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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
Genetics in Medicine, Volume 23, No. 7, Year 2021
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Description
Purpose: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. Conclusion: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes. © 2021, The Author(s).
Authors & Co-Authors
Dinulos, Mary Beth Palko
United States, Lebanon
Dartmouth-hitchcock Medical Center
United States, Hanover
Dartmouth College
Reigstad, Hallvard Martin
Norway, Bergen
Haukeland Universitetssjukehus
Houge, Gunnar Douzgos
Norway, Bergen
Haukeland Universitetssjukehus
Jeffery, Stephen C.C.
United Kingdom, London
St George’s, University of London
Mortimer, Peter S.
United Kingdom, London
St George’s, University of London
United Kingdom, London
St George's University Hospitals Nhs Foundation Trust
Kilby, Mark D.
United Kingdom, Birmingham
University of Birmingham
United Kingdom, Birmingham
Birmingham Women’s and Children’s Nhs Foundation Trust
Hempel, Maja
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Mansour, Sahar Mahmoud
United Kingdom, London
St George’s, University of London
Statistics
Citations: 4
Authors: 8
Affiliations: 15
Identifiers
Doi:
10.1038/s41436-021-01136-7
ISSN:
10983600
Research Areas
Genetics And Genomics