Germline pathogenic variant in PIK3CA leading to symmetrical overgrowth with marked macrocephaly and mild global developmental delay.
Mol Genet Genomic Med
; 7(8): e845, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31290289
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Deficiências do Desenvolvimento
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Megalencefalia
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Classe I de Fosfatidilinositol 3-Quinases
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adolescent
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article