Cerebral vascular malformations

Gene: NOS3

I don't know

Comment on mode of inheritance: As reviewed by Alexandra Njegic, there are two unrelated cases and some functional evidence available for the association of biallelic variants with MMA. However, there is only one case with monoallelic NOS3 variant. The pathogenicity of this monoallelic variant was not explored in detail in the publication.

Hence, the gene should be rated amber and the MOI should be set to BIALLELIC.

The 'watchlist' tag has been added to review this gene in light of new evidence.

Created: 23 Apr 2025, 10:11 a.m. | Last Modified: 23 Apr 2025, 10:11 a.m.

Panel Version: 3.35

PMID:36941667 analysed six patients from a cohort of 126 consecutive unrelated probands with Moyamoya angiopathy (MMA) of unknown etiology. Two of these six patients were identified with homozygous NOS3 variants, of which one is missense (c.1942T> C, p.(Cys648Arg)) and the other is splice-site variant (c.1502 + 1G > C). Both probands with NOS3 variants suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. There is also some functional evidence available for both variants.

PMID:37383439 reported six patients with Moyamoya disease, of which one patient was identified with monoallelic missense NOS3 variant (c.1684G>A; p.Glu562Lys.

Created: 23 Apr 2025, 10:06 a.m. | Last Modified: 23 Apr 2025, 10:06 a.m.

Panel Version: 3.32

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Moyamoya disease, MONDO:0016820

Publications

• 36941667
• 37383439

I don't know

2 papers with a different mode of inheritance shown; pathogenicity of AD variant not explored in detail.
37383439: 1/6 Moyamoya disease patients with a NOS3 heterozygous variant, pathogenicity not provided.
36941667: 6 probands from consanguineous parentage with MMA, 2 NOS3 homozygous variants. In vitro studies, splice donor site variant leads to lack of eNOS in endothelial progenitor cells derived from the affected proband. Missense variant leads to reduced eNOS protein expression (HEK cells).
Sources: Literature

Created: 8 Apr 2025, 2:55 p.m. | Last Modified: 8 Apr 2025, 2:59 p.m.

Panel Version: 3.20

Mode of inheritance
Other

Phenotypes
Moyamoya Disease; Moyamoya Angiopathy

Publications

• 37383439
• 36941667