Segmental overgrowth disorders - Deep sequencing
Gene: ARAFEnsemblGeneIds (GRCh38): ENSG00000078061
EnsemblGeneIds (GRCh37): ENSG00000078061
OMIM: 311010, Gene2Phenotype
ARAF is in 2 panels
3 reviews
Achchuthan Shanmugasundram (Genomics England Curator)
The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) following NHS Genomic Medicine Service approval.Created: 4 Dec 2024, 5:08 p.m. | Last Modified: 4 Dec 2024, 5:08 p.m.
Panel Version: 3.19
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Arina Puzriakova (Genomics England Curator)
Comment on list classification: New gene added by Tom Cullup (GOSH). ARAF is not currently associated with any phenotype in OMIM or G2P. Although only two patients have been reported with the same missense variant, functional studies including an animal model provide strong support of pathogenicity (outlined below). Evidence of this variant specific gene-disease relationship is sufficiently compelling to rate this gene as green at the next GMS panel update.
- PMID: 31263281 (2019):
To date, only two unrelated patients have been reported with the same missense GoF variant in ARAF (c.640T>C:p.S214P) who both had a complex lymphatic anomaly (no haplotype analysis was done). Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions. A zebrafish model recapitulated the lymphatic phenotype. The cellular, zebrafish and patient clinical phenotypes were all rescued with with a MEK inhibitor.Created: 25 Jul 2023, 11:32 a.m. | Last Modified: 25 Jul 2023, 11:35 a.m.
Panel Version: 3.6
Tom Cullup (Great Ormond Street Hospital)
Two patients described in Li et al with lymphatic anomaly, with same activating missense; functional studies support activating effect including zebrafish model.
Sources: Expert listCreated: 9 May 2023, 11:02 a.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
central conducting lymphatic anomaly
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Details
- Mode of Inheritance
- X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
- Sources
-
- Expert Review Green
- NHS GMS
- Expert list
- Phenotypes
-
- central conducting lymphatic anomaly
- Tags
- OMIM
- 311010
- Clinvar variants
- Variants in ARAF
- Penetrance
- unknown
- Publications
- Mode of Pathogenicity
- Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
- Panels with this gene
History Filter Activity
Added Tag
Achchuthan Shanmugasundram (Genomics England Curator)Tag gene-checked tag was added to gene: ARAF.
Removed Tag, Removed Tag
Achchuthan Shanmugasundram (Genomics England Curator)Tag Q3_23_promote_green was removed from gene: ARAF. Tag Q3_23_NHS_review was removed from gene: ARAF.
Added New Source, Added New Source, Status Update
Achchuthan Shanmugasundram (Genomics England Curator)Source NHS GMS was added to ARAF. Source Expert Review Green was added to ARAF. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Removed Tag, Added Tag
Arina Puzriakova (Genomics England Curator)Tag treatable was removed from gene: ARAF. Tag Q3_23_NHS_review tag was added to gene: ARAF.
Added Tag
Arina Puzriakova (Genomics England Curator)Tag treatable tag was added to gene: ARAF.
Added Tag
Arina Puzriakova (Genomics England Curator)Tag Q3_23_promote_green tag was added to gene: ARAF.
Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity
Arina Puzriakova (Genomics England Curator)gene: ARAF was added gene: ARAF was added to Segmental overgrowth disorders - Deep sequencing. Sources: Expert Review Amber,Expert list Mode of inheritance for gene: ARAF was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: ARAF were set to 31263281 Phenotypes for gene: ARAF were set to central conducting lymphatic anomaly Penetrance for gene: ARAF were set to unknown Mode of pathogenicity for gene: ARAF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments