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Genet Med. 2016 Dec;18(12):1226-1234. doi: 10.1038/gim.2016.32. Epub 2016 Apr 21.

Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.

Author information

1
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
3
Praxis für Humangenetik, Bremen, Germany.
4
Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
5
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
6
Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
7
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
8
Department of Medical Genetics, Medical Faculty, Namık Kemal University, Tekirdag, Turkey.
9
Sozialpädiatrisches Zentrum Coburg, Coburg, Germany.
10
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
11
Department of Child Neurology, Justus-Liebig-University, Giessen, Germany.
12
Facharztzentrum Pädiatrie und Humangenetik, Martin Luther Universität Halle-Wittenberg, Halle (Saale), Germany.
13
Institut für Klinische Genetik, TU Dresden, Dresden, Germany.
14
Department for Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.
15
Darmstädter Kinderkliniken, University Hospital Frankfurt, Frankfurt, Germany.
16
Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
17
Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, India.
18
Praxis für Humangenetik, München, Germany.
19
Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
20
Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
21
Institute of Human Genetics, Ludwig-Maximilian University, Munich, Germany.
22
Praxis für Kinder- und Jugendmedizin, Volkach, Germany.
23
Centre for Pediatric and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

PMID:
27101134
DOI:
10.1038/gim.2016.32
[Indexed for MEDLINE]

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