Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes.

Objective: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated.

Research Design And Methods: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes.

Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study.

Background: Rare biallelic pathogenic mutations in PCSK1 (encoding proprotein convertase subtilisin/kexin type 1 [PC1/3]) cause early-onset obesity associated with various endocrinopathies. Setmelanotide has been approved for carriers of these biallelic mutations in the past 3 years. We aimed to perform a large-scale functional genomic study focusing on rare heterozygous variants of PCSK1 to decipher their putative impact on obesity risk.