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Phenotype–genotype analysis of 242 individuals with RASopathies : 18‐year experience of a tertiary center in Brazil
Author(s) -
Bertola Débora R.,
Castro Matheus A. A.,
Yamamoto Guilherme L.,
Honjo Rachel S.,
Ceroni José Ricardo,
Buscarilli Michele M.,
Freitas Amanda B.,
Malaquias Alexsandra C.,
Pereira Alexandre C.,
Jorge Alexander A. L.,
PassosBueno Maria Rita,
Kim Chong A.
Publication year - 2020
Publication title -
american journal of medical genetics part c: seminars in medical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.419
H-Index - 101
eISSN - 1552-4876
pISSN - 1552-4868
DOI - 10.1002/ajmg.c.31851
Subject(s) - noonan syndrome , ptpn11 , costello syndrome , phenotype , sanger sequencing , genetics , biology , genotype , gene , mutation , kras
We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11 , SOS1 , RAF1 , LZTR1 , and RIT1 , detected by Sanger and next‐generation sequencing. The latter was applied to 126 individuals, with a positive yield of 63% in genes of the RAS/MAPK cascade. We present evidence that there are some allelic differences in PTPN11 across distinct populations. We highlight the clinical aspects that pose more medical concerns, such as the cardiac anomalies, bleeding diathesis and proliferative lesions. The genotype–phenotype analysis between the RASopathies showed statistically significant differences in some cardinal features, such as craniofacial and cardiac anomalies, the latter also statistically significant for different genes in Noonan syndrome. We present two individuals with a Noonan syndrome phenotype, one with an atypical, structural cardiac defect, harboring variants in genes mainly associated with isolated hypertrophic cardiomyopathy and discuss the role of these variants in their phenotype.