Mosaic skin disorders - deep sequencing

Gene: ARAF

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 but the phenotype is more within scope of the R110 Segmental overgrowth disorders – Deep sequencing panel. Therefore rating as amber on this panel and green on R110.

- 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, 11:32 a.m.

Panel Version: 2.2

Green List (high evidence)

Two patients described in Li et al with lymphatic anomaly, with same activating missense; functional studies support activating effect including zebrafish model.
Sources: Expert list

Created: 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

• 31263281

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments