Studies on HIF-2α variants have shed light on genotype-phenotype correlations in Pacak-Zhuang syndrome. Here, we propose the combination of the timing of variant acquisition and molecular pathogenicity into a schema to understand phenotypic severity, with implications for other diseases.

Alkassi, Cole et al. provide a conceptual framework for understanding how the molecular characteristics and spatiotemporal distribution of HIF2α variants impact the disease phenotype in Pacak–Zhuang Syndrome. This schema has application not only to this syndrome, but also hereditary cancer syndromes and other mosaic diseases.

Center for Adrenal Endocrine Tumors AKESO 158 00 Prague 5 Czech Republic

Center for Human Genetics Clemson University Greenwood SC 29646 USA

Department of Genetics and Biochemistry Clemson University Clemson SC 29631 USA

National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda MD 20892 USA

Neuro Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA

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