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Noonan syndrome and Neurofibromatosis type I in a family with a novel mutation in NF1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Bondeson/Annerén)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Dept. of Genetics, Children´s Hospital of Eastern Ontario, University of Ottawa, Canada.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2009 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 76, no 6, 524-534 p.Article in journal (Refereed) Published
Abstract [en]

Noonan Syndrome (NS) and Neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, while skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 - a condition known as Neurofibromatosis-Noonan Syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present.

We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Place, publisher, year, edition, pages
2009. Vol. 76, no 6, 524-534 p.
Keyword [en]
mutation, Neurofibromatosis-Noonan syndrome, NFNS, Noonan syndrome, RAS-MAPK
National Category
Medical and Health Sciences
Research subject
Clinical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-100777DOI: 10.1111/j.1399-0004.2009.01233.xISI: 000272128300006PubMedID: 19845691OAI: oai:DiVA.org:uu-100777DiVA: diva2:210980
Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. RAS-MAPK syndromes - a Clinical and Molecular Investigation
Open this publication in new window or tab >>RAS-MAPK syndromes - a Clinical and Molecular Investigation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The RAS-MAPK syndromes are a group of clinically and genetically related disorders, characterized by cardiac defects, facial dysmorphism, cutaneous abnormalities and neurocognitive impairment. The pathogenesis is dysregulation of the RAS-MAPK pathway, and several genes within the pathway are involved.

The present thesis aimed at identifying genetic causes in three of the RAS-MAPK syndromes - Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and Neurofibromatosis-Noonan syndrome (NFNS) - and at correlating genotype with phenotype.

A mutation analysis of six genes associated with the RAS-MAPK syndromes in NS and CFC patients revealed mutations in 10/31 patients. The results suggested more complex genetic overlap and genetic heterogeneity among these syndromes than previously believed. Subsequently, gene dosage imbalances of seven RAS-MAPK-syndrome-related genes were investigated in mutation-negative patients. A multiplex ligation-dependent probe amplification strategy was developed that excluded copy number changes of these genes as a common mechanism in NS.

Genetic causes of clinical variability in NS were investigated where an atypical and severe NS patient was described. In addition, multiple café-au-lait (CAL) spots affected the patient and four otherwise healthy family members. Molecular analysis of four candidate genes revealed a previously described de novo PTPN11 mutation and an inherited NF1 variant in the patient. Neither of them explained the CAL spots trait, which consequently represented a distinct entity. The results suggested that the atypical and severe phenotype in the patient could be a consequence of an additive effect.

Finally, a family displaying NFNS was investigated clinically and molecularly revealing a novel mutation in the GAP-domain of NF1. Furthermore, the results suggested that other RAS-MAPK-syndrome-related genes are not involved in NFNS. A proposal of prioritizing the GAP-domain of NF1 in NFNS was presented.

Conclusively, these studies contribute to further understanding of the RAS-MAPK syndromes and facilitate the diagnostic process and future prognosis prediction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 92 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 452
Keyword
RAS-MAPK syndromes, Noonan syndrome, Neurofibromatosis type I, cardio-facio-cutaneous syndrome, mutation, multiplex ligation-dependent probe amplification, gene
National Category
Medical Genetics
Research subject
Clinical Genetics
Identifiers
urn:nbn:se:uu:diva-100804 (URN)978-91-554-7508-6 (ISBN)
Public defence
2009-05-20, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-29 Created: 2009-04-07 Last updated: 2011-02-24Bibliographically approved
2. Genetic and Clinical Investigation of Noonan Spectrum Disorders
Open this publication in new window or tab >>Genetic and Clinical Investigation of Noonan Spectrum Disorders
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Noonan spectrum disorders belong to the RASopathies, a group of clinically related developmental disorders caused by dysregulation of the RAS-MAPK pathway. This thesis describes genetic and clinical investigations of six families with Noonan spectrum disorders.

In the first family, the index patient presented with severe Noonan syndrome (NS) and multiple café-au-lait (CAL) spots, while four additional family members displayed multiple CAL spots only. Genetic analysis of four RAS-MAPK genes revealed a de novo PTPN11 mutation and a paternally inherited NF1 mutation, which could explain the atypically severe NS, but not the CAL spots trait in the family. The co-occurrence of two mutations was also present in another patient with a severe/complex NS-like phenotype. Genetic analysis of nine RASopathy-associated genes identified a de novo SHOC2 mutation and a maternally inherited PTPN11 mutation. The latter was also identified in her brother. Both the mother and the brother displayed mild phenotypes of NS. The results from these studies suggest that an additive effect of co-occurring mutations contributes to severe/complex NS phenotypes.

The inherent difficulty in diagnosing Noonan spectrum disorders is evident in families with neurofibromatosis-Noonan syndrome (NFNS). An analysis of nine RASopathy-associated genes in a five-generation family with NFNS revealed a novel NF1 mutation in all affected family members. Notably, this family was initially diagnosed with NS and CAL spots. The clinical overlap between NS and NFNS was further demonstrated in three additional NFNS families. An analysis of twelve RASopathy-associated genes revealed three different NF1 mutations, all segregating with the disorder in each family. These mutations have been reported in patients with NF1, but have, to our knowledge, not been associated with NFNS previously. Together, these findings support the notion that NFNS is a variant of NF1. Due to the clinical overlap between NS and NFNS, we propose screening for NF1 mutations in NS patients negative for mutations in NS-associated genes, preferentially when CAL spots are present.

In conclusion, this thesis suggests that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway contributes to the clinical variability observed within Noonan spectrum disorders and further demonstrates the importance of accurate genetic diagnosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 830
Keyword
RASopathies, Noonan syndrome, neurofibromatosis type 1, neurofibromatosis-Noonan syndrome, RAS-MAPK pathway, mutation
National Category
Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-183325 (URN)978-91-554-8511-5 (ISBN)
Public defence
2012-12-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-16 Created: 2012-10-24 Last updated: 2013-01-23Bibliographically approved

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