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Published on: April 4, 2018
Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients
E A Croonen1, W Nillesen, C Schrander
1Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Molecular Syndromology
|July 26, 2013
Summary
Noonan syndrome (NS) genetic analysis identified mutations in RAS-MAPK pathway genes in 42% of patients lacking PTPN11 mutations. This highlights the genetic heterogeneity of NS and suggests novel gene involvement.
Area of Science:
- Genetics
- Molecular Biology
- Clinical Medicine
Background:
- Noonan syndrome (NS) is an autosomal dominant disorder with characteristic facial dysmorphisms, short stature, and congenital heart defects.
- NS is genetically heterogeneous, overlapping with other RASopathies caused by mutations affecting the RAS-MAPK pathway.
- Commonly implicated genes include PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1, and SPRED1.
Purpose of the Study:
- To perform a genotype-phenotype analysis in 33 patients clinically diagnosed with Noonan syndrome but without PTPN11 mutations.
- To investigate mutations in genes associated with RASopathies (excluding NF1 and SPRED1) in this patient cohort.
- To correlate identified mutations with clinical phenotypes and assess the diagnostic significance of core NS features.
Main Methods:
- Genetic analysis was conducted on 33 patients with a clinical diagnosis of Noonan syndrome.
- Mutation screening focused on genes within the RAS-MAPK pathway, excluding NF1 and SPRED1.
- Phenotypic data was collected and analyzed in conjunction with genetic findings.
Main Results:
- Mutations were identified in 14 (42%) of the NS patients studied.
- Specific mutations found include SOS1 (7 patients), RAF1 (3 patients), and KRAS, MAP2K2, BRAF, and SHOC2 (1 patient each).
- Patients with BRAF or MAP2K2 mutations were diagnosed with cardio-facio-cutaneous syndrome; the SHOC2 mutation case presented with Noonan-like syndrome with loose anagen hair.
Conclusions:
- The study confirms the genetic heterogeneity of Noonan syndrome beyond PTPN11 mutations, with other RAS-MAPK pathway genes frequently implicated.
- The reduced prevalence of typical NS features (face, stature, heart defect) in mutation-negative patients underscores the importance of these specific symptoms.
- The findings suggest that novel genes likely contribute to Noonan syndrome, as all mutation-negative cases met diagnostic criteria.
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