Familial Hirschsprung Disease

Gene: PHOX2B

Green List (high evidence)

PHOX2B (paired like homeobox 2b)
EnsemblGeneIds (GRCh38): ENSG00000109132
EnsemblGeneIds (GRCh37): ENSG00000109132
OMIM: 603851, Gene2Phenotype
PHOX2B is in 11 panels

3 reviews

Erwin Brosens (Erasmus MC)

Green List (high evidence)

repeat expansion
Created: 30 Jun 2017, 1:11 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Rebecca Foulger (Genomics England curator)

Comment when marking as ready: Marked PHOX2B as ready: 20th July 2017.
Created: 20 Jul 2017, 12:45 p.m.
Added 'nucleotide-repeat-expansion' tag based on OMIM, Literature, Notes in Expert list submitted by Sumitra Chhabra & co (Alder Hey - Erasmus MC) and Reviewer comment from Erwin Brosens. Although most pathogenic variants in PHOX2B are nucleotide repeat expansions, there are other non-expansion variations that cause HSCR. Therefore I have kept the 'nucleotide-repeat-expansion' tag, but rated PHOX2B green.
Created: 20 Jul 2017, 12:40 p.m.
Comment on list classification: Kept rating as Green: Clear gene:disease causation link. Although the most common pathogenic mutations in PHOX2B (>90%) are increased GCG triplet repeats, producing a protein with an expanded polyalanine tract, there are non-polyalanine repeat mutations (NPARMs) outside this region that contribute to phenotypes incuding Hirschsprung disease (see comments for individual papers). Arianna Tucci also notes that the repeat expansion is small (and not unstable) and it is likely to be picked up by the current standard analysis. Also, the evidence is enough to make it green for non-PARMs.
Created: 20 Jul 2017, 12:37 p.m.
Comment on mode of inheritance: Updated MOI to 'NOT imprinted' based on review by Erwin Brosens.
Created: 20 Jul 2017, 12:33 p.m.
Case of a non-polyalanine repeat mutation (NPARM):
In affected members of a family previously described by Maris et al. (2002) in which 7 members spanning 3 generations had neuroblastoma (MIM:613013), 2 of whom also had Hirschsprung disease (MIM:142623), Mosse et al. (2004, PMID:15338462) identified a heterozygous 1-bp deletion in the PHOX2B gene, 676delG, resulting in a frameshift and a slightly truncated protein lacking the second polyalanine tract.
Created: 20 Jul 2017, 12:29 p.m.
Possible case of a non-polyalanine repeat mutation (NPARM):
In a male patient born to nonconsanguineous parents with a combination of Hirschsprung disease and neuroblastoma, Trochet et al. (2004, PMID:15024693) identified heterozygosity for a 421C-G transversion (p.R141G) in PHOX2B. HSCR was diagnosed in the neonatal period. Note that the R141G variant in this patient was inherited from the healthy mother.
Created: 20 Jul 2017, 12:23 p.m.
Case of a non-polyalanine repeat mutation (NPARM): Lombardo et al., 2017 (PMID:28422456) evaluated 3 family members with a heterozygous c.234C>G transition resulting in a premature stop codon in exon 1 of PHOX2B. 2 siblings in the family had a Hirschsprung diagnosis. The transmitting parent did not have HSCR but did have congenital heart disease (see Fig 1 in paper).
Created: 20 Jul 2017, 12:20 p.m.
Mouse model summarised in PMID:27370713: Total intestinal aganglionosis in homozygotes.
Created: 1 Jun 2017, 3:36 p.m.

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

animal model confirmation. functional test confirming deleterious variants
Created: 8 May 2017, 10:36 a.m.

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
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
OMIM
603851
Clinvar variants
Variants in PHOX2B
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

18 Oct 2017, Gel status: 4

panel promoted to version 1

Rebecca Foulger (Genomics England curator)

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.

20 Jul 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

20 Jul 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

20 Jul 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

20 Jul 2017, Gel status: 3

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for PHOX2B was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

20 Jul 2017, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PHOX2B were set to 28543993; 27370713; 28371199; 24182656; 28422456;15024693

6 Jun 2017, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

PHOX2B was added to Familial Hirschsprung Diseasepanel. Source: UKGTN

6 Jun 2017, Gel status: 2

Set Mode of Inheritance, Added New Source

Rebecca Foulger (Genomics England curator)

PHOX2B was added to Familial Hirschsprung Diseasepanel. Source: Illumina TruGenome Clinical Sequencing Services Model of inheritance for gene PHOX2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

6 Jun 2017, Gel status: 1

Added New Source

Rebecca Foulger (Genomics England curator)

PHOX2B was added to Familial Hirschsprung Diseasepanel. Source: Radboud University Medical Center, Nijmegen

1 Jun 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PHOX2B were set to 28543993; 27370713

1 Jun 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PHOX2B were set to 28543993

8 May 2017, Gel status: 0

Created

Rebecca Foulger (Genomics England curator)

PHOX2B was created by rfoulger

8 May 2017, Gel status: 0

Added New Source

Rebecca Foulger (Genomics England curator)

PHOX2B was added to Familial Hirschprungs Diseasepanel. Sources: Alder Hey - Erasmus MC