobox protein 1b gene