Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
Publication Title
Genetics in medicine : official journal of the American College of Medical Genetics
Document Type
Article
Publication Date
4-13-2026
Keywords
washington; isb
Abstract
Purpose: 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.
Methods: 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.
Results: 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 veno-occlusive disease is the most common mechanism. Clinical risk factors for PH in AOS include CMTC, prominent dilated subcutaneous veins and intra-uterine growth restriction.
Conclusion: We identify the prevalent genetic cause of pulmonary hypertension in AOS and highlight a potential therapeutic approach.
Area of Special Interest
Women & Children
Specialty/Research Institute
Pediatrics
Specialty/Research Institute
Pulmonary Medicine
Specialty/Research Institute
Institute for Systems Biology
DOI
10.1016/j.gim.2026.102579
