Publication Date
4-6-2023
Journal
American Journal of Human Genetics
DOI
10.1016/j.ajhg.2023.03.005
PMID
36996813
PMCID
PMC10119151
PubMedCentral® Posted Date
3-29-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Mice, Alleles, Brain Diseases, Cell Adhesion Molecules, Endothelial Cells, Intracranial Hemorrhages, Nervous System Malformations, Neurodevelopmental Disorders, Tight Junctions, Humans, ESAM, tight junctions, blood-brain barrier, neurodevelopmental disorders, intracranial hemorrhage, global developmental delay, intellectual disability, epilepsy, retinopathy, pregnancy loss, exome sequencing
Abstract
The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as “tightjunctionopathies.”
Graphical Abstract
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