title: Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP)--pure coincidence?
abstract: 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.
authors.affiliation: Institute of Clinical Genetics, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Döcker
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Schubach
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Menzel
authors.affiliation: Institute of Clinical Genetics, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Spaich
authors.affiliation: Institute of Clinical Genetics, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Heinz-Dieter
authors.initials: HD
authors.lastname: Gabriel
authors.affiliation: University Hospital, Institute of Human Genetics, University of Magdeburg, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Institute of Clinical Genetics, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.affiliation: 1] Institute of Clinical Genetics, Klinikum Stuttgart, Stuttgart, Germany [2] CeGaT GmbH, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D058534:Class I Phosphatidylinositol 3-Kinases; D055028:Comparative Genomic Hybridization; D003241:Consanguinity; D059472:Exome; D014644:Genetic Variation; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D058627:Megalencephaly / Q000175:diagnosis* / Q000235:genetics*; D008954:Models, Biological; D010375:Pedigree; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D017445:Skin Diseases, Vascular / Q000175:diagnosis* / Q000235:genetics*; D013684:Telangiectasis / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11