Cargando…

Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

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 nov...

Descripción completa

Detalles Bibliográficos
Autores principales: Martin-Almedina, Silvia, Ogmen, Kazim, Sackey, Ege, Grigoriadis, Dionysios, Karapouliou, Christina, Nadarajah, Noeline, Ebbing, Cathrine, Lord, Jenny, Mellis, Rhiannon, Kortuem, Fanny, Dinulos, Mary Beth, Polun, Cassandra, Bale, Sherri, Atton, Giles, Robinson, Alexandra, Reigstad, Hallvard, Houge, Gunnar, von der Wense, Axel, Becker, Wolf-Henning, Jeffery, Steve, Mortimer, Peter S., Gordon, Kristiana, Josephs, Katherine S., Robart, Sarah, Kilby, Mark D., Vallee, Stephanie, Gorski, Jerome L., Hempel, Maja, Berland, Siren, Mansour, Sahar, Ostergaard, Pia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257501/
https://www.ncbi.nlm.nih.gov/pubmed/33864021
http://dx.doi.org/10.1038/s41436-021-01136-7
_version_ 1783718327861903360
author Martin-Almedina, Silvia
Ogmen, Kazim
Sackey, Ege
Grigoriadis, Dionysios
Karapouliou, Christina
Nadarajah, Noeline
Ebbing, Cathrine
Lord, Jenny
Mellis, Rhiannon
Kortuem, Fanny
Dinulos, Mary Beth
Polun, Cassandra
Bale, Sherri
Atton, Giles
Robinson, Alexandra
Reigstad, Hallvard
Houge, Gunnar
von der Wense, Axel
Becker, Wolf-Henning
Jeffery, Steve
Mortimer, Peter S.
Gordon, Kristiana
Josephs, Katherine S.
Robart, Sarah
Kilby, Mark D.
Vallee, Stephanie
Gorski, Jerome L.
Hempel, Maja
Berland, Siren
Mansour, Sahar
Ostergaard, Pia
author_facet Martin-Almedina, Silvia
Ogmen, Kazim
Sackey, Ege
Grigoriadis, Dionysios
Karapouliou, Christina
Nadarajah, Noeline
Ebbing, Cathrine
Lord, Jenny
Mellis, Rhiannon
Kortuem, Fanny
Dinulos, Mary Beth
Polun, Cassandra
Bale, Sherri
Atton, Giles
Robinson, Alexandra
Reigstad, Hallvard
Houge, Gunnar
von der Wense, Axel
Becker, Wolf-Henning
Jeffery, Steve
Mortimer, Peter S.
Gordon, Kristiana
Josephs, Katherine S.
Robart, Sarah
Kilby, Mark D.
Vallee, Stephanie
Gorski, Jerome L.
Hempel, Maja
Berland, Siren
Mansour, Sahar
Ostergaard, Pia
author_sort Martin-Almedina, Silvia
collection PubMed
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.
format Online
Article
Text
id pubmed-8257501
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group US
record_format MEDLINE/PubMed
spelling pubmed-82575012021-07-23 Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes Martin-Almedina, Silvia Ogmen, Kazim Sackey, Ege Grigoriadis, Dionysios Karapouliou, Christina Nadarajah, Noeline Ebbing, Cathrine Lord, Jenny Mellis, Rhiannon Kortuem, Fanny Dinulos, Mary Beth Polun, Cassandra Bale, Sherri Atton, Giles Robinson, Alexandra Reigstad, Hallvard Houge, Gunnar von der Wense, Axel Becker, Wolf-Henning Jeffery, Steve Mortimer, Peter S. Gordon, Kristiana Josephs, Katherine S. Robart, Sarah Kilby, Mark D. Vallee, Stephanie Gorski, Jerome L. Hempel, Maja Berland, Siren Mansour, Sahar Ostergaard, Pia Genet Med Article 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. Nature Publishing Group US 2021-04-16 2021 /pmc/articles/PMC8257501/ /pubmed/33864021 http://dx.doi.org/10.1038/s41436-021-01136-7 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Martin-Almedina, Silvia
Ogmen, Kazim
Sackey, Ege
Grigoriadis, Dionysios
Karapouliou, Christina
Nadarajah, Noeline
Ebbing, Cathrine
Lord, Jenny
Mellis, Rhiannon
Kortuem, Fanny
Dinulos, Mary Beth
Polun, Cassandra
Bale, Sherri
Atton, Giles
Robinson, Alexandra
Reigstad, Hallvard
Houge, Gunnar
von der Wense, Axel
Becker, Wolf-Henning
Jeffery, Steve
Mortimer, Peter S.
Gordon, Kristiana
Josephs, Katherine S.
Robart, Sarah
Kilby, Mark D.
Vallee, Stephanie
Gorski, Jerome L.
Hempel, Maja
Berland, Siren
Mansour, Sahar
Ostergaard, Pia
Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
title Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
title_full Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
title_fullStr Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
title_full_unstemmed Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
title_short Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
title_sort janus-faced ephb4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257501/
https://www.ncbi.nlm.nih.gov/pubmed/33864021
http://dx.doi.org/10.1038/s41436-021-01136-7
work_keys_str_mv AT martinalmedinasilvia janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT ogmenkazim janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT sackeyege janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT grigoriadisdionysios janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT karapouliouchristina janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT nadarajahnoeline janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT ebbingcathrine janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT lordjenny janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT mellisrhiannon janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT kortuemfanny janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT dinulosmarybeth janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT poluncassandra janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT balesherri janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT attongiles janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT robinsonalexandra janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT reigstadhallvard janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT hougegunnar janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT vonderwenseaxel janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT beckerwolfhenning janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT jefferysteve janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT mortimerpeters janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT gordonkristiana janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT josephskatherines janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT robartsarah janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT kilbymarkd janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT valleestephanie janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT gorskijeromel janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT hempelmaja janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT berlandsiren janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT mansoursahar janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes
AT ostergaardpia janusfacedephb4associateddisordersnovelpathogenicvariantsandunreportedintrafamilialoverlappingphenotypes