EPHB4 – Capillary Malformation-Arteriovenous Malformation 2

EPHB4 encodes a transmembrane tyrosine kinase receptor critical for vascular development. Heterozygous variants in EPHB4 have been established as causative for capillary malformation-arteriovenous malformation 2 (CM-AVM2) with an autosomal dominant inheritance pattern.

Genetic studies identified pathogenic EPHB4 variants in 54 unrelated index patients, including 27 predicted loss-of-function alleles (premature stop codons or splice-site alterations) and 20 missense substitutions, with cosegregation demonstrated in five families (PMID:28687708). An independent cohort of ten HHT-gene–negative probands revealed seven additional pathogenic variants, with mosaicism in one case, confirming variable expressivity (PMID:30760892).

Affected individuals display multifocal cutaneous capillary malformations, telangiectasia (HP:0001009), and epistaxis (HP:0000421) in the majority of cases (8/10 and 6/10, respectively), and rare central nervous system arteriovenous malformations (2/10) (PMID:30760892). One representative allele is c.1099G>T (p.Gly367Ter), a recurrent stop-gain variant observed in CM-AVM2 families.

The variant spectrum comprises predominantly truncating mutations consistent with EPHB4 haploinsufficiency. No common founder alleles have been reported; each pathogenic variant appears to be private to individual pedigrees.

Functional assays in HEK293 cells and primary endothelial cultures confirmed that disease-associated missense and truncating alleles abolish EPHB4 phosphorylation and disrupt downstream RAS-MAPK signaling, recapitulating the vascular phenotypes observed in humans (PMID:28687708). These data support a loss-of-function mechanism underlying CM-AVM2.

Integration of genetic and experimental findings strongly supports a Strong ClinGen gene-disease association driven by over 60 unrelated probands, multi-family segregation, and concordant functional data. EPHB4 mutation analysis should be included in molecular panels for patients with capillary malformations and suspected hereditary hemorrhagic telangiectasia.

Key Take-home: Heterozygous EPHB4 loss-of-function variants cause CM-AVM2 via autosomal dominant haploinsufficiency, with implications for diagnosis, genetic counseling, and targeted surveillance.

References

• Genetics in medicine • 2019 • Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? PMID:30760892
• Circulation • 2017 • Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling PMID:28687708

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