PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution
| العنوان: | PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution |
|---|---|
| المؤلفون: | Lim Jiin Yin, Beth Martin, Mark J. Stephan, Mariana Aracena, Cynthia J. Curry, Inge Krägeloh-Mann, Karen W. Gripp, Koenraad Devriendt, Michael Painter, Livia Garavelli, William B. Dobyns, Rachel Straussberg, Agustina Lanoel, Marie-Claude Addor, Margaret L. McKinnon, Luigi Boccuto, John Graham, Katrina Tatton-Brown, James D. Reggin, Jay Shendure, Colin C. Pritchard, Charles E. Schwartz, Mary Ella M Pierpont, Ian A. Glass, Fiona Stewart, Sulagna C. Saitta, Angeline Hwei Meeng Lai, Evan A. Boyle, Erin Torti, Anne Goriely, Michael T. Gabbett, Melanie Napier, Nicole Martin, Melissa T. Carter, Lisa Worgan, Renzo Guerrini, Katta M. Girisha, Ghayda M. Mirzaa, Chitra Prasad, Rachael Bradshaw, Leah W. Burke, Martin Kircher, Hulya Kayserilli, Andrew E. Timms, Jane Juusola, Karen D. Tsuchiya, Catherine E. Keegan, Robert L. Conway, David Chitayat, Kaylee Park, Hilde Van Esch, Aditi Shah Parikh, Maria R. Cordisco, Valerio Conti, Sondhya Ghedia, Raoul C.M. Hennekam, Sarah Collins, Bridget C. O’Connor, Stephen R. Braddock, Carissa Olds |
| المساهمون: | ANS - Complex Trait Genetics, APH - Amsterdam Public Health, Paediatric Genetics |
| المصدر: | JCI insight, vol. 1, no. 9, pp. 18p. JCI insight, 1(9). The American Society for Clinical Investigation Paediatrics Publications JCI Insight |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Genetics, Sanger sequencing, Somatic cell, Class I Phosphatidylinositol 3-Kinases/genetics, Female, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Malformations of Cortical Development/genetics, Mosaicism, Mutation, Phenotype, Tissue Distribution, Vascular Malformations/genetics, General Medicine, Biology, Molecular biology, 3. Good health, Variable Expression, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, Targeted ngs, symbols, Amplicon sequencing, Tissue distribution, Class I Phosphatidylinositol 3-Kinases, neoplasms, Research Article |
| الوصف: | Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations. The clinical and molecular spectrum of PIK3CA-related developmental disorders are correlated with types of mutations, tissue distributions, and levels of mosaicism with the clinical phenotype. |
| وصف الملف: | application/pdf; Print |
| اللغة: | English |
| تدمد: | 2379-3708 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4e277962199864ba9a67d6d7a87cffb7 https://serval.unil.ch/notice/serval:BIB_4CC9606A7F29 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4e277962199864ba9a67d6d7a87cffb7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
|---|