**8. Conclusions and Perspectives**

Major discoveries have been made in the field of PA research over the last few years mainly due to the application of next-generation sequencing methods. Four familial forms of hyperaldosteronism are now recognized with the genetic basis of three of these uncovered by exome sequencing. Somatic mutations have been identified in ion channels and transporters that alter intracellular ion homeostasis and drive the constitutive aldosterone production in over half of aldosterone-producing adenomas. Differential gene expression studies have further highlighted key signalling pathways and molecular mechanisms that may drive cell proliferation and aldosterone overproduction in aldosterone-producing adenomas. Transcriptome analysis methods may have a future application in the identification of prognostic markers to identify post-operative cardiovascular events.

**Acknowledgments:** This work was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 694913 to Martin Reincke) and by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 "The Adrenal: Central Relay in Health and Disease" to Felix Beuschlein, Martin Reincke and Tracy A. Williams; and grants RE 752/20-1 to Martin Reincke and grants BE 2177/13-1 and BE 2177/18-1 to Felix Beuschlein) and the Else Kröner-Fresenius Stiftung in support of the German Conns Registry-Else-Kröner Hyperaldosteronism Registry (2013\_A182 and 2015\_A171 to Martin Reincke).

**Author Contributions:** All the authors contributed substantially to the work presented in this manuscript. Tracy A. Williams conceived the work; Felix Beuschlein, Martin Reincke and Isabella Castellano contributed materials; Eva Sušnik performed immunohistochemistry; Lucie S. Meyer, Yuhong Yang and Martina Tetti performed the literature search and prepared art work and tables; Elke Tatjana Aristizabal Prada wrote the first draft of the manuscript; Tracy A. Williams, Felix Beuschlein and Martin Reincke revised the manuscript; all authors critically revised the final version.

**Conflicts of Interest:** The authors declare no conflict of interest.
