Lipodystrophy - childhood onset

Gene: EPHX1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 31 Dec 2025, 7:17 p.m. | Last Modified: 31 Dec 2025, 7:17 p.m.

Panel Version: 4.66

This gene is approved to upgrade to Green when TD eligibility and Clinical Indication name is expanded to Severe insulin resistance and lipodystrophy syndromes.

Created: 17 Jun 2024, 8:59 a.m. | Last Modified: 17 Jun 2024, 8:59 a.m.

Panel Version: 4.54

Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) in support of the association of this gene with lipodystrophy and severe insulin resistance. Hence, this gene can be promoted to green rating in the next GMS review.

Created: 8 Aug 2023, 6:10 a.m. | Last Modified: 8 Aug 2023, 6:10 a.m.

Panel Version: 4.34

Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.

Created: 8 Aug 2023, 6:04 a.m. | Last Modified: 8 Aug 2023, 6:11 a.m.

Panel Version: 4.34

This gene was added on recommendation of NHSE Genomic Medicine Service:
EPHX1 is an epoxide hydroxylase, highly expressed in liver and adipose tissue. De novo missense mutations (p.Thr333Pro and p.Gly430Arg) in EPHX1 carried in heterozygosity were implicated in a lipoatrophic diabetes syndrome in two unrelated probands (PMID: 34342583). In vitro characterisation demonstrated loss of enzyme activity in these two mutants and localisation studies demonstrated aggregation of the mutant EPHX1 isoforms in the ER, suggestive of a dominant negative mechanism of action. Consistent with a causal role for EPHX1 in the affected probands' syndrome, circulating epoxy fatty acids were found to be elevated. Variants implicated in the described clinical syndrome caused EPHX1 to form oligomeric complexes and aggregate in the ER. As such it is likely that simple loss of function mutations in EPHX1 do not cause this syndrome, and a dominant negative effect of the EPHX1 mutants is likely the causal mechanism. Consistent with this EPHX1 appears to be LOF tolerant (pLI gnomad = 0, https://gnomad.broadinstitute.org/gene/ENSG00000143819)

Created: 2 Aug 2023, 11:35 a.m. | Last Modified: 7 Aug 2023, 1:02 p.m.

Panel Version: 4.31

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Lipodystrophy, Severe Insulin Resistance

Publications

• 34342583

Mode of pathogenicity
Other