Arg1809 substitution in neurofibromin: further evidence of a genotype–phenotype correlation in neurofibromatosis type 1

Santoro, Claudia; Maietta, A.; Giugliano, Teresa; Melis, Daniela; Perrotta, Silverio; Piluso, Giulio

doi:10.1038/ejhg.2015.93

Cited by 36 publications

(43 citation statements)

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“…This uncertainty negatively impacts quality of life [Vranceanu et al., ]. Recently 29 patients from 12 families carrying an NF1 missense mutation at Arg1809 were reported with a phenotype of multiple CALMs and freckling, without cutaneous or visible plexiform neurofibromas, Lisch nodules, typical osseous lesions or symptomatic OPGs, and with facial features suggestive of Noonan syndrome in 50% [Pinna et al., ; Santoro et al., ], in line with our initial findings [Rojnueangnit et al., ]. Here, we report a cohort of 136 patients from 98 unrelated families carrying one of five different constitutional missense mutations affecting NF1 codon 1809 in exon 29 [38].…”

Section: Introductionsupporting

confidence: 87%

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High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

et al. 2015

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Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.

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Section: Introductionsupporting

confidence: 87%

“…First value are data from this study; second values are the data combined from this and previous studies (Ekvall et al., ; Nyström et al., ; Pinna et al., ; Santoro et al., ); between round brackets: percentages.…”

Section: Introductionmentioning

confidence: 98%

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

et al. 2015

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“… b Based on data from Pinna et al (), Rojnueangnit et al (), Ekvall et al (), Nyström et al (), and Santoro et al ().…”

Section: Resultsunclassified

Clinical spectrum of individuals with pathogenic N F1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1

et al. 2019

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“…The absence of genotype‐phenotype correlations in NF1 has been the rule for several years. Recently, some benign NF1 phenotypes were associated with distinctive NF1 mutations . NLS or Legius syndrome, characterized by CALMs, freckles and learning disabilities without increased oncological risk, was associated with mutations in SPRED1 .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, some benign NF1 phenotypes were associated with distinctive NF1 mutations. [5][6][7][8] NLS or Legius syndrome, characterized by CALMs, freckles and learning disabilities without increased oncological risk, was associated with mutations in SPRED1. 9 The highly variable phenotype and age-related appearance of some clinical features complicate NF1 diagnosis, particularly in childhood and in differential diagnosis with other RASopathies, including NLS, NS and NSML.…”

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confidence: 99%

Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype

et al. 2017

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Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-yearold boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes.Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain. K E Y W O R D Sgenotype-phenotype correlation, NF1, NGS, plexiform neurofibromas, RASopathies, SOS1

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Arg1809 substitution in neurofibromin: further evidence of a genotype–phenotype correlation in neurofibromatosis type 1

Cited by 36 publications

References 12 publications

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

Clinical spectrum of individuals with pathogenic N F1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1

Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype

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