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Brugger, M.* ; Lauri, A.* ; Zhen, Y.* ; Gramegna, L.L.* ; Zott, B.* ; Sekulić, N.* ; Fasano, G.* ; Kopajtich, R. ; Cordeddu, V.* ; Radio, F.C.* ; Mancini, C.* ; Pizzi, S.* ; Paradisi, G.* ; Zanni, G.* ; Vasco, G.* ; Carrozzo, R.* ; Palombo, F.* ; Tonon, C.* ; Lodi, R.* ; La Morgia, C.* ; Arelin, M.* ; Blechschmidt, C.* ; Finck, T.* ; Sørensen, V.* ; Kreiser, K.* ; Strobl-Wildemann, G.* ; Daum, H.* ; Michaelson-Cohen, R.* ; Ziccardi, L.* ; Zampino, G.* ; Prokisch, H. ; Abou Jamra, R.* ; Fiorini, C.* ; Arzberger, T.* ; Winkelmann, J. ; Caporali, L.* ; Carelli, V.* ; Stenmark, H.* ; Tartaglia, M.* ; Wagner, M.

Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.

Am. J. Hum. Genet. 111, 594-613 (2024)

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The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Escrt-ii ; Autophagy ; Developmental And Epileptic Encephalopathy ; Leukoencephalopathy ; Neurogenetics ; Optic Atrophy; Escrt-ii; Neurodevelopmental Disorder; Growth-factor; Autophagy; Complex; Mutations

ISSN (print) / ISBN 0002-9297

e-ISSN 1537-6605

Journal American Journal of Human Genetics, The

Quellenangaben Volume: 111, Issue: 3, Pages: 594-613

Publisher Elsevier

Publishing Place New York, NY

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants
Istituto Superiore di Sanita
Italian Ministry of Research
Hertie Foundation
European Reference Network for Rare Neurological Diseases
Italian Ministry of Health