title: Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.
abstract: Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Ekvall
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sjörs
authors.forename: Anders
authors.initials: A
authors.lastname: Jonzon
authors.forename: Mauno
authors.initials: M
authors.lastname: Vihinen
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bondeson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017253:Neurofibromatoses / Q000175:diagnosis* / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000175:diagnosis* / Q000235:genetics*; D009634:Noonan Syndrome / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
keywords: NF1; RAS-MAPK pathway; RASopathies; mutation; neurofibromatosis type 1; neurofibromatosis-Noonan syndrome