VCP variants cause Adams-Oliver syndrome with or without pulmonary hypertension

Adams-Oliver syndrome (AOS) is a genetically heterogeneous disorder with cardinal features of aplasia cutis congenita and terminal limb reduction defects. A minority of individuals with AOS develop potentially lethal pulmonary hypertension (PH) in infancy, a subgroup that has been refractory to genetic explanation.

We studied a cohort of individuals with AOS and no genetic diagnosis by genome and exome sequencing. We characterized rare, identified substitution variants in valosin-containing protein (VCP) in vitro using ATP hydrolysis, cryogenic-electron microscopy, thermal stability, and response to CB-5083, a VCP inhibitor.

We report a new genetic etiology for AOS in 6 families with PH and 1 family without it. We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling. Additionally, we find that CB-5083 inhibits the overactive ATP hydrolysis. Review of published cases of AOS with PH suggests that pulmonary vein stenosis is the most common mechanism. Clinical risk factors for PH in AOS include cutis marmorata telangiectatica congenita, prominent dilated subcutaneous veins and intrauterine growth restriction.

We identify the prevalent genetic cause of pulmonary hypertension in AOS and highlight a potential therapeutic approach.