title: Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.
abstract: BACKGROUND
  Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases.
  
  
  METHODS
  A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently.
  
  
  RESULTS
  We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations.
  
  
  CONCLUSIONS
  We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.
authors: Unidade de Genética, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Guilherme Lopes
authors: GL
authors: Yamamoto
authors: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Meire
authors: M
authors: Aguena
authors: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors: Monika
authors: M
authors: Gos
authors: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors: Christina
authors: C
authors: Hung
authors: Department of Child Neurology, Medical University of Silesia, Katowice, Poland.
authors: Jacek
authors: J
authors: Pilch
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: Somayyeh
authors: S
authors: Fahiminiya
authors: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors: Anna
authors: A
authors: Abramowicz
authors: Nemours Children's Hospital Orlando, Orlando, Florida, USA.
authors: Ingrid
authors: I
authors: Cristian
authors: Unidade de Genética, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Michelle
authors: M
authors: Buscarilli
authors: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Michel Satya
authors: MS
authors: Naslavsky
authors: Departamento de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Alexsandra C
authors: AC
authors: Malaquias
authors: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Mayana
authors: M
authors: Zatz
authors: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors: Olaf
authors: O
authors: Bodamer
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: Jacek
authors: J
authors: Majewski
authors: Departamento de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Alexander A L
authors: AA
authors: Jorge
authors: Instituto de Cardiologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Alexandre C
authors: AC
authors: Pereira
authors: Unidade de Genética, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Chong Ae
authors: CA
authors: Kim
authors: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Maria Rita
authors: MR
authors: Passos-Bueno
authors: Unidade de Genética, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors: Débora Romeo
authors: DR
authors: Bertola
mesh_terms: D015331:Cohort Studies; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction; D020664:Son of Sevenless Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism
chemical_list: C509917:LZTR1 protein, human; C485509:SOS2 protein, human; D020664:Son of Sevenless Proteins; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: High-Throughput Nucleotide Sequencing; LZTR1; Noonan Syndrome; Rasopathies; SOS2