期刊
GENETICS IN MEDICINE
卷 23, 期 7, 页码 1315-1324出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-021-01136-7
关键词
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资金
- British Heart Foundation (BHF) [SP/13/5/30288, FS/15/39/31526, MR/P011543/1]
- Medical Research Council (MRC) [MR/P011543/1]
- Fonds National Suisse de la Recherche Scientifique (FNS) [CRSII5_177191/1]
- Wellcome Trust
- Department of Health (England), through the Health Innovation Challenge Fund [HICF-R7-396]
- Wellcome Trust Sanger Institute [WT098051]
- National Institute for Health Research (NIHR), through the Comprehensive Clinical Research Network (CCRN)
- Swiss National Science Foundation (SNF) [CRSII5_177191] Funding Source: Swiss National Science Foundation (SNF)
This study reveals that novel variants of EPHB4 have different pathogenic mechanisms in various clinical phenotypes, and protein expression and subcellular localization studies are helpful in predicting the pathogenesis of EPHB4 variants. The study also uncovers the occurrence of intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops and CM-AVM2.
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.
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