Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways

Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole-exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant, p.Ala1603Tyr, in NOTCH3 meeting the filtering criteria. Further analysis of WES data of 222 patients with unexplained FPL identified two unrelated patients with FPL with novel heterozygous (p.Cys1600Tyr and p.Gln1552Pro) NOTCH3 variants. All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3. RNA sequencing and proteomics analysis of skin fibroblasts revealed significantly higher RNA and protein expression of NOTCH3 and activation of widespread senescence pathways in the patients with FPL versus control study participants. NOTCH3 is highly expressed in adipose tissue and plays many crucial roles in developmental patterning, cell fate decisions, regulation of cell survival, and proliferation. We conclude that gain-of-function missense variants in the negative regulatory region of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways. This novel variety of FPL should be considered for patients without obesity but with early- or childhood-onset diabetes.

• Molecular genetic defects in some ultra-rare subtypes of familial partial lipodystrophies (FPLs) remain unidentified.

• We investigated whether novel gene variants explain FPL in some undiagnosed patients.

• We found novel heterozygous gain-of-function missense variants clustered in the heterodimerization domain of the negative regulatory region of NOTCH3 in three unrelated families with FPL.

• Our study suggests that gain-of-function missense variants in the heterodimerization domain of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways.