Targeted gene(s)/phenotype under study
RASopathies, Noonan and related disorders, ORPHA: 536391
Fetal hypertrophic cardiomyopathy (HCM) is rarely detected in prenatal ultrasound investigations, however, represents a major risk factor for congestive heart failure and consecutively, early mortality. RASopathies, especially if caused by pathogenic germline variants in RAF1, RIT1, and MRAS amongst others, are associated with a risk of severe fetal HCM. Nonetheless, molecular genetic testing is not commonly performed in this setting, mostly due to ambiguous genotype-phenotype correlations.
In the absence of a cure, new hope for a functional pharmaceutical intervention is sparked by the notion that the pathogenically enhanced signal transduction in the RAS-MAPK pathway can be modulated by downstream MEK1/2-inhibition. Indeed, individual case reports in recent years have reported first results with compelling evidence hinting towards a significant and durable benefit in patients treated with MEK1/2-inhibitors. However, to date identification of affected individuals remains scarce, rendering confident genotype-phenotype correlation difficult.
To this end, we aim to establish a descriptive cohort of foetuses and patients, who were diagnosed with a RASopathy and who were found to be affected by HCM in the prenatal context, in order to better characterize the genotype-phenotype correlations and potentially facilitate a transition towards possible clinical trial in the future. For this descriptive work, we aim to include all foetuses and patients with a molecular diagnosis of RASopathy, and in whom HCM has been identified in the prenatal or immediate postnatal period, regardless of outcome and severity.
Dr. Guillaume Jouret
Dr. Dominik Brado
National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg
Specific requirements beyond clinical data and genotype data sharing
- Re-analysis of DNA samples: Depending on the success of the collaboration
- Resampling of patients: Depending on the success of the collaboration
- Linked to a translational/basic research project: Depending on the success of the collaboration