NEDIHSS has been associated with bi-allelic LoF variants in ESAM. In particular, nonsense (c.35T>A, p.L12*), frameshift (c.115del, p.R39Gfs*33; c.287del, p.P96Lfs*33), and splicing (c.451+1G>A) homozygous variants were identified in thirteen affected individuals from Turkey, Algeria, Spain, and Israel. Since ESAM encodes an endothelial cell-selective adhesion molecule related to JAM proteins playing a pivotal role in the formation and maintenance of the blood-brain barrier, whose disruption leads to cerebrovascular manifestations. In vitro assays showed severely impaired tubulogenic process in the endothelial colony-forming cells isolated from an individual carrying the c.115del variant, recapitulating previous evidence in null mice. Considering the relatively aspecific phenotypic manifestations of NEDIHSS, exome sequencing (preferentially of the trio) would be recommended to diagnose this condition in both prenatal and postnatal settings.
Previously, a de novo heterozygous frameshift variant was reported in a subject affected by schizophrenia and developmental delay. Although more evidence is needed, it could be hypothesised that monoallelic LoF variants in ESAM may at most contribute (possibly together with other factors) to mild neurological phenotypes, in contrast to the severe phenotype observed in homozygous probands.
ESAM