Clinical Staging and Genetic Profiling of Korean Patients with Primary Lymphedema Using Whole-Exome Sequencing: Preliminary Results

Abstract Lymphedema is a progressive disease caused by lymphatic flow blockage in the lymphatic pathway. Primary (hereditary) lymphedema is caused by genetic mutations without secondary causes. However, the underlying cause of primary lymphedema remains obscure, and gene sequencing studies on a sizable patient cohort are lacking. We performed clinical profiling on Korean primary lymphedema patients based on their phenotypes and using lymphoscintigraphy and made genetic diagnoses using a next-generation sequencing panel consisting of 60 lymphedema-related genes. Of 27 patients, 21% had lymphedema of the upper extremities, 81% had lymphedema of the lower extremities, and two patients had lymphedema in both. Based on International Society of Lymphology staging, 14, 10, and 3 patients had stage 3, 2, and 1 lymphedema, respectively. Genetic abnormalities were identified in six patients: a pathogenic variant of CELSR1 in two patients, variants of uncertain significance (VUSs) of CELSR1 in two patients, a VUS of SOS1 in one patient, and a pathogenic variant of MPI and VUSs of TIE1, FLT4, and PIEZO1 in one patient. The clinical and genetic profile of hereditary lymphedema reported here is the first such data series reported in South Korea. Our study highlights the need for genetic screening in primary lymphedema diagnosis.