Genetic Variants in the Transcription Factor Network: The Impact of <i>FOXC1, NOTCH1, RORC, FOXC</i>2 and <i>SOX18</i> in Primary Lymphedema.

Lymphedema is a chronic inflammatory disease caused by defective lymphatic system function or development that proceeds in ab-normal fluid drainage and edema of the peripheral tissues. This retrospective study evaluates the potential role of transcription factors in the development of primary lymphedema. We analyzed 408 Italian primary lymphedema patients for pathogenic variants in genes related to the transcription factor network. Eighteen likely pathogenic genetic variants were identified in 5 genes - <i>FOXC1, FOXC2, NOTCH1, RORC,</i> and <i>SOX18</i> - most of which have not been previously reported in the literature. Although majority of these genetic variants resulted in premature termination of the proteins, a single missense variant was identified in <i>FOXC2</i> and analyzed in this study using molecular modeling approaches to evaluate its structural changes. These results suggested possible deleterious effects of the analyzed variant and supported its potential pathogenicity. Our findings provide additional evidence that associates variants in transcription factors to the onset of lymphedema and support the addition of the candidate genes <i>FOXC1, NOTCH1,</i> and <i>RORC</i> in primary lymphedema diagnostic practice.