CLINICAL REPORT Two Independent de novo Mutations as a Cause for Neurofibromatosis Type 1 and Noonan Syndrome in a Single Family Eric Pasmant, 1,2 * Jeanne Amiel, 3,4 Diana Rodriguez, 5,6,7 Michel Vidaud, 1,2 Dominique Vidaud, 1,2 and B eatrice Parfait 1,2 1 Service de Biochimie et de G en etique Mol eculaire, H^ opital Cochin AP-HP, Paris, France 2 UMR745 INSERM, Universit e Paris Descartes, Sorbonne Paris Cit e, Facult e des Sciences Pharmaceutiques et Biologiques, Paris, France 3 Unit e INSERM U781, Universit e Paris Descartes, Sorbonne Paris Cit e, Paris, France 4 Service de G en etique, H^ opital Necker-Enfant Malades, AP-HP, Paris, France 5 INSERM U676, Paris, France 6 Service de neurologie p ediatrique, H^ opital Armand Trousseau, AP-HP, Paris, France 7 UPMC Universit e de Paris 06, Paris, France Manuscript Received: 8 September 2011; Manuscript Accepted: 6 May 2012 Here we report on a family with two siblings born to unrelated healthy parents, one with neurofibromatosis type 1 (NF1) and the other with Noonan syndrome (NS). Molecular investigations performed on the NF1 and PTPN11 genes showed two inde- pendent de novo mutations as a cause for NF1 in the NF1 proband and NS in her affected brother. Both de novo mutations were potentially of paternal origin, given the advanced paternal age at the time of conception. Ó 2012 Wiley Periodicals, Inc. Key words: de novo mutation; Neurofibromatosis type 1; Noonan syndrome; paternal age effect INTRODUCTION Both neurofibromatosis type 1 (NF1; OMIM 162200) and Noonan syndrome (NS; OMIM 163950) are autosomal dominant disorders, with an estimated incidence of 1 in 3,000–4,000 [Sabbagh et al., 2009] and 1 in 1,000–2,500 live births [Tartaglia et al., 2011], respectively. Here, we report on a family with an unusual presen- tation of NF1 and NS in two siblings. CLINICAL REPORT The 10-year-old propositus was the second child born to unrelated healthy parents. Her clinical presentation met the diagnostic cri- teria for NF1, with a large congenital plexiform neurofibroma of the left foot and multiple caf  e-au-lait macules. She had no manifes- tations of NS. However, NS was diagnosed at the age of three in her 13-year-old brother, due to short stature, hypertelorism, short broad neck, thoracic deformity, and moderate cardiac abnormal- ities including mild pulmonary valve stenosis and mitral insuffi- ciency. He had no manifestations of NF1. MOLECULAR INVESTIGATION Mutation screening was performed by direct DNA sequencing using an ABI Prism 3130 automatic DNA sequencer (Applied Biosystems). Informed consent was obtained from the two patients and their parents. Total RNA extracted from the NF1 proband- derived lymphoblastoid cell line was reverse transcribed and ampli- fied using NF1 cDNA-specific oligonucleotides. Genomic DNA extracted from peripheral blood leukocytes was amplified using primers specific for PTPN11 coding exons (NM_002834) and sequenced. Conflicts of interest: None. *Correspondence to: Eric Pasmant, PharmD, PhD, UMR745 INSERM, Universit  e Paris Descartes, Sorbonne Paris Cit  e, Facult  e des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, Paris 75006, France. E-mail: eric.pasmant@gmail.com Article first published online in Wiley Online Library (wileyonlinelibrary.com): DOI 10.1002/ajmg.a.35496 How to Cite this Article: Pasmant E, Amiel J, Rodriguez D, Vidaud M, Vidaud, D, Parfait B. 2012. Two independent de novo mutations as a cause for neurofibromatosis type 1 and Noonan syndrome in a single family. Am J Med Genet Part A. Ó 2012 Wiley Periodicals, Inc. 1