Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?
| Autor: | Christiane Spaich, Saskia Biskup, Deborah Bartholdi, Martin Zenker, Dennis Döcker, M. Menzel, Max Schubach, Heinz-Dieter Gabriel |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cutis marmorata Class I Phosphatidylinositol 3-Kinases Short Report Protein Tyrosine Phosphatase Non-Receptor Type 11 Skin Diseases Vascular Biology Models Biological LEOPARD Syndrome Consanguinity Phosphatidylinositol 3-Kinases Germline mutation Genetics medicine Humans Abnormalities Multiple Exome Telangiectasis Megalencephaly Child Germ-Line Mutation Genetics (clinical) Exome sequencing Comparative Genomic Hybridization Macrocephaly Genetic Variation High-Throughput Nucleotide Sequencing medicine.disease Pedigree PTPN11 Phenotype Overgrowth syndrome medicine.symptom |
| Zdroj: | European Journal of Human Genetics. 23:409-412 |
| ISSN: | 1476-5438 1018-4813 |
| DOI: | 10.1038/ejhg.2014.118 |
| Popis: | Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly—thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations. |
| Databáze: | OpenAIRE |
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