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Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype–phenotype associations and guide medical therapy in individuals with vascular anomalies.

Meiosis in the budding yeast Saccharomyces cerevisiaeis used to create haploid yeast spores from a diploid mother cell. During meiosis II, cytokinesis occurs by closure of the prospore membrane, a membrane that initiates at the spindle pole body and grows to surround each of the haploid meiotic products. Timely prospore membrane closure requires SPS1, which encodes an STE20family GCKIII kinase. To identify genes that may activate SPS1, we utilized a histone phosphorylation defect of sps1mutants to screen for genes with a similar phenotype and found that cdc15shared this phenotype. CDC15encodes a Hippo-like kinase that is part of the mitotic exit network. We find that Sps1complexes with Cdc15, that Sps1phosphorylation requires Cdc15, and that CDC15is also required for timely prospore membrane closure. We also find that SPS1, like CDC15, is required for meiosis II spindle disassembly and sustained anaphase II release of Cdc14in meiosis. However, the NDR-kinase complex encoded by DBF2/DBF20MOB1which functions downstream of CDC15in mitotic cells, does not appear to play a role in spindle disassembly, timely prospore membrane closure, or sustained anaphase II Cdc14release. Taken together, our results suggest that the mitotic exit network is rewired for exit from meiosis II, such that SPS1replaces the NDR-kinase complex downstream of CDC15.