Phenotype–genotype analysis of 242 individuals with <scp>RASopathies</scp>: 18‐year experience of a tertiary center in Brazil

Bertola, Débora Romeo; Castro, Matheus Augusto Araújo; Yamamoto, Guilherme Lopes; Honjo, Rachel Sayuri; Ceroni, José Ricardo Magliocco; Buscarilli, Michele M; Freitas, Amanda Brasil de; Malaquias, Alexsandra C.; Pereira, Alexandre C.; Jorge, Alexander A L; Passos‐Bueno, Maria Rita; Kim, Chong

doi:10.1002/ajmg.c.31851

Cited by 14 publications

(20 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most prevalent mutation in European and North American populations, c.922A > G (p.Asn308Asp), was not found in this Brazilian study. A more recent Brazilian cohort with 242 individuals with RASopathies, of which 185 had a NS diagnosis, showed that PTPN11 p.Asn308Asp variant as the most prevalent in the cohort (21.4%) (Bertola et al, 2020). Rodríguez et al (2013) performed a molecular characterization of Chilean patients with clinical NS diagnosis and identified PTPN11 pathogenic variants in four out of 18 patients, but none with p.Asn308Asp.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical and molecular characterization of Noonan syndrome patients tends to be similar between patients of different ethnic backgrounds (Kruszka et al, 2017). Few studies have aimed to examine these features in the Latin American population (Bertola et al, 2006; Chinton, Huckstadt, Moresco, Gravina, & Obregon, 2019; Rodríguez, Unanue, Hernández, Heath, & Cassorla, 2013; Bertola et al, 2020). However, there are no reported studies in the Colombian population.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia

Lores

Prada

Ramírez‐Montaño

et al. 2020

American J of Med Genetics Pt C

View full text Add to dashboard Cite

Our aim was to characterize the phenotype and genotype of individuals with Noonan syndrome in Colombia. There are published cohorts of Noonan individuals from several countries in Latin America including Brazil, Chile, and Argentina, but none from Colombia. We described 26 individuals with NS from a single large referral center in the South West of Colombia using an established database in the genetics department and hospital records search using ICD‐10 codes. All patients included in this study were evaluated by a medical geneticist and have molecular confirmation of NS diagnosis. The median age at referral was 3.5 years (range, 0–39), and at molecular diagnosis was 5 years (range, 0–40). Patients mostly originated from the southwest region of Colombia (19/26, 73%). Pathogenic variants in PTPN11 are the most common cause of NS in Colombian individuals followed by SHOC2 and SOS1 variants. The prevalence of cardiomyopathy was low in this population compared to other populations. Further research is needed with a larger sample size and including different regions of Colombia to correlate our findings. This study provides new information about time to diagnosis of NS in Colombia, genotypes, and provides important information to help develop guidelines for diagnosis and management of this disease in the region.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia

Lores

Prada

Ramírez‐Montaño

et al. 2020

American J of Med Genetics Pt C

View full text Add to dashboard Cite

show abstract

“…All mutations found were missense and favour the open con guration of the enzyme allowing its permanent catalytic function [6; 22]. Among the more frequent variants, p.Asn308Asp has been also recorded as the most prevalent in other populations, reaching ~20% in Europe, USA, Argentina [20; 23], Brazil [24] and 11% in South India [11]. It should be noted that intellectual disability of variable degree was negatively associated with PTPN11 mutations compared to other genes tested.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Clinical Profile of patients referred as Noonan or Noonan-like Syndrome in Greece: a cohort of 86 patients

Papadopoulos

Papadopoulou

Kosma

et al. 2022

Preprint

View full text Add to dashboard Cite

Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, Rasopathies, due to the implication of mutations in more than 10 genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease’s prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 patients. Patients identified as NS or NS-like syndrome from a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and Next-Generation-Sequencing, comprising 14 different genes. Heterozygous variants were revealed in 11/14 genes: PTPN11 (32.5%), RIT1 (8.1%), SOS1 (4.7%), A2ML1 (4.7%), SPRED1 (3.5%), BRAF (1.2%), CBL (1.2%), KRAS (1.2%), MAP2K1 (1.2%); RAF1 (1.2%); SHOC2 (1.2%), corresponding to 59.5% of positivity in our population. The genotype-phenotype analysis showed statistically significant differences regarding craniofacial dysmorphisms (p=0.0015), pulmonary valve stenosis (PS) (p<0.001) and neurological features (p<0.001) between patients harboring a mutation in any of the tested genes and mutation-free patients. Patients with at least one mutation had 7.36 times greater odds to develop PS compared to mutation-negative patients [OR=7.36, 95%; CI= (2.69,20.18)]. Conclusion: Craniofacial dysmorphism, neurological defects and PS prevail among mutation positive compared to mutation negative NS and NS-like patients. The significant prevalence of the Ras/MAPK mutations (28%), other than PTPN11, in Greek patients, highlights the necessity of a wider spectrum of molecular diagnosis.

show abstract

“…Of note, in 1 case who died on scene and was not autopsied, molecular genetics identified a pathogenic variant for a Noonan syndrome due to a mutation in PTPN11. 28 The presence of this syndrome was not known to the family before even though the index patient lost his mother by SUD at young age.…”

Section: Discussionmentioning

confidence: 99%

The emergency medical service has a crucial role to unravel the genetics of sudden cardiac arrest in young, out of hospital resuscitated patients

et al. 2021

View full text Add to dashboard Cite

Background: Genetics of sudden cardiac deaths (SCD) remains frequently undetected. Genetic analysis is recommended in undefined selected cases in the 2021 ERC-guideline. The emergency medical service and physicians (EMS) may play a pivotal role for unraveling SCD by saving biomaterial for later molecular autopsy. Since for high-throughput DNA-sequencing (NGS) high quality genomic DNA is needed. We investigated in a prospective proof-of-concept study the role of the EMS for the identification of genetic forms of SCDs in the young. Methods: We included patients aged 1-50 years with need for cardiopulmonary resuscitation attempts (CPR). Cases with non-natural deaths were excluded. In two German counties with 562,904 residents 39,506 services were analysed. Paired end panel-sequencing was performed, and variants were classified according to guidelines of the American College of Medical Genetics (ACMG). Results: 769 CPR-attempts were recorded (1.95% of all EMS-services; CPR-incidence 68/100,000). In 103 cases CPR were performed in patients < 50y. 58% died on scene, 26% were discharged from hospital. 24 subjects were included for genotyping. Of these 33% died on scene, 37.5% were discharged from hospital. 25% of the genotyped patients were carriers of (likely) pathogenic (ACMG-4/-5) variants. 67% carried variants with unknown significance (ACMG-3). 2 of them had familial history for arrhythmogenic cardiomyopathy or had to be re-classified as ACMG-4 carriers due to whole exome sequencing. Conclusion:The EMS contributes especially in fatal OHCA-cases to increase the yield of identified genetic conditions by collecting a blood sample on scene. Thus, the EMS can contribute significantly to primary and secondary prophylaxis in aected families.

show abstract

Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

Cited by 14 publications

References 58 publications

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia

Molecular and Clinical Profile of patients referred as Noonan or Noonan-like Syndrome in Greece: a cohort of 86 patients

The emergency medical service has a crucial role to unravel the genetics of sudden cardiac arrest in young, out of hospital resuscitated patients

Contact Info

Product

Resources

About