Clinical And Molecular Cenetic Characteristics Of Rasopathy-associated Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy(HCM)is a common hereditary cardiovascular disease characterized by unexplained cardiac hypertrophy and narrowing of the ventricular chamber,accounting for 20% to 30% of children with primary cardiomyopathy.It is one of the most crucial factors of sudden cardiac death in adolescents.Germline mutations in the RAS/mitogen-activated protein kinase(RAS/MAPK)pathway component can cause malformation syndromes such as Noonan syndrome,which is the most common cause of HCM in children under 4 years of age.At present,there is a lack of systematic research on the etiology of childhood cardiomyopathy in China,and there is still insufficient understanding of the natural history and molecular genetic characteristics of RASopathy-associated HCM.This study analyzed the clinical data of children with HCM diagnosed and treated by Shanghai Children’s Medical Center,and explored the clinical features and molecular genetics of RASopathy-associated HCM,in order to provide a basis for clinical diagnosis and treatment for the pediatric HCM patients in China.Objective: To explore the clinical and molecular genetic features and prognostic characteristics of RASopathy-associated HCM in China,and to provide a basis for early diagnosis and reasonable treatment.Methods: A total of 168 children with HCM were enrolled in the Department of Cardiology,Shanghai Children’s Medical Center,Shanghai Jiao Tong University School of Medicine between January 1,2012 and August 31,2018.Cardiomyopathyrelated pathogenic genes were sequenced in the study subjects and their parents who were collected.Combined with the diagnostic criteria of RASopathies,the subjects were clinically grouped into "RASopathy-associated HCM group" and "nonsyndromic HCM group".All children included in the study were followed up to analyze the clinical features,pathogenic genes and prognosis of RASopathyassociated HCM.Results: A total of 47 children(28.0%)with RASopathy-associated HCM were diagnosed,including 27 males and 20 females.The median age at the first diagnosis was 3.0([IQR] 0.5,9.3)months and 40 patients(85.1%)were diagnosed within 1 year of age;There were 121 children(72.0%)with non-syndromic HCM,including 75 males and 46 females.The median age of first diagnosis was 12.6([IQR] 3.7,72.1)months and 61 patients(50.4%)were diagnosed with HCM for the first time within 1 year of age.The age of the first diagnosis of HCM was statistically different between the two groups(p<0.01).32 patients(68.0%)with RAS/MAPK malformation syndrome had congenital heart disease(CHD),including 27 cases(57.4%)with atrial septal defect(ASD)and 16 cases(34.0%)with pulmonary stenosis(PVS).In the non-syndromic group,28 patients(23.1%)had CHD,including 18 patients(14.9%)with ASD and 7 patients(5.8%)with PVS.There was a statistically significant difference between the two groups(p<0.01).In the first diagnosis of HCM,32 patients(68.1%)had bilateral ventricular hypertrophy in the RASopathy-associated HCM group and 57(47.1%)had biventricular hypertrophy in the Non-syndromic HCM group.There was a statistically significant difference between the two groups(p< 0.05);21 patients(44.7%)in the RASopathy-associated HCM group had left ventricular outflow tract obstruction(LVOTO),and 43 patients(35.5%)in the Non-syndromic HCM group had LVOTO.There was no significant difference between the two groups(p>0.05).The most prevalent single allele missense mutations in children with RASopathy-associated HCM were PTPN11(19/47),followed by RAF1(11/47),KRAS(5/47),and RIT1(4/47),BRAF(3/47),SOS1(2/47),HRAS(1/47),and SHOC2(1/47);Moreover,two compound heterozygous missense mutations in the LZTR1 gene were identified in one patient with the Noonan syndrome-related HCM.The overall follow-up rate was 94.6% in this study and the follow-up time was 46.5([IQR] 17.0,74.3)months.Three patients with a mutation in exon 13 of the PTPN11 gene died of cardiac failure at the ages of 3.0,3.5,and 6.0 months from the initial diagnosis of HCM,and the remaining 44 patients survived until the study was terminated,including 5 patients with spontaneous regression of their cardiac hypertrophy.4 patients died in non-syndromic HCM group,and there was no significant difference in cumulative mortality between RASopathy-associated HCM group and non-syndromic HCM group(p>0.05).Conclusions: RASopathy is an important cause of pediatric HCM,especially in infants,and has a high degree of genetic heterogeneity.PTPN11 is the most common pathogenic gene of RASopathy-associated HCM.Genetic testing using Panel including RAS/MAPK pathway-related genes or Whole Exon Sequencing contributes to early diagnosis of this disease.RASopathy-associated HCM tends to involve bilateral ventricular walls,and is more likely to be concomitant with ASD and PVS.The prognosis of children with this disease is generally good,but some specific mutations in exon 13 of PTPN11 gene may be associated with rapid progressive HCM and early death.