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Genetic and Clinical Investigation of Noonan Spectrum Disorders
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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 [en]
RASopathies, Noonan syndrome, neurofibromatosis type 1, neurofibromatosis-Noonan syndrome, RAS-MAPK pathway, mutation
National Category
Medical Genetics
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-183325ISBN: 978-91-554-8511-5 (print)OAI: oai:DiVA.org:uu-183325DiVA: diva2:562541
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
List of papers
1. A severe form of Noonan syndrome and autosomal dominant café-au-lait spots: evidence for different genetic origins
Open this publication in new window or tab >>A severe form of Noonan syndrome and autosomal dominant café-au-lait spots: evidence for different genetic origins
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2009 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, no 4, 693-698 p.Article in journal (Refereed) Published
Abstract [en]

Aim: The clinical overlap among Noonan syndrome (NS), cardio-facio-cutaneous (CFC), LEOPARD and Costello syndromes as well as Neurofibromatosis type 1 is extensive, which complicates the process of diagnosis. Further genotype–phenotype correlations are required to facilitate future diagnosis of these patients. Therefore, investigations of the genetic cause of a severe phenotype in a patient with NS and the presence of multiple café-au-lait spots (CAL) spots in the patient and four members of the family were performed. Methods: Mutation analyses of candidate genes, PTPN11, NF1, SPRED1 and SPRED2, associated with these syndromes, were conducted using DNA sequencing. Results: A previously identified de novo mutation, PTPN11 F285L and an inherited NF1 R1809C substitution in the index patient were found. However, neither PTPN11 F285L, NF1 R1809C, SPRED1 nor SPRED2 segregated with CAL spots in the family. The results indicate that the familial CAL spots trait in this family is caused by a mutation in another gene, distinct from previous genes associated with CAL spots in these syndromes. Conclusion: We suggest that the atypical severe symptoms in the index patient may be caused by an additive effect on the F285L mutation in PTPN11 by another mutation, for example the NF1 R1809C or alternatively, the not yet identified gene mutation associated with CAL spots in this family.

Keyword
Café-au-lait spots, Mutation, NF1, Noonan syndrome, PTPN11
National Category
Medical Genetics
Research subject
Clinical Genetics
Identifiers
urn:nbn:se:uu:diva-100802 (URN)10.1111/j.1651-2227.2008.01170.x (DOI)000263965400022 ()19120036 (PubMedID)
Note

De två (2) sista författarna delar sistaförfattarskapet.

Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2017-12-13Bibliographically approved
2. Co-Occurring SHOC2 and PTPN11 Mutations in a Patient With Severe/Complex Noonan Syndrome-Like Phenotype
Open this publication in new window or tab >>Co-Occurring SHOC2 and PTPN11 Mutations in a Patient With Severe/Complex Noonan Syndrome-Like Phenotype
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2011 (English)In: American Journal of Medical Genetics Part A, ISSN 1552-4825, Vol. 155, no 6, 1217-1224 p.Article in journal (Refereed) Published
Abstract [en]

Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A> G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c. 1226G>C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, cafe-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p. Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.

Keyword
Noonan syndrome, SHOC2, PTPN11, RAS-MAPK pathway, mutation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156160 (URN)10.1002/ajmg.a.33987 (DOI)000291944200003 ()
Available from: 2011-07-13 Created: 2011-07-12 Last updated: 2013-01-23Bibliographically approved
3. Noonan syndrome and Neurofibromatosis type I in a family with a novel mutation in NF1
Open this publication in new window or tab >>Noonan syndrome and Neurofibromatosis type I in a family with a novel mutation in NF1
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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.

Keyword
mutation, Neurofibromatosis-Noonan syndrome, NFNS, Noonan syndrome, RAS-MAPK
National Category
Medical and Health Sciences
Research subject
Clinical Genetics
Identifiers
urn:nbn:se:uu:diva-100777 (URN)10.1111/j.1399-0004.2009.01233.x (DOI)000272128300006 ()19845691 (PubMedID)
Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2017-12-13Bibliographically approved
4. Mutations in NF1 in families with neurofibromatosis type I and neurofibromatosis-Noonan syndrome
Open this publication in new window or tab >>Mutations in NF1 in families with neurofibromatosis type I and neurofibromatosis-Noonan syndrome
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-183324 (URN)
Available from: 2012-10-24 Created: 2012-10-24 Last updated: 2013-01-23

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