A 4,302-patient cohort study of association of rare genetic alterations with endocrine disorders

Endocrine pathologies including disorders such as diabetes and dysfunctions of endocrine glands, are frequently associated with genetic predisposition. This study investigated the association of endocrine diseases with genetic variants, copy number variations (CNVs), and mutational load of molecular pathways in 4302 patients with 409 ICD-10 diagnoses who underwent DNA testing using next-generation sequencing at the National Medical Research Center for Endocrinology (Moscow) from November 2017 till January 2024. We analyzed rare protein-altering genetic variants using three control cohorts (gnomAD3, RUSeq healthy, experimental).  We identified 143 associated variants for diabetes mellitus and 188 genetic variants across other 18 different ICD-10 groups of diagnoses, including 25% and 30% of previously undescribed variants, respectively. In addition, we investigated the aggregation of genetic variants across individual genes and their functional ensembles (molecular pathways) and identified 105 and 101 associations with ICD-10 diagnoses, respectively. In addition, we identified 35 pathogenic and 91 likely pathogenic CNVs in 925 patients with whole exome sequencing profiles. Among them, 9 and 44 CNVs, respectively, were not previously described. Totally, we found statistically significant associations between CNVs and endocrine pathologies for 168 genes. These results expand our understanding of endocrine disease mechanisms and may indicate new potential therapeutic targets.