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.

Coordinating clinicians/researchers

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