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Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2021 Dec; Vol. 185 (12), pp. 3623-3633. Date of Electronic Publication: 2021 Jun 29. - Publication Year :
- 2021
-
Abstract
- RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.<br /> (© 2021 Wiley Periodicals LLC.)
- Subjects :
- Adolescent
Adult
Child
Child, Preschool
Cleft Palate genetics
Cleft Palate physiopathology
Costello Syndrome genetics
Costello Syndrome physiopathology
Ectodermal Dysplasia genetics
Ectodermal Dysplasia physiopathology
Facies
Failure to Thrive genetics
Failure to Thrive physiopathology
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Heart Defects, Congenital genetics
Heart Defects, Congenital physiopathology
Humans
Infant
Knee Dislocation genetics
Knee Dislocation physiopathology
Male
Mutation
Neurofibromatoses epidemiology
Neurofibromatoses pathology
Noonan Syndrome epidemiology
Noonan Syndrome pathology
Phenotype
Pyloric Stenosis genetics
Pyloric Stenosis physiopathology
Young Adult
Neurofibromatoses genetics
Neurofibromin 1 genetics
Noonan Syndrome genetics
Proto-Oncogene Proteins c-raf genetics
Transcription Factors genetics
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 185
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 34184824
- Full Text :
- https://doi.org/10.1002/ajmg.a.62410