title: SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.
abstract: BACKGROUND
  Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS.
  
  
  RESULTS
  We investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene.
  
  
  CONCLUSIONS
  We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Judith
authors.initials: J
authors.lastname: Allanson
authors.forename: Silke
authors.initials: S
authors.lastname: Pauli
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.forename: Helmuth-Guenther
authors.initials: HG
authors.lastname: Doerr
authors.forename: Harald
authors.initials: H
authors.lastname: Gaspar
authors.forename: Michael
authors.initials: M
authors.lastname: Hofbeck
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Anja
authors.initials: A
authors.lastname: Nowka
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Silke
authors.initials: S
authors.lastname: Reif
authors.forename: Christian
authors.initials: C
authors.lastname: von Schnakenburg
authors.forename: Heide
authors.initials: H
authors.lastname: Seidel
authors.forename: Lars-Erik
authors.initials: LE
authors.lastname: Wehner
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.forename: Susanne
authors.initials: S
authors.lastname: Bauhuber
authors.forename: Verena
authors.initials: V
authors.lastname: Matejas
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomas
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D000595:Amino Acid Sequence; D001827:Body Height; D003251:Constriction, Pathologic; D005260:Female; D006331:Heart Diseases / Q000151:congenital / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009634:Noonan Syndrome / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D012871:Skin Diseases / Q000235:genetics*; D013577:Syndrome; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism
chemical_list: D020837:SOS1 Protein; D020663:ras Guanine Nucleotide Exchange Factors