title: Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations.
abstract: RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Yaoita
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.affiliation: Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Department of Medical Genetics, Osaka Medical Center, Research Institute for Maternal and Child Health, Izumi, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Neonatology, The Jikei University Hospital, Tokyo, Japan.
authors.forename: Shion
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Division of Clinical Genetics, Nippon Medical School Hospital, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Pediatric Cardiology, Hokkaido Medical Center for Child Health and Rehabilitation, Sapporo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yokozawa
authors.affiliation: Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzumura
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nakahara
authors.affiliation: Department of Cardiology, Nagano Children's Hospital, Nagano, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Department of Pediatrics, Yokohama City University Hospital, Yokohama, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Hokosaki
authors.affiliation: Department of Pediatrics, Mie University, Tsu, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ohmori
authors.affiliation: Department of Pediatrics, Mie University, Tsu, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Ohsuke
authors.initials: O
authors.lastname: Migita
authors.affiliation: Department of Pediatrics, Yodogawa Christian Hospital, Osaka, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Mima
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos-Simarro
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
authors.forename: Sixto
authors.initials: S
authors.lastname: García-Miñaúr
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Division of Genomic Medicine Support and Genetic Counseling, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawame
authors.affiliation: Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. aokiy@med.tohoku.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D002675:Child, Preschool; D002916:Chylothorax / Q000235:genetics; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies / Q000379:methods*; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics*; D048208:Nuchal Translucency Measurement; D010996:Pleural Effusion / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D020837:SOS1 Protein; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C486776:RIT1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins