Prenatal-onset hypertrophic cardiomyopathy in 54 patients with RASopathies: understanding phenotype-genotype correlations for risk stratification, medical management and targeted therapies
Clinical Genetics and Therapeutics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction:
The medical management of patients with RASopathies is challenging, especially when presenting with hypertrophic cardiomyopathy (HCM). Prenatal-onset HCM is rare and potentially severe, with clinical presentations ranging from stable conditions to rapidly progressing and fatal courses. Early genotyping and precise understanding of the phenotype-genotype correlations is crucial for risk stratification of HCM progression, and may enable patients to benefit from MEK or mTOR inhibitors. Our aim is to provide new insights into the understanding of genotype-phenotype correlations of prenatal-onset HCM in patients with RASopathies, to better delineate high-risk genotypes, guide the medical management and treatment indications, as well as facilitate a transition to future clinical trials.
Methods:
This international multicenter cohort study was conducted thanks to the collaborative platform of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA. We established a three-factor correlation study based on 1) genotype, 2) a scoring system for prenatal cardiac and extra-cardiac findings, and 3) a stratification score for postnatal prognosis. Each fetal clinical presentation was graded on a scale from 0 to 10, and the postnatal prognosis score classified patients into four groups according to the severity of the postnatal evolution (Grade I: non-obstructive asymptomatic HCM; Grade IV: severe symptomatic Ventricular Outflow Track Obstruction (VOTO), refractory to pharmacotherapy, admission in Neonatal Intensive Care Unit for heart failure, and/or lethal progression). These two scores were designed for the purposes of this study.
Results:
We report the first cohort of patients with prenatal and neonatal-onset RASopathy-induced HCM (R-HCM), consisting of 4 fetuses and 50 live-born patients with causative variants in the genes PTPN11 (16 patients), RAF1 (14 patients), RIT1 (11 patients), BRAF (5 patients), HRAS (3 patients), SHOC2 (2 patients), MRAS, RRAS2 and MAP2K. Of the live-born patients, HCM progressed unfavorably and resulted in Grade IV prognosis in 26% (13/50) of patients. Of these, 3 were eligible for heart transplantation, and 3 were treated with MEK inhibitors. 77% (10/13) of patients with Grade IV prognosis died within the first 7 months of life.
RAF1 was associated with the poorest prognosis: 71% of patients (10/14) progressed to symptomatic and refractory VOTO (Grade III and IV). In contrast, variants in RIT1, known to be associated with a high prevalence of HCM, resulted in Grade I or II R-HCM in 56% of our patients, and Grade IV in only 10% (1/9). Interestingly, although patients with variants in PTPN11 are known as exhibiting a low prevalence of R-HCM, PTPN11 was the leading cause of R-HCM in our cohort: 30% (16/54) of all patients had PTPN11 variants, clustered in the region of the phosphatase catalytic domain and in the interacting region between the N-SH2 domain and the catalytic domain. Those specific variants are expected to reduce the catalytic function, which is a different mechanism than in classical Noonan syndrome.
Remarkably, BRAF is the only gene for which the presence and severity of extra-cardiac fetal ultrasound findings correlated with a poorer prognosis in the post-natal period, whereas 43% (3/7) of patients with Grade IV R-HCM attributed to RAF1 variants had no extra-cardiac ultrasound finding during pregnancy.
Conclusion:
For the first time, we report a large cohort of fetuses and patients with prenatal and neonatal-onset R-HCM. We contribute to the stratification of genotypes into risk categories, to delineate high-risk genotypes of R-HCM progression in infancy. We established a stratification of postnatal prognostic and prenatal findings, making it possible to identify early high-risk patients for rapid and potentially life-threatening R-HCM.
The medical management of patients with RASopathies is challenging, especially when presenting with hypertrophic cardiomyopathy (HCM). Prenatal-onset HCM is rare and potentially severe, with clinical presentations ranging from stable conditions to rapidly progressing and fatal courses. Early genotyping and precise understanding of the phenotype-genotype correlations is crucial for risk stratification of HCM progression, and may enable patients to benefit from MEK or mTOR inhibitors. Our aim is to provide new insights into the understanding of genotype-phenotype correlations of prenatal-onset HCM in patients with RASopathies, to better delineate high-risk genotypes, guide the medical management and treatment indications, as well as facilitate a transition to future clinical trials.
Methods:
This international multicenter cohort study was conducted thanks to the collaborative platform of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA. We established a three-factor correlation study based on 1) genotype, 2) a scoring system for prenatal cardiac and extra-cardiac findings, and 3) a stratification score for postnatal prognosis. Each fetal clinical presentation was graded on a scale from 0 to 10, and the postnatal prognosis score classified patients into four groups according to the severity of the postnatal evolution (Grade I: non-obstructive asymptomatic HCM; Grade IV: severe symptomatic Ventricular Outflow Track Obstruction (VOTO), refractory to pharmacotherapy, admission in Neonatal Intensive Care Unit for heart failure, and/or lethal progression). These two scores were designed for the purposes of this study.
Results:
We report the first cohort of patients with prenatal and neonatal-onset RASopathy-induced HCM (R-HCM), consisting of 4 fetuses and 50 live-born patients with causative variants in the genes PTPN11 (16 patients), RAF1 (14 patients), RIT1 (11 patients), BRAF (5 patients), HRAS (3 patients), SHOC2 (2 patients), MRAS, RRAS2 and MAP2K. Of the live-born patients, HCM progressed unfavorably and resulted in Grade IV prognosis in 26% (13/50) of patients. Of these, 3 were eligible for heart transplantation, and 3 were treated with MEK inhibitors. 77% (10/13) of patients with Grade IV prognosis died within the first 7 months of life.
RAF1 was associated with the poorest prognosis: 71% of patients (10/14) progressed to symptomatic and refractory VOTO (Grade III and IV). In contrast, variants in RIT1, known to be associated with a high prevalence of HCM, resulted in Grade I or II R-HCM in 56% of our patients, and Grade IV in only 10% (1/9). Interestingly, although patients with variants in PTPN11 are known as exhibiting a low prevalence of R-HCM, PTPN11 was the leading cause of R-HCM in our cohort: 30% (16/54) of all patients had PTPN11 variants, clustered in the region of the phosphatase catalytic domain and in the interacting region between the N-SH2 domain and the catalytic domain. Those specific variants are expected to reduce the catalytic function, which is a different mechanism than in classical Noonan syndrome.
Remarkably, BRAF is the only gene for which the presence and severity of extra-cardiac fetal ultrasound findings correlated with a poorer prognosis in the post-natal period, whereas 43% (3/7) of patients with Grade IV R-HCM attributed to RAF1 variants had no extra-cardiac ultrasound finding during pregnancy.
Conclusion:
For the first time, we report a large cohort of fetuses and patients with prenatal and neonatal-onset R-HCM. We contribute to the stratification of genotypes into risk categories, to delineate high-risk genotypes of R-HCM progression in infancy. We established a stratification of postnatal prognostic and prenatal findings, making it possible to identify early high-risk patients for rapid and potentially life-threatening R-HCM.