Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Mussa Alessandro, Leoni Chiara, Iacoviello Matteo, Carli Diana, Ranieri Carlotta, Pantaleo Antonino, Buonuomo Paola Sabrina, Bagnulo Rosanna, Ferrero Giovanni Battista, Bartuli Andrea, Melis Daniela, Maitz Silvia, Loconte Daria Carmela, Turchiano Antonella, Piglionica Marilidia, De Luisi Annunziata, Susca Francesco Claudio, Bukvic Nenad, Forleo Cinzia, Selicorni Angelo, Zampino Giuseppe, Onesimo Roberta, Cappuccio Gerarda, Garavelli Livia, Novelli Chiara, Memo Luigi, Morando Carla, Della Monica Matteo, Accadia Maria, Capurso Martina, Piscopo Carmelo, Cereda Anna, Di Giacomo Marilena Carmela, Saletti Veronica, Spinelli Alessandro Mauro, Lastella Patrizia, Tenconi Romano, Dvorakova Veronika, Irvine Alan D, Resta Nicoletta
Аннотация
METHODS: We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed.
RESULTS: 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK.
CONCLUSION: We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping 'vascular' phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.