| Autor: |
Zenner K; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.; Division of Pediatric Otolaryngology, Department of Head and Neck Surgery, University of Washington, Seattle, Washington, USA., Cheng CV; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA., Jensen DM; Center For Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA., Timms AE; Center For Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA., Shivaram G; Department of Radiology, University of Washington, Seattle, USA., Bly R; Division of Pediatric Otolaryngology, Department of Head and Neck Surgery, University of Washington, Seattle, Washington, USA., Ganti S; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington, USA., Whitlock KB; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington, USA., Dobyns WB; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.; Department of Pediatrics, Division Genetic Medicine, University of Washington, Seattle, Washington, USA., Perkins J; Division of Pediatric Otolaryngology, Department of Head and Neck Surgery, University of Washington, Seattle, Washington, USA., Bennett JT; Center For Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.; Department of Pediatrics, Division Genetic Medicine, University of Washington, Seattle, Washington, USA. |
| Abstrakt: |
Lymphatic malformations (LMs) are congenital, nonneoplastic vascular malformations associated with postzygotic activating PIK3CA mutations. The mutation spectrum within LMs is narrow, with the majority having 1 of 3 hotspot mutations. Despite this relative genetic homogeneity, clinical presentations differ dramatically. We used molecular inversion probes and droplet digital polymerase chain reaction to perform deep, targeted sequencing of PIK3CA in 271 affected and unaffected tissue samples from 81 individuals with isolated LMs and retrospectively collected clinical data. Pathogenic PIK3CA mutations were identified in affected LM tissue in 64 individuals (79%) with isolated LMs, with variant allele fractions (VAFs) ranging from 0.1% to 13%. Initial analyses revealed no correlation between VAF and phenotype variables. Recognizing that different mutations activate PI3K to varying degrees, we developed a metric, the genotype-adjusted VAF (GVAF), to account for differences in mutation strength, and found significantly higher GVAFs in LMs with more severe clinical characteristics including orofacial location or microcystic structure. In addition to providing insight into LM pathogenesis, we believe GVAF may have broad applicability for genotype-phenotype analyses in mosaic disorders. |
