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

ABSTRACT: 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.

SUBMITTER: Brugger M

PROVIDER: S-EPMC10940020 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Brugger Melanie M Lauri Antonella A Zhen Yan Y Gramegna Laura L LL Zott Benedikt B Sekulić Nikolina N Fasano Giulia G Kopajtich Robert R Cordeddu Viviana V Radio Francesca Clementina FC Mancini Cecilia C Pizzi Simone S Paradisi Graziamaria G Zanni Ginevra G Vasco Gessica G Carrozzo Rosalba R Palombo Flavia F Tonon Caterina C Lodi Raffaele R La Morgia Chiara C Arelin Maria M Blechschmidt Cristiane C Finck Tom T Sørensen Vigdis V Kreiser Kornelia K Strobl-Wildemann Gertrud G Daum Hagit H Michaelson-Cohen Rachel R Ziccardi Lucia L Zampino Giuseppe G Prokisch Holger H Abou Jamra Rami R Fiorini Claudio C Arzberger Thomas T Winkelmann Juliane J Caporali Leonardo L Carelli Valerio V Stenmark Harald H Tartaglia Marco M Wagner Matias M

American journal of human genetics 20240228 3

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 encepha ...[more]

PMID: 38423010

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Project description:ObjectiveGamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult central nervous system, plays an important role during embryonic neural network formation. GAD67 is the rate-limiting enzyme in GABA synthesis, and its deficiency leads to developmental and epileptic encephalopathy 89 (DEE 89). Patients who suffered from this syndrome generally manifested severe to profound neurodevelopmental delay, seizures, and often congenital anomalies such as the cleft palate or/and omphalocele. Up to now, only three papers on this syndrome have been published, and our knowledge about the disease's clinical course and pathophysiology is in its infancy.MethodsWe used whole-exome sequencing (WES) and multiple in-silico tools to detect a potential causative variant in a patient with severe neurodevelopmental delay and refractory epilepsy. Moreover, by molecular docking and molecular dynamics simulation, we investigate the effect of the candidate variant on the GAD67 function and structure.ResultsWES data analysis revealed a novel deleterious variant (NM_000817.3: c.850C>T; p.Leu284Phe) in the GAD1 gene, which encodes the GAD67 enzyme. Molecular docking and molecular dynamics simulation showed that this variant has deleterious effects on the structure and function of the GAD67. This study's patient, in addition to typical symptoms of the DEE89, showed microcephaly and clonus in the toe, which were novel clinical findings.SignificanceOur findings expand the mutational and clinical spectrum of DEE 89. Also, by gathering clinical symptoms and genetic findings of previously reported cases, moreover providing a comprehensive clinical picture of the disease, we found that there was no common drug therapy among patients whose epilepsy was controlled. Furthermore, the comparison of clinical symptoms between patients with missense and truncating mutations did not show any significant clinical difference, except that patients with missense mutations did not show cleft palates or omphaloceles.

Dataset Information

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

Publications

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

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