Familial Hirschsprung Disease (Version 1.11)

Description

This panel is NO LONGER ACTIVELY MAINTAINED.

Please use with caution, as the gene list has not been recently updated. Reviews added to this panel are no longer a priority for curation and may not be followed up.

Please consider using an NHS Genomic Medicine Service (GMS) panel instead. The full list of GMS panels can be found here: https://nhsgms-panelapp.genomicsengland.co.uk/panels, with links back to PanelApp should you wish to leave a review on the panel.

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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.

Panel Activity

9 reviewers

Sarah Leigh (Genomics England Curator)

Group: Other
Workplace: Other
Rebecca Foulger (Genomics England curator)

Group: Other
Workplace: Other
Louise Daugherty (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
Eleanor Williams (Genomics England Curator)

Group: Other
Workplace: Other
Zornitza Stark (Australian Genomics)

Group: Other
Workplace: Other clinical service

63 Entities

63 reviewed, 8 green

List	Entity	Reviews	Mode of inheritance	Details
Filter Entities 63 Entitiess
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 Alder Hey - Erasmus MC Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen 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 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 Alder Hey - Erasmus MC Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen Phenotypes Waardenburg syndrome, type 4A, OMIM:277580 {Hirschsprung disease, susceptibility to, 2}, OMIM:600155 ?ABCD syndrome, OMIM:600501 Colonic aganglionosis Shah-Waardenburg syndrome Long-segment Hirschsprung's disease Short-segment Hirschsprung's disease Tags monogenic-polygenic
Green List (high evidence)	KIF1BP	4 reviews 1 green	BIALLELIC, autosomal or pseudoautosomal	Sources Alder Hey - Erasmus MC Expert Review Green Illumina TruGenome Clinical Sequencing Services Other Phenotypes Goldberg-Shprintzen megacolon syndrome, 609460 (includes Hirschsprung disease) GOSHS Tags new-gene-name
Green List (high evidence)	L1CAM	2 reviews 1 green	X-LINKED: hemizygous mutation in males, biallelic mutations in females	Sources Alder Hey - Erasmus MC Expert Review Green Radboud University Medical Center, Nijmegen Phenotypes Hydrocephalus with Hirschsprung disease, 307000 Tags monogenic-polygenic
Green List (high evidence)	PHOX2B	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen UKGTN 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 List (high evidence)	RET	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Alder Hey - Erasmus MC Eligibility statement prior genetic testing Expert Review Green Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen UKGTN 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 List (high evidence)	SOX10	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Alder Hey - Erasmus MC Expert Review Green Illumina TruGenome Clinical Sequencing Services Other Radboud University Medical Center, Nijmegen 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 Tags
Green List (high evidence)	ZEB2	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Eligibility statement prior genetic testing Emory Genetics Laboratory Expert Review Green Illumina TruGenome Clinical Sequencing Services UKGTN 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 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 List (moderate evidence)	DENND3	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 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 List (moderate evidence)	ECE1	3 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Expert Review Amber Radboud University Medical Center, Nijmegen Phenotypes ?Hirschsprung disease, cardiac defects, and autonomic dysfunction, 613870 Tags watchlist
Amber List (moderate evidence)	GDNF	3 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Alder Hey - Erasmus MC Expert Review Amber Illumina TruGenome Clinical Sequencing Services Radboud University Medical Center, Nijmegen 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 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 List (moderate evidence)	NCLN	3 reviews	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Alder Hey - Erasmus MC Expert Review Amber Phenotypes susceptibility to Hirschsprung disease Tags mosaicism watchlist
Amber List (moderate evidence)	NKX2-1	2 reviews 1 red	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Amber Other Phenotypes Hirschsprung disease short-segment aganglionosis Tags watchlist
Amber List (moderate evidence)	NRG1	4 reviews 1 green	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Alder Hey - Erasmus MC Expert Review Amber Phenotypes susceptibility to Hirschsprung disease Tags watchlist
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 List (moderate evidence)	NUP98	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 List (moderate evidence)	SEMA3C	3 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Expert Review Amber Phenotypes susceptibility to Hirschsprung disease Tags watchlist
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 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 List (moderate evidence)	VCL	3 reviews	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Alder Hey - Erasmus MC Expert Review Amber Phenotypes susceptibility to Hirschsprung disease short-segment Hirschsprung disease (S-HSCR) Tags watchlist
Red List (low evidence)	ABCC9	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Tags
Red List (low evidence)	ARID1B	2 reviews 1 red	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease Tags
Red List (low evidence)	ARVCF	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes HSCR Hirschsprung s Disease risk Tags
Red List (low evidence)	BACE2	2 reviews	Unknown	Sources Expert Review Red Other Phenotypes HSCR Tags watchlist
Red List (low evidence)	COMT	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes HSCR Hirschsprung s Disease risk Tags
Red List (low evidence)	CREBBP	2 reviews 1 red	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Red Literature Phenotypes Rubinstein-Taybi syndrome and Hirschsprung disease Tags
Red List (low evidence)	DLL3	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR HSCR susceptibility Tags
Red List (low evidence)	DNMT3B	2 reviews 1 red	Unknown	Sources Expert Review Red Other Phenotypes long-segment Hirschsprung disease Tags polygenic
Red List (low evidence)	DSCAM	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Down syndrome-associated HSCR Tags
Red List (low evidence)	ELP1	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Hirschsprung disease (HSCR) Tags
Red List (low evidence)	FZD3	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease Tags
Red List (low evidence)	GABRG2	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Risk of Hirschsprung Disease Tags
Red List (low evidence)	GAL	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease HD Tags
Red List (low evidence)	GAP43	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease HD Tags
Red List (low evidence)	GHRL	2 reviews 1 red	BIALLELIC, autosomal or pseudoautosomal	Sources Expert Review Red Literature Phenotypes Hirschsprung disease (HSCR) Tags
Red List (low evidence)	IL11	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Tags
Red List (low evidence)	INMT	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Tags
Red List (low evidence)	MAPK10	2 reviews	Unknown	Sources Expert Review Red Literature Phenotypes association with HSCR Tags cnv
Red List (low evidence)	MBTPS2	2 reviews 1 red	X-LINKED: hemizygous mutation in males, biallelic mutations in females	Sources Expert Review Red Other Phenotypes IFAP syndrome with or without BRESHECK syndrome, 308205 Tags
Red List (low evidence)	MED12	2 reviews 1 red	X-LINKED: hemizygous mutation in males, biallelic mutations in females	Sources Expert Review Red Literature Phenotypes Hirschsprung disease HSCR Tags
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 List (low evidence)	MIR369	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes HSCR Hirschsprung's disease Tags
Red List (low evidence)	NRSN1	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease HD Tags
Red List (low evidence)	NRTN	2 reviews 1 red	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Expert Review Red Phenotypes susceptibility to Hirschsprung disease Tags polygenic
Red List (low evidence)	NTRK3	2 reviews 1 red	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease Tags monogenic-polygenic
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 List (low evidence)	PSPN	2 reviews 1 red	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Expert Review Red Phenotypes susceptibility to Hirschsprung disease Tags
Red List (low evidence)	PTCH1	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR HSCR susceptibility Tags
Red List (low evidence)	RELN	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease HD Risk of Hirschsprung Disease Tags
Red List (low evidence)	RMRP	3 reviews 1 red	BIALLELIC, autosomal or pseudoautosomal	Sources Expert Review Red Other Phenotypes Cartilage-hair hypoplasia (MIM:250250) with Hirschsprung disease Tags locus-type-rna-long-non-coding
Red List (low evidence)	RORA	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Tags
Red List (low evidence)	SAMD9	3 reviews	MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown	Sources Expert Review Red Literature Phenotypes MIRAGE syndrome 617053 Tags
Red List (low evidence)	SEMA3A	3 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Alder Hey - Erasmus MC Expert Review Red Phenotypes susceptibility to Hirschsprung disease Tags
Red List (low evidence)	SLC6A20	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Tags
Red List (low evidence)	SMO	2 reviews 1 green 1 red	BIALLELIC, autosomal or pseudoautosomal	Sources Expert list Expert Review Red Phenotypes postaxial polydactyly MONDO:0020927 Microcephaly HP:0000252 congenital heart disease MONDO:0005453 Hirschsprung disease MONDO:0018309 Tags
Red List (low evidence)	SOX2	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes association with HSCR Tags cnv
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 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 Tags
Red List (low evidence)	VAMP5	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes risk of HSCR Tags
Red List (low evidence)	WNT3A	2 reviews 1 red	Unknown	Sources Expert Review Red Literature Phenotypes Hirschsprung disease Tags

Major version comments

18th October 2017: Revised and approved to Version 1.0 after expert and curator review. An expert list from Mr. Simon Kenny and Professor Robert Hofstra's groups (Alder Hey - Erasmus MC) formed the basis of the original panel. The expert list was then expanded based on a review of literature. Many of the literature genes remain red on the V1.0 panel as they were identified through association studies and/or they represent susceptibility/risk factors for Hirschsprung's disease (HSCR). Sumita Chhabra (Alder Hey) and Erwin Brosens (Erasmus) provided extensive feedback for genes on the panel, together with reviews from Merce Garcia-Barcelo.

Familial Hirschsprung Disease (Version 1.11)

9 reviewers

63 Entities

63 reviewed, 8 green

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