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1 De Novo FZR1 Loss-Of-Function Variants Cause Developmental And medRxiv preprint doi: https://doi.org/10.1101/2021.06.12.21256778; this version posted June 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies including Myoclonic Atonic Epilepsy Sathiya N. Manivannan1,2, Jolien Roovers3,4, Noor Smal5, Candace T. Myers6, Dilsad Turkdogan7, Filip Roelens8, Oguz Kanca1,2, Hyung-Lok Chung1,2, Tasja Scholz9, Katharina Hermann10, Tatjana Bierhals9, S. Hande Caglayan11, Hannah Stamberger5,12, MAE working group of EuroEPINOMICS RES Consortium, Heather Mefford6, Peter de Jonghe3,4,12, Shinya Yamamoto1,2,13,14,15,*, Sarah Weckhuysen5,12,16,*, Hugo J. Bellen1, 2, 13, 14, 15, 17,* Affiliation 1Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA. 2Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, 77030, USA. 3Neurogenetics group, VIB Center for Molecular Neurology, VIB, Antwerp, 2610, Belgium. 4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, 2610, Belgium. 5Applied&Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, 2610, Belgium. 6Center for Pediatric Neurological Disease Research, Department of Cell & Molecular Biology St. Jude Children’s Research Hospital, Memphis, TN 30105 7Division of Child Neurology, Department of Pediatrics, Marmara University, Faculty of Medicine, Turkey. 8Child Neurology, AZ Delta, Roeselare, Belgium. 9Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.06.12.21256778; this version posted June 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 10Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany 11Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey. 12Department of Neurology, University Hospital Antwerp, Antwerp, 2650, Belgium. 13Department of Neuroscience, BCM, Houston, TX 77030, USA. 14Program in Developmental Biology, BCM, Houston, TX 77030, USA. 15Development, Disease Models & Therapeutics Graduate Program, BCM, Houston, TX 77030, USA. 16Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, 2650, Belgium. 17Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. *Corresponding authors: Sarah Weckhuysen: +32 3 2651870 [email protected] Hugo J. Bellen: +1-713-798-5272, [email protected] Myoclonic Atonic Epilepsy (MAE) working group of EuroEPINOMICS RES Consortium: Dana Craiu (Pediatric Neurology Clinic II, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Carol Davila (University of Medicine, Bucharest, Romania; Pediatric Neurology Clinic), Ingo Helbig (Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Renzo Guerrini (Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer, University of Florence, Florence, Italy), Anna-Elina Lehesjoki (Folkhälsan Institute of Genetics, Helsinki, Finland; Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland), Carla Marini (Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer, 2 medRxiv preprint doi: https://doi.org/10.1101/2021.06.12.21256778; this version posted June 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . University of Florence, Florence, Italy), Hiltrud Muhle (Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Rikke S Møller (Danish Epilepsy Centre, Dianalund, Denmark), Bernd Neubauer (Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany), Deb Pal (Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK), Katalin Sterbova (Child Neurology Department, University Hospital Motol, Prague, Czech Republic), Pasquale Striano (Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, ‘G Gaslini Institute’, Genova, Italy), Tiina Talvik (Department of Pediatrics, University of Tartu, Tartu, Estonia; Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia), Sarah von Spiczak (Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany), Hande Caglayan (Department of Molecular Biology and Genetics Istanbul, Boğaziçi University, Istanbul, Turkey), Yvonne Weber (Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany), Dorota Hoffman-Zacharska (Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland). 3 medRxiv preprint doi: https://doi.org/10.1101/2021.06.12.21256778; this version posted June 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . Abstract FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment by regulating cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental epileptic encephalopathies (DEE) and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Two variants led to the same amino acid change. All individuals had a DEE with childhood onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the DEE subtype Myoclonic Atonic Epilepsy (MAE). We provide gene burden testing using two independent statistical tests to support FZR1 association with DEE. Further, we provide functional evidence that the missense variants are loss-of-function (LOF) alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homolog fzr and overexpression studies, we show that patient variants do not support proper neurodevelopment. With the recent report of a patient with neonatal-onset DEE with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and DEE, and expands the associated phenotype. We conclude that heterozygous LOF of FZR1 leads to DEE associated with a spectrum of neonatal to childhood onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed MAE/DEE cases. 4 medRxiv preprint doi: https://doi.org/10.1101/2021.06.12.21256778; this version posted June 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . Introduction Developmental and Epileptic Encephalopathies (DEEs) are a heterogeneous group of disabling disorders, characterized by a combination of severe epilepsy and neurodevelopmental problems1. Seizures in DEE patients usually have an early age-of-onset and are often refractory to anti-epileptic drugs. The majority of DEE cases are thought to have a genetic basis, usually in the form of rare de novo variants with a highly disruptive effect on gene expression or protein function. Pathogenic variants in more than a hundred genes have been associated with a DEE phenotype so far2-4. Identifying the causal variant in a DEE patient can bring an end to an often long and stressful diagnostic odyssey and may lead to improved or targeted treatment for a subset of the cases2; 5; 6. We set out to identify novel variants in DEE patients by screening a large cohort of patients with Myoclonic Atonic Epilepsy (MAE), a sub-type of DEE, as part of the efforts of the EuroEPINOMICS-RES consortium7. MAE is characterized by generalized seizure types including myoclonic, atonic, myoclonic atonic, absence and tonic-clonic seizures. The seizure onset is typically between 7 months and 6 years8. Using a combination approach of trio whole- exome sequencing (WES) and subsequent screening with a targeted gene panel including candidate genes for MAE, we identified two individuals diagnosed with MAE who each carried a unique de novo missense
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