Limb disordersGene: EPHA4
regulatory rearrangements (not intragenic mutations) cause severe limb phenotypes: Lupianez Cell 161:1012-25;2015
Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.
Panel Version: 1.24
Comment on list classification: Rating this gene as amber for now. Deletion of a region including this gene has been reported in PMID: 25959774 - Lupiáñez et al 2015, however the mechanism for pathogenicity and deliniating reigion needs clarification.
Created: 29 Nov 2019, 12:39 p.m. | Last Modified: 29 Nov 2019, 1:04 p.m.
Panel Version: 1.141
A curation request has been submitted to Clingen regarding the regions of deletion, duplication and inversion around EPHA4 reported in PMID: 25959774 - Lupiáñez et al 2015.
Created: 29 Nov 2019, 12:37 p.m. | Last Modified: 29 Nov 2019, 12:37 p.m.
Panel Version: 1.137
EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype.
PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families:
Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. They detected a significant upregulation of Pax3 in DelB/+ limbs in mice, and DelB/+ (brachydactyly-like deletion) mice showed strong misexpression of Pax3 in the distal anterior part of the autopod, in a pattern resembling endogenous Epha4 expression.
Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects
Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008)
Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts.
Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp
Created: 12 Aug 2019, 2:24 p.m. | Last Modified: 29 Nov 2019, 12:36 p.m.
Panel Version: 1.137
Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list
Created: 1 Aug 2019, 4:41 p.m.
Mode of inheritance
Gene: epha4 has been classified as Amber List (Moderate Evidence).
gene: EPHA4 was added gene: EPHA4 was added to Limb disorders. Sources: Expert list Mode of inheritance for gene: EPHA4 was set to Unknown Review for gene: EPHA4 was set to AMBER