|
|||||
|
|
Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction |
|
| Authors: | Philippine Garret Frédéric Ebstein Geoffroy Delplancq Blandine Dozieres-Puyravel Aïcha Boughalem Stéphane Auvin Yannis Duffourd Sandro Klafack Barbara A. Zieba Sana Mahmoudi Karun K. Singh Laurence Duplomb Christel Thauvin-Robinet Jean-Marc Costa Elke Krüger Detlef Trost Alain Verloes Laurence Faivre Antonio Vitobello |
| Affiliation: | 1. UMR1231 GAD, Inserm – Université Bourgogne-Franche Comté, Dijon, France;2. Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, Greifswald, Germany;3. UMR1231 GAD, Inserm – Université Bourgogne-Franche Comté, Dijon, France Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France;4. AP-HP, Hôpital Robert Debré, Service de Neurologie pédiatrique, Paris, France;5. Laboratoire CERBA, Saint-Ouen l'Aumône, France;6. AP-HP, Hôpital Robert Debré, Service de Neurologie pédiatrique, Paris, France UMR1141 INSERM, Université Paris Diderot, Paris, France;7. Service de Pédiatrie, Centre Hospitalier René-Dubos, Pontoise, France;8. Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada;9. UMR1231 GAD, Inserm – Université Bourgogne-Franche Comté, Dijon, France Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France Centre de Référence Maladies Rares “déficience intellectuelle”, centre de génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France;10. UMR1141 INSERM, Université Paris Diderot, Paris, France |
| Abstract: | Heterozygous microdeletions of chromosome 15q13.3 (MIM: 612001) show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Rare patients carrying homozygous deletions show more severe phenotypes including epileptic encephalopathy, hypotonia and poor growth. For years, CHRNA7 (MIM: 118511), was considered the candidate gene that could account for this syndrome. However, recent studies in mouse models have shown that OTUD7A/CEZANNE2 (MIM: 612024), which encodes for an ovarian tumor (OTU) deubiquitinase, should be considered the critical gene responsible for brain dysfunction. In this study, a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy was referred to our genetics center. Trio exome sequencing (tES) analysis identified a homozygous OTUD7A missense variant (NM_130901.2:c.697C>T), predicted to alter an ultraconserved amino acid, p.(Leu233Phe), lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient-derived fibroblasts and in OTUD7A knockout HAP1 cell line. We provide evidence that biallelic pathogenic OTUD7A variation is linked to early-onset epileptic encephalopathy and proteasome dysfunction. |
| Keywords: | 15q13.3 microdeletion CHRNA7 OTUD7A proteasome |