Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.
Noonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited.



We sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed.



Eleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent.



RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226-1234.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Karim
K
Kouz
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Christina
0000-0002-5414-7126
C
Lissewski
Praxis für Humangenetik, Bremen, Germany.
Stephanie
S
Spranger
Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
Diana
D
Mitter
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Angelika
A
Riess
Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Vanesa
V
Lopez-Gonzalez
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Sabine
S
Lüttgen
Department of Medical Genetics, Medical Faculty, Namık Kemal University, Tekirdag, Turkey.
Hatip
0000-0003-4488-3186
H
Aydin
Sozialpädiatrisches Zentrum Coburg, Coburg, Germany.
Florian
F
von Deimling
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Christina
C
Evers
Department of Child Neurology, Justus-Liebig-University, Giessen, Germany.
Andreas
0000-0003-0235-5211
A
Hahn
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Maja
M
Hempel
Facharztzentrum Pädiatrie und Humangenetik, Martin Luther Universität Halle-Wittenberg, Halle (Saale), Germany.
Ulrike
U
Issa
Institut für Klinische Genetik, TU Dresden, Dresden, Germany.|Department for Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Anne-Karin
0000-0002-3201-2642
AK
Kahlert
Darmstädter Kinderkliniken, University Hospital Frankfurt, Frankfurt, Germany.
Adrian
A
Lieb
Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Pablo
P
Villavicencio-Lorini
Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Maria Juliana
MJ
Ballesta-Martinez
Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, India.
Sheela
S
Nampoothiri
Praxis für Humangenetik, München, Germany.
Angela
A
Ovens-Raeder
Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Alena
A
Puchmajerová
Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
Robin
R
Satanovskij
Institute of Human Genetics, Ludwig-Maximilian University, Munich, Germany.
Heide
H
Seidel
Praxis für Kinder- und Jugendmedizin, Volkach, Germany.
Stephan
S
Unkelbach
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.|Centre for Pediatric and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
Bernhard
0000-0002-7796-2991
B
Zabel
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Kerstin
K
Kutsche
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Martin
M
Zenker
D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D018631:ras Proteins / Q000235:genetics*
C486776:RIT1 protein, human; D018631:ras Proteins