De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Appenzeller, Silke; Balling, Rudi; Barišić, Nina; Baulac, Stéphanie; Çağlayan, Hande; Craiu, Dana; Jonghe, Peter De; Depienne, Christel; Dimova, Petia; Djémié, Tania; Gormley, Padhraig; Guerrini, Renzo; Helbig, Ingo; Hjalgrim, Helle; Hoffman-Zacharska, Dorota; Jähn, Johanna A.; Klein, Karl Martin; Koeleman, Bobby; Komárek, Vladimı́r; Krause, Roland; Kuhlenbäumer, Gregor; LeGuern, Eric; Lehesjoki, Anna‐Elina; Lemke, Johannes R.; Lerche, Holger; Linnankivi, Tarja; Marini, Carla; May, Patrick; Møller, Rikke S.; Muhle, Hiltrud; Pal, Deb K.; Palotie, Aarno; Pendziwiat, Manuela; Robbiano, Angela; Roelens, Filip; Rosenow, Felix; Selmer, Kaja Kristine; Serratosa, Joan; Sisodiya, Sanjay M.; Stephani, Ulrich; Štěrbová, Katalin; Striano, Pasquale; Suls, Arvid; Talvik, Tiina; Spiczak, Sarah von; Weber, Yvonne; Weckhuysen, Sarah; Zara, Federico; Abou‐Khalil, Bassel; Alldredge, Brian K.; Andermann, Eva; Andermann, Frédérick; Amrom, Dina; Bautista, Jocelyn F.; Bluvstein, Judith; Boro, Alex; Cascino, Gregory D.; Consalvo, D.; Crumrine, Patricia K.; Devinsky, Orrin; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel J.; Geller, Eric B.; Glynn, Simon; Haas, Kevin R.; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta M.; Kanner, Andrés M.; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Eric H.; Kuperman, Rachel; McGuire, Shannon M.; Motika, Paul; Novotny, Edward J.; Paolicchi, Juliann; Parent, Jack M.; Park, Kristen; Sadleir, Lynette G.; Shellhaas, Renée A.; Shih, Jerry J.; Singh, Rani K.; Sirven, Joseph; Smith, Michael C.; Sullivan, Joe; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P.G.; Allmen, Gretchen K. Von; Weisenberg, Judith; Widdess‐Walsh, Peter; Winawer, Melodie R.; Allen, Andrew S.; Berkovic, Samuel F.; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis J.; Eichler, Evan E.; Epstein, Michael P.; Glauser, Tracy A.; Goldstein, David B.; Han, Yujun; Heinzen, Erin L.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Marson, Anthony G; Mefford, Heather C; Nieh, Sahar Esmaeeli; O’Brien, Terence J.; Ottman, Ruth; Petrou, Stephen; Petrovski, Steve; Poduri, Annapurna; Ruzzo, Elizabeth K.; Scheffer, Ingrid E.; Sherr, Elliott H.

doi:10.1016/j.ajhg.2016.12.012

Cited by 42 publications

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“…The DD cohort combined previously published de novo DD and ID studies which used similar cohort inclusion/exclusion criteria [3,4,[9][10][11]. The EPI cohort included published trio data sets from (356/822 trios, 43%) [1,12] as well as 466 (56% of the 822 trios) exome-wide de novo data that were recently published [13]. As control data, we used variant data from 2078 trios sequenced with the same technology as the ASD patient cohort.…”

Section: Patient and Genetic Datamentioning

confidence: 99%

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

et al. 2020

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Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods: Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results: We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint.

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Section: Patient and Genetic Datamentioning

confidence: 99%

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

et al. 2020

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“…All identified variants have been deposited in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) under the name "UGDH001". Whole dataset from Family F3 was already published 66 and deposited in the European Genome-phenome Archive, accession numbers EGAS00001000190, EGAS00001000386, and EGAS00001000048. Whole datasets from Families F5 and F15 are available upon request from the corresponding authors.…”

Section: Data Availabilitymentioning

confidence: 99%

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

et al. 2020

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Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

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“…We have found a novel de novo variant in the DNM1 gene in a girl with the infantile epileptic encephalopathy. Since the DNM1 gene came as a candidate from a study of de novo mutations in large cohorts of epileptic patients [3], together 28 patients from 27 families with 18 different pathogenic variants (including our patient) have been described (Suppl. Fig.).…”

Section: Discussionmentioning

confidence: 99%

“…The symptom of epilepsy is variable and in two patients, including ours, we found a nonepileptic myoclonus and delayed myelination on MRI. Moreover, the severity of features can be influenced by other genetic or environmental factors [1,3].…”

Section: Discussionmentioning

confidence: 99%

DNM1 encephalopathy − atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene

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et al. 2018

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De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Abstract: In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom's name was misspelled as Amron. The authors regret the error.

Cited by 42 publications

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Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

DNM1 encephalopathy − atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene

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