Background: Activating pathogenic variants in PIK3CA gene usually occur at a mosaic status and underlie a variety of segmental overgrowth phenotypes. Germline variants in PIK3CA have been rarely reported, described in a total of 12 patients with macrocephaly to date. Clinical and prognostic features of these germline variants have not been described in detail yet. Methods: Targeted deep sequencing by custom panel of the 21 genes involved in the PI3K/AKT/mTOR pathway was performed in a 13-year-old boy with macrocephaly and physical overgrowth. PI3K/AKT/mTOR pathway analysis was performed in fibroblasts by Western blot. The effects of miransertib (AKT inhibitor) and rapamycin (mTOR inhibitor) were assessed. Results: A de novo pathogenic variant (c.1090G>C; p.Gly364Arg) in PIK3CA gene was detected in a non-mosaic status in peripheral blood cells, buccal smears, and skin fibroblasts. Increased levels of phosphorylated AKT residues were observed in fibroblasts, rescued by miransertib. Conclusion: Germline variants in PIK3CA are associated to a mild phenotype characterized by overgrowth, severe macrocephaly, mild intellectual disability, and few dysmorphic features. Investigations of PI3K/AKT/mTOR pathway should be performed in patients with severe macrocephaly and unspecific physical overgrowth. Longitudinal studies to assess prognosis and cancer predisposition are recommended.

Zollino, M., Ranieri, C., Grossi, V., Leoni, C., Lattante, S., Mazza, D., Simone, C., Resta, N., Germline pathogenic variant in PIK3CA leading to symmetrical overgrowth with marked macrocephaly and mild global developmental delay, <<MOLECULAR GENETICS & GENOMIC MEDICINE>>, 2019; 7 (8): e845-e845. [doi:10.1002/mgg3.845] [http://hdl.handle.net/10807/147249]

Germline pathogenic variant in PIK3CA leading to symmetrical overgrowth with marked macrocephaly and mild global developmental delay

Zollino, M.
;
Leoni, C.;Lattante, S.;Mazza, D.;
2019

Abstract

Background: Activating pathogenic variants in PIK3CA gene usually occur at a mosaic status and underlie a variety of segmental overgrowth phenotypes. Germline variants in PIK3CA have been rarely reported, described in a total of 12 patients with macrocephaly to date. Clinical and prognostic features of these germline variants have not been described in detail yet. Methods: Targeted deep sequencing by custom panel of the 21 genes involved in the PI3K/AKT/mTOR pathway was performed in a 13-year-old boy with macrocephaly and physical overgrowth. PI3K/AKT/mTOR pathway analysis was performed in fibroblasts by Western blot. The effects of miransertib (AKT inhibitor) and rapamycin (mTOR inhibitor) were assessed. Results: A de novo pathogenic variant (c.1090G>C; p.Gly364Arg) in PIK3CA gene was detected in a non-mosaic status in peripheral blood cells, buccal smears, and skin fibroblasts. Increased levels of phosphorylated AKT residues were observed in fibroblasts, rescued by miransertib. Conclusion: Germline variants in PIK3CA are associated to a mild phenotype characterized by overgrowth, severe macrocephaly, mild intellectual disability, and few dysmorphic features. Investigations of PI3K/AKT/mTOR pathway should be performed in patients with severe macrocephaly and unspecific physical overgrowth. Longitudinal studies to assess prognosis and cancer predisposition are recommended.
Inglese
Zollino, M., Ranieri, C., Grossi, V., Leoni, C., Lattante, S., Mazza, D., Simone, C., Resta, N., Germline pathogenic variant in PIK3CA leading to symmetrical overgrowth with marked macrocephaly and mild global developmental delay, <<MOLECULAR GENETICS & GENOMIC MEDICINE>>, 2019; 7 (8): e845-e845. [doi:10.1002/mgg3.845] [http://hdl.handle.net/10807/147249]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/147249
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 3
social impact