Segmental overgrowth disorders - Deep sequencing
Gene: ARAFComment 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
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
Tag treatable was removed from gene: ARAF. Tag Q3_23_NHS_review tag was added to gene: ARAF.
Tag treatable tag was added to gene: ARAF.
Tag Q3_23_promote_green tag was added to gene: ARAF.
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