Anna Lehman, Sana Ahmed, Arezoo Mohajeri, Alison M. Berezuk, Dhiraj Mannar, Spencer Cholak, Katharine S. Tuttle, James T. Bennett, Jeanine Aparecida Magno, Mark Hannibal, Gordana Kovacevik, Vladimir Kuburovic, M.E. Suzanne Lewis, Oana Moldovan, Zoe Nelson, Salmo Raskin, Anthony M. Vandersteen, Jared C. Roach, Sriram Subramaniam, Millan S. Patel
University of British Columbia. University of Washington School of Medicine. Universidade Regional de Blumenau. C. S. Mott Children’s Hospital and University of Michigan. Mother and Child Health Care Institute of Serbia. Hospital de Santa Maria. Federal University of Parana. Izaak Walton Killam Health Centre. Institute for Systems Biology.
Canada, United States, Brazil, Serbia, Sweden and Portugal
Genetics in Medicine
Genet Med 2026;
DOI: 10.1016/j.gim.2026.102579
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.
Category
Stenosis or Obstruction of Normal Pulmonary Venous Connections
Absence or Atresia of Normal Pulmonary Venous Connections
Genetic Factors Influencing the Onset, Severity or Outcome of Disease
Year of Publication: 2026
Age Focus: Pediatric or Adult
Article Type: Retrospective Observational Cohort Studies (>10 patients)
Article Access: Free PDF File or Full Text Article Available Through PubMed or DOI: Yes