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Background  Pulmonary hypertension (PH) remains one of the rarest and deadliest diseases. Pulmonary Capillary Hemangiomatosis (PCH) is one of the sub-classes of PH. It was identified using histological and molecular tools and is characterized by the proliferation of capillaries into the alveolar septae. Mutations in the gene encoding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) have recently been linked to this particular subgroup of PH.    Methods  In our effort to unveil the genetic basis of idiopathic and familial cases of PH in Lebanon, we have used whole exome sequencing to document known and/or novel mutations in genes that could explain the underlying phenotype.    Results  We showed bi-allelic mutations in  EIF2AK4  in two non-consanguineous families: a novel non-sense mutation c.1672C > T (p.Q558*) and a previously documented deletion c.560_564drlAAGAA (p.K187Rfs9*). Our histological analysis coupled with the CT-scan results showed that the two patients with the p.Q558* mutation have PH. In contrast, only one of the individuals harboring the p.K187Rfs9* variant has a documented PCH while his older brother remains asymtomatic. Differential analysis of the variants in the genes of the neighboring network of  EIF2AK4  between the two siblings identified a couple of interesting missense mutations that could account for this discrepancy.    Conclusion  These findings represent a novel documentation of the involvement of  EIF2AK4  in the different aspects of pulmonary hypertension. The absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype is still a major hurdle in our understanding of the disease.

Novel EIF2AK4 mutations in histologically proven pulmonary capillary hemangiomatosis and hereditary pulmonary arterial hypertension