Herein, in an effort to discover novel genetic mutations that contribute to lymphatic disease, we used next generation sequencing (NGS) for unbiased gene search and near-infrared fluorescence lymphatic imaging (NIRFLI) to phenotype family members and discovered that a mutation in the inositol polyphosphate phosphatase-like 1 (INPPL1) gene that encodes SH2-domain containing 5′-inositol phosphatase-2 (SHIP2) may be associated with lymphatic abnormalities in a nucleus family of varied expressivity of lymphedema. Here, INPPL1 is linked to lymphedema.