Genetic landscape of RASopathies in Chinese: Three decades' experience in Hong Kong

Abstract

RASopathies are a group of genetic disorders due to dysregulation of the RAS‐MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety‐one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well‐known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re‐evaluation of the current tumor surveillance recommendation maybe warranted.

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

“…Citations for Table 1: Tidyman and Rauen (); Aoki et al (); Yamamoto et al (); Tajan, Paccoud, Branka, Edouard, and Yart (); Yu et al ().…”

Development of clinical genetics in Asia

“…The study includes 192 Chinese patients with Noonan syndrome and various forms of rasopathies with molecular confirmation by sanger sequencing. The findings highlight clinically significant phenotype and genotype differences seen in Asian patients that were not present in the literature focusing on Western patients (Yu et al, ). This study adds to the international efforts to describe syndromes including Noonan syndrome in more diverse populations with the goal of creating a universally accessible electronic Altas of human malformation syndromes in diverse populations (Kruszka et al, ).…”

“…Further drawing attention to rare diseases that are known to be heterogenous but lack detailed description in minority populations is an analysis of rasopathies by Yu et al This article presents the largest cohort of rasopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients (Yu et al, ). The study includes 192 Chinese patients with Noonan syndrome and various forms of rasopathies with molecular confirmation by sanger sequencing.…”

RASopathies due to de novo pathogenic variants: clinical features, genetic findings and outcomes in nine neonates born with congenital heart defects

“…Taken together, the RASopathies represent one of the most prevalent groups of malformation syndromes affecting greater than 1 in 1,000 individuals equally distributed in females and males [ 6 ]. While most individuals with RASopathies share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a mild or attenuated phenotype to a severe phenotype with infantile lethal complications [ 8 ]. Furthermore, less major clinical features were recognized in neonatal or infantile period [ 9 ] than the manifestations in toddlerhood and beyond.…”