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. 2023 Feb;60(2):163-173.
doi: 10.1136/jmedgenet-2021-108093. Epub 2022 Mar 7.

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

Alessandro Mussa  1   2 , Chiara Leoni  3 , Matteo Iacoviello  4 , Diana Carli  1   5 , Carlotta Ranieri  4 , Antonino Pantaleo  4 , Paola Sabrina Buonuomo  6 , Rosanna Bagnulo  4 , Giovanni Battista Ferrero  7 , Andrea Bartuli  6 , Daniela Melis  8 , Silvia Maitz  9 , Daria Carmela Loconte  4 , Antonella Turchiano  4 , Marilidia Piglionica  4 , Annunziata De Luisi  4 , Francesco Claudio Susca  4 , Nenad Bukvic  4 , Cinzia Forleo  10 , Angelo Selicorni  11 , Giuseppe Zampino  3 , Roberta Onesimo  3 , Gerarda Cappuccio  12 , Livia Garavelli  13 , Chiara Novelli  14 , Luigi Memo  15 , Carla Morando  15 , Matteo Della Monica  16 , Maria Accadia  17 , Martina Capurso  4 , Carmelo Piscopo  16 , Anna Cereda  18 , Marilena Carmela Di Giacomo  19 , Veronica Saletti  20 , Alessandro Mauro Spinelli  21 , Patrizia Lastella  22 , Romano Tenconi  23 , Veronika Dvorakova  24 , Alan D Irvine  24 , Nicoletta Resta  25
Affiliations

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

Alessandro Mussa et al. J Med Genet. 2023 Feb.

Abstract

Background: Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.

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.

Keywords: genetic testing; genotype; molecular medicine; phenotype; sequence analysis, DNA.

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Conflict of interest statement

Competing interests: None declared.

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