Exome sequencing (ES) of a pediatric cohort with chronic endocrine diseases: a single-center study (within the framework of the TRANSLATE-NAMSE project)

Background Endocrine disorders are heterogeneous and include a significant number of rare monogenic diseases. Methods We performed exome sequencing (ES) in 106 children recruited from a single center within the TRANSLATE‑NAMSE project. They were categorized into subgroups: proportionate short stature (PSS), disproportionate short stature (DSS), hypopituitarism (H), differences in sexual development (DSD), syndromic diseases (SD) and others. Results The overall diagnostic yield was 34.9% ( n = 37/106), including 5 patients with variants in candidate genes, which have contributed to collaborations to identify gene-disease associations. The diagnostic yield varied significantly between subgroups: PSS: 16.6% (1/6); DSS: 18.8% (3/16); H: 17.1% (6/35); DSD: 37.5% (3/8); SD: 66.6% (22/33); others: 25% (2/8). Confirmed diagnoses included 75% ultrarare diseases. Three patients harbored more than one disease-causing variant, resulting in dual diagnoses. Conclusions ES is an effective tool for genetic diagnosis in pediatric patients with complex endocrine diseases. An accurate phenotypic description, including comprehensive endocrine diagnostics, as well as the evaluation of variants in multidisciplinary case conferences involving geneticists, are necessary for personalized diagnostic care. Here, we illustrate the broad spectrum of genetic endocrinopathies that have led to the initiation of specific treatment, surveillance, and family counseling. Graphical Abstract