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Badmann, S.* ; Saparov, A. ; Harrer, P. ; Beuschlein, J.* ; Daumer-Haas, C.* ; Graf, E.* ; Ludwig, C.* ; Mergner, J.* ; Brunet, T.* ; Jacob, M.* ; Prokisch, H. ; Winkelmann, J. ; Meitinger, T.* ; Zech, M. ; Wagner, M.

Splice effect of a synonymous variant in AP4B1: Multiomics approach establishes the diagnosis in two sisters with spastic paraplegia.

Hum. Mutat. 2026:8645235 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Patients with suspected monogenic disorders often remain undiagnosed after exome sequencing. We report a family with two sisters affected by a complex spastic paraplegia. Initial exome sequencing had identified monoallelic pathogenic nonsense variants in AP4S1 and AP4B1, subunits of the adaptor protein complex 4 (AP-4), suggesting digenic inheritance. As digenic inheritance has not been established for AP-4–associated disorders, we applied a multiomics approach including genome sequencing, RNA sequencing and proteomics to clarify the genetic cause. By RNA sequencing a predicted synonymous variant (NM_006594.5:c.969G > A), compound heterozygous to the nonsense variant in AP4B1 and previously considered as benign, was re-prioritized as aberrant splicing was demonstrated. Proteomics showed reduced abundance of AP-4 components AP4B1 and AP4M1 and an upregulation of the cargo protein ATG9A, confirming AP-4 deficiency. Although the AP4S1 variant resulted in nonsense-mediated decay, the identification of biallelic causative variants in AP4B1 established the diagnosis of monogenic “Spastic paraplegia 47, autosomal recessive” while the initial hypothesis of digenic inheritance was refuted. This study illustrates the value of multiomics approaches in the diagnostic workflow of rare diseases and the potential for pathogenicity of synonymous variants.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ap4b1 ; Hsp ; Proteomics ; Rna Sequencing ; Splice Effect ; Synonymous Variant
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Zeitschrift Human Mutation
Quellenangaben Band: 2026, Heft: 1, Seiten: , Artikelnummer: 8645235 Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institiute of Neurogenomics (ING)
Förderungen Else Krner-Fresenius-Stiftung
Institute for Advanced Study
Free State of Bavaria
Bavarian Genomes Network for Rare Disorders
Projekt DEAL
Bundesministerium fr Bildung und Forschung
Technische Universitt Mnchen
EJP RD