Description
Familial Hirschsprung Disease Eligibility Statement:

Familial Hirschsprung Disease inclusion criteria
Diagnosis of Hirschsprung disease (HSCR) as proven with histology AND ONE OR MORE OF
1. Family history of HSCR, at least 2 affected first or second degree members, OR
2. Parental consanguinity, OR
3. HSCR occurring as part of a syndrome or with other anomalies

Familial Hirschsprung Disease exclusion criteria

Prior genetic testing guidance
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Familial Hirschsprung Disease prior genetic testing genes
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: 
RET and other tests as relevant if additional features are present e.g. microarray, ZEB2 (Mowat-Wilson syndrome).

Closing statement
These requirements will be kept under continual review during the main programme and may be subject to change.

5 reviewers

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Helen Brittain (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Sumita Chhabra (University of Liverpool / Alder Hey Children's Hospital)

    Group: Other NHS organisation
    Workplace: Research lab

  • Erwin Brosens (Erasmus MC)

    Group: GENE consortium member
    Workplace: Research lab

  • Merce Garcia-Barcelo (The University of Hong kong)

    Group: Other
    Workplace: Research lab

62 genes

62 reviewed, 8 green

List Gene Reviews Mode of inheritance Details
62 genes
Green Green List (high evidence)
KIF1BP
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Alder Hey - Erasmus MC
Phenotypes
  • Goldberg-Shprintzen megacolon syndrome, 609460 (includes Hirschsprung disease)
  • GOSHS
Green Green List (high evidence)
EDN3
3 reviews
1 green
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease 4, 613712
  • {Hirschsprung disease, susceptibility to, 4}, 613712
  • Waardenburg syndrome, type 4B, 613265
  • Hirschsprung Disease, Dominant
  • Waardenburg syndrome
  • WS4B
  • total colonic aganglionosis
  • short-segment Hirschsprung disease
Tags
  • monogenic-polygenic
Green Green List (high evidence)
EDNRB
3 reviews
1 green
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Radboud University Medical Center, Nijmegen
  • Alder Hey - Erasmus MC
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • susceptibility to Hirschsprung disease 2, 600155
  • Waardenburg syndrome, type 4A, 277580
  • {Hirschsprung disease, susceptibility to, 2}, 600155
  • Waardenburg syndrome, type 4A, 277580
  • Hirschsprung Disease, Recessive
  • Waardenburg
  • HSCR (short-segment type)
  • colonic aganglionosis
  • Shah-Waardenburg syndrome
  • long-segment Hirschsprung's disease
  • short-segment Hirschsprung's disease
Tags
  • monogenic-polygenic
Green Green List (high evidence)
L1CAM
2 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Alder Hey - Erasmus MC
Phenotypes
  • Hydrocephalus with Hirschsprung disease, 307000
Tags
  • monogenic-polygenic
Green Green List (high evidence)
PHOX2B
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • UKGTN
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Alder Hey - Erasmus MC
Phenotypes
  • Central hypoventilation syndrome, congenital, with or without Hirschsprung disease, 209880
  • Neuroblastoma with Hirschsprung disease, 613013
  • Congenital Central Hypoventilation Syndrome
  • Central Hypoventilation Syndrome, Congenital, 209880
Tags
  • nucleotide-repeat-expansion
Green Green List (high evidence)
RET
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
  • Radboud University Medical Center, Nijmegen
  • Eligibility statement prior genetic testing
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease 1, 142623
  • {Hirschsprung disease, susceptibility to, 1}, 142623
  • Hirschsprung Disease, Susceptibility To, 1, 142623
  • Hirschsprung Disease, Dominant
Tags
  • monogenic-polygenic
Green Green List (high evidence)
SOX10
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Other
  • Alder Hey - Erasmus MC
Phenotypes
  • Waardenburg syndrome with Hirschsprung disease (WS4C), 613266
  • PCWH syndrome, 609136 (includes Hirschsprung disease, long-segment)
  • Waardenburg syndrome, type 4C, 613266
  • Waardenburg Syndrome
  • PCWH Syndrome
Green Green List (high evidence)
ZEB2
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • UKGTN
  • Eligibility statement prior genetic testing
  • Alder Hey - Erasmus MC
  • Expert Review Green
  • Emory Genetics Laboratory
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Mowat-Wilson syndrome, 235730
  • Mowat-Wilson Syndrome, 235730
  • MWS
  • Hirschsprung disease
  • Mental retardation and distinct facial features, with or without Hirschsprung disease
Tags
  • cnv
Amber Amber List (moderate evidence)
CELSR3
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
DENND3
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
DHCR7
2 reviews
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Other
Phenotypes
  • Smith-Lemli-Opitz syndrome (MIM:270400) and Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
ECE1
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Radboud University Medical Center, Nijmegen
  • Alder Hey - Erasmus MC
Phenotypes
  • ?Hirschsprung disease, cardiac defects, and autonomic dysfunction, 613870
Tags
  • watchlist
Amber Amber List (moderate evidence)
GDNF
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease 3, 613711
  • {Hirschsprung disease, susceptibility to, 3}, 613711
  • Hirschsprung Disease, Dominant
  • short-segment HSCR
  • long-segment HSCR
Tags
  • watchlist
Amber Amber List (moderate evidence)
GFRA1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Alder Hey - Erasmus MC
  • Expert Review Amber
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
NCLN
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • mosaicism
  • watchlist
Amber Amber List (moderate evidence)
NKX2-1
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Other
  • Expert Review Amber
Phenotypes
  • Hirschsprung disease
  • short-segment aganglionosis
Tags
  • watchlist
Amber Amber List (moderate evidence)
NRG1
4 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
NRG3
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Alder Hey - Erasmus MC
  • Expert Review Amber
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • cnv
Amber Amber List (moderate evidence)
NUP98
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
SEMA3C
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
SEMA3D
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Alder Hey - Erasmus MC
  • Expert Review Amber
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
TBATA
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Alder Hey - Erasmus MC
  • Expert Review Amber
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • watchlist
Amber Amber List (moderate evidence)
VCL
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
  • short-segment Hirschsprung disease (S-HSCR)
Tags
  • watchlist
Red Red List (low evidence)
ABCC9
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
Red Red List (low evidence)
ARID1B
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • Hirschsprung disease
Red Red List (low evidence)
ARVCF
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • HSCR
  • Hirschsprung s Disease risk
Red Red List (low evidence)
BACE2
2 reviews
Unknown
Sources
  • Expert Review Red
Phenotypes
  • HSCR
Tags
  • watchlist
Red Red List (low evidence)
COMT
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • HSCR
  • Hirschsprung s Disease risk
Red Red List (low evidence)
CREBBP
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • Rubinstein-Taybi syndrome and Hirschsprung disease
Red Red List (low evidence)
DLL3
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
  • HSCR susceptibility
Red Red List (low evidence)
DNMT3B
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Other
Phenotypes
  • long-segment Hirschsprung disease
Tags
  • polygenic
Red Red List (low evidence)
DSCAM
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
  • Down syndrome-associated HSCR
Red Red List (low evidence)
ELP1
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
  • Hirschsprung disease (HSCR)
Red Red List (low evidence)
FZD3
2 reviews
1 red
Unknown
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • Hirschsprung disease
Red Red List (low evidence)
GABRG2
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Risk of Hirschsprung Disease
Red Red List (low evidence)
GAL
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Hirschsprung disease
  • HD
Red Red List (low evidence)
GAP43
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Hirschsprung disease
  • HD
Red Red List (low evidence)
GHRL
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • Hirschsprung disease (HSCR)
Red Red List (low evidence)
IL11
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
Red Red List (low evidence)
INMT
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
Red Red List (low evidence)
MAPK10
2 reviews
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • association with HSCR
Tags
  • cnv
Red Red List (low evidence)
MBTPS2
2 reviews
1 red
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Other
  • Expert Review Red
Phenotypes
  • IFAP syndrome with or without BRESHECK syndrome, 308205
Red Red List (low evidence)
MED12
2 reviews
1 red
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • Hirschsprung disease
  • HSCR
Red Red List (low evidence)
MIR146A
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Hirschsprung disease risk
Tags
  • locus-type-rna-micro
Red Red List (low evidence)
MIR369
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • HSCR
  • Hirschsprung's disease
Red Red List (low evidence)
NRSN1
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Hirschsprung disease
  • HD
Red Red List (low evidence)
NRTN
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Tags
  • polygenic
Red Red List (low evidence)
NTRK3
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • Hirschsprung disease
Tags
  • monogenic-polygenic
Red Red List (low evidence)
PIGV
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Other
Phenotypes
  • Hyperphosphatasia with mental retardation syndrome 1, MIM:239300 and Hirschsprung disease
Tags
  • watchlist
Red Red List (low evidence)
PSPN
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Red Red List (low evidence)
PTCH1
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
  • HSCR susceptibility
Red Red List (low evidence)
RELN
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Hirschsprung disease
  • HD
  • Risk of Hirschsprung Disease
Red Red List (low evidence)
RMRP
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Other
Phenotypes
  • Cartilage-hair hypoplasia (MIM:250250) with Hirschsprung disease
Red Red List (low evidence)
RORA
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
Red Red List (low evidence)
SAMD9
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • MIRAGE syndrome 617053
Red Red List (low evidence)
SEMA3A
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Alder Hey - Erasmus MC
Phenotypes
  • susceptibility to Hirschsprung disease
Red Red List (low evidence)
SLC6A20
2 reviews
1 red
Unknown
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • risk of HSCR
Red Red List (low evidence)
SOX2
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • association with HSCR
Tags
  • cnv
Red Red List (low evidence)
TCF4
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • risk of HSCR
Tags
  • cnv
Red Red List (low evidence)
TUBA1A
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • lissencephaly and Hirschsprung disease
Red Red List (low evidence)
VAMP5
2 reviews
1 red
Unknown
Sources
  • Literature
  • Expert Review Red
Phenotypes
  • risk of HSCR
Red Red List (low evidence)
WNT3A
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Hirschsprung disease

0 STRs

0 reviewed, 0 green

List STR Reviews Mode of inheritance Details
0 STRss

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