Primary Ovarian Insufficiency_Premature Ovarian Failure

Gene: NOTCH2

Green List (high evidence)

At least 4 missense (in 5 women) with suggestive loss of function mechanisms and supporting mouse models
PMID: 32772338 - variable Hajdu-Cheney syndrome phenotype in family. Affected daughter with truncating variant not expected to cause NMD (pTrp2253Ter) had hypothalamic hypogonadism as a feature of the condition, but mother did not.
PMID: 32312275 - mother and daughter in a POI pedigree were both heterozygous for the missense p.Asp1853His (6 hets in gnomAD v2.1). In vitro functional assays of the variant demonstrated that it wasn't an activating mutation.
PMID: 30304577, 28505269 - 4 unrelated women with POI heterozygous for missense variants (p.Ser1804Leu, p.Gln1811His, p.Leu2408His, p.Pro2359Ala) and 1 woman suspected biallelic (p.Ala2316Val & p.Leu2408His). In vitro luciferase reporter assays in KGN cells demonstrated reduced function for S1804L (15% less), A2316V (27% less), and P2359A (14% less), the other missense were similar to WT. Additionally, p.Leu2408His has 583 hets in gnomAD v2.1. Suggested that POI is associated with loss of function, rather than the gain of function variants that cause Hajdu-Cheney syndrome and Alagille syndrome.
PMID: 28283672 - supporting conditional knockout mouse models
Sources: Literature

Created: 29 Nov 2021, 2:48 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Primary ovarian insufficiency

Publications

• 34794894
• 32772338
• 32312275
• 30304577
• 28505269
• 28283672