Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil. Issue 4 (31st October 2020)

• Record Type: Journal Article
• Authors: 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.; Passos‐Bueno, Maria Rita; Kim, Chong A.
• Other Names: Prada Carlos E guestEditor.; Schwartz Ida guestEditor.; Cavalcanti Denise guestEditor.; Zarate Yuri A guestEditor.
• Is Part Of: American journal of medical genetics. Volume 184:Issue 4(2020)
• Page Start: 896
• Page End: 911
• Publication Date: 2020-10-31
• Subjects: genotype–phenotype correlation -- next‐generation sequencing -- Noonan syndrome -- RAS/MAPK pathway -- RASopathies; Medical genetics -- Periodicals; 616.04205
• DOI: 10.1002/ajmg.c.31851
• Languages: English
• ISSNs: 1552-4868

Abstract

Abstract: 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.