Systemic artery to pulmonary artery aneurysm malformations associated with variants at MCF2L

Arteriovenous malformations (AVM) are characterized by abnormal vessels connecting arteries and veins resulting in a disruption of normal blood flow. Hereditary hemorrhagic telangiectasia (HHT) is the most common cause of pulmonary AVM characterized by a right to left shunt. Here we describe a distinct malformation where the flow of blood was from a systemic artery to the pulmonary artery (PA) resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT. This distinct malformation was identified in seven probands, one from a multiplex family containing 10 affected individuals from five generations. To identify the molecular basis of this distinct malformation, we performed exome sequencing (ES) on the seven probands and the affected paternal female cousin from the multiplex family. PhenoDB was used to prioritize candidate causative variants along with burden analysis. We describe the clinical and radiological details of the new systemic artery to PA malformation with or without pulmonary artery aneurysm (SA-PA(A)) and recommend distinct treatment techniques. Moreover, ES analysis revealed possible causative variants identified in three families with variants in a novel candidate disease gene, MCF2L. Further functional studies will be necessary to better understand the molecular mechanisms involved on SA-PA(A) malformation, however our findings suggest that MCF2L is a novel disease gene associated with SA-PA(A).