De novo variants in neurodevelopmental disorders with epilepsy (original) (raw)

References

  1. McTague, A., Howell, K. B., Cross, J. H., Kurian, M. A. & Scheffer, I. E. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 15, 304–316 (2016).
    Article PubMed Google Scholar
  2. Myers, C. T. & Mefford, H. C. Advancing epilepsy genetics in the genomic era. Genome Med. 7, 91 (2015).
    Article PubMed PubMed Central CAS Google Scholar
  3. Scheffer, I. E. et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 58, 512–521 (2017).
    Article PubMed PubMed Central Google Scholar
  4. McGrother, C. W. et al. Epilepsy in adults with intellectual disabilities: prevalence, associations and service implications. Seizure 15, 376–386 (2006).
    Article PubMed Google Scholar
  5. Thomas, S., Hovinga, M. E., Rai, D. & Lee, B. K. Brief report: prevalence of co-occurring epilepsy and autism spectrum disorder: the U.S. National Survey of Children’s Health 2011–2012. J. Autism Dev. Disord. 47, 224–229 (2017).
    Article PubMed Google Scholar
  6. Robinson, E. B. et al. Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. Proc. Natl. Acad. Sci. USA 111, 15161–15165 (2014).
    Article PubMed CAS Google Scholar
  7. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433–438 (2017).
    Article CAS Google Scholar
  8. Li, J. et al. Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database. Mol. Psychiatry 21, 290–297 (2016).
    Article PubMed CAS Google Scholar
  9. Berg, A. T. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51, 676–685 (2010).
    Article PubMed Google Scholar
  10. Berg, A. T. & Millichap, J. J. The 2010 revised classification of seizures and epilepsy. Continuum (Minneap. Minn.) 19, 571–597 (2013).
    Google Scholar
  11. Helbig, I. & Tayoun, A. A. Understanding genotypes and phenotypes in epileptic encephalopathies. Mol. Syndromol. 7, 172–181 (2016).
    Article PubMed PubMed Central CAS Google Scholar
  12. Trump, N. et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J. Med. Genet. 53, 310–317 (2016).
    Article PubMed PubMed Central CAS Google Scholar
  13. Depienne, C. et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J. Med. Genet. 46, 183–191 (2009).
    Article PubMed CAS Google Scholar
  14. Weckhuysen, S. et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 81, 1697–1703 (2013).
    Article PubMed PubMed Central CAS Google Scholar
  15. Wolff, M. et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in _SCN2A_-related disorders. Brain 140, 1316–1336 (2017).
    Article PubMed Google Scholar
  16. Stamberger, H. et al. STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy. Neurology 86, 954–962 (2016).
    Article PubMed CAS Google Scholar
  17. Howell, K. B., Harvey, A. S. & Archer, J. S. Epileptic encephalopathy: use and misuse of a clinically and conceptually important concept. Epilepsia 57, 343–347 (2016).
    Article PubMed Google Scholar
  18. Chambers, C., Jansen, L. A. & Dhamija, R. Review of commercially available epilepsy genetic panels. J. Genet. Couns. 25, 213–217 (2016).
    Article PubMed Google Scholar
  19. Lemke, J. R. et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53, 1387–1398 (2012).
    Article PubMed CAS Google Scholar
  20. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).
    Article PubMed PubMed Central CAS Google Scholar
  21. Zaidi, S. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013).
    Article PubMed PubMed Central CAS Google Scholar
  22. Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017).
    Article PubMed PubMed Central CAS Google Scholar
  23. Lelieveld, S. H. et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat. Neurosci. 19, 1194–1196 (2016).
    Article PubMed CAS Google Scholar
  24. EuroEPINOMICS-RES Consortium. Epilepsy Phenome/Genome Project & Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 95, 360–370 (2014).
  25. Hamdan, F. F. et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10, e1004772 (2014).
    Article PubMed PubMed Central CAS Google Scholar
  26. de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).
    Article PubMed CAS Google Scholar
  27. Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012).
    Article PubMed CAS Google Scholar
  28. Helbig, K. L. et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet. Med. 18, 898–905 (2016).
    Article PubMed CAS Google Scholar
  29. Fischbach, G. D. & Lord, C. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68, 192–195 (2010).
    Article PubMed CAS Google Scholar
  30. Samocha, K. E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014).
    Article PubMed PubMed Central CAS Google Scholar
  31. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
    Article PubMed PubMed Central CAS Google Scholar
  32. Kosmicki, J. A. et al. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat. Genet. 49, 504–510 (2017).
    Article PubMed PubMed Central CAS Google Scholar
  33. Reimand, J. et al. g:Profiler-a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res. 44, W83–W89 (2016).
    Article PubMed PubMed Central CAS Google Scholar
  34. OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence (Oxford Centre for Evidence-Based Medicine, Oxford, 2009).
  35. Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
    Article PubMed PubMed Central Google Scholar
  36. Mulley, J. C., Scheffer, I. E., Petrou, S. & Berkovic, S. F. Channelopathies as a genetic cause of epilepsy. Curr. Opin. Neurol. 16, 171–176 (2003).
    Article PubMed CAS Google Scholar
  37. Rehm, H. L. et al. ClinGen: the Clinical Genome Resource. N. Engl. J. Med. 372, 2235–2242 (2015).
    Article PubMed PubMed Central CAS Google Scholar
  38. Weckhuysen, S. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15–25 (2012).
    Article PubMed CAS Google Scholar
  39. Wagnon, J. L. et al. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Ann. Clin. Transl. Neurol. 3, 114–123 (2015).
    Article PubMed PubMed Central CAS Google Scholar
  40. Blanchard, M. G. et al. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J. Med. Genet. 52, 330–337 (2015).
    Article PubMed PubMed Central CAS Google Scholar
  41. Wilkie, A. O. The molecular basis of genetic dominance. J. Med. Genet. 31, 89–98 (1994).
    Article PubMed PubMed Central CAS Google Scholar
  42. Haynes, W. A., Tomczak, A. & Khatri, P. Gene annotation bias impedes biomedical research. Sci. Rep. 8, 1362 (2018).
    Article PubMed PubMed Central Google Scholar
  43. MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014).
    Article PubMed PubMed Central CAS Google Scholar
  44. Millichap, J. J. et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol. Genet. 2, e96 (2016).
    Article PubMed PubMed Central CAS Google Scholar
  45. De Giorgis, V. & Veggiotti, P. GLUT1 deficiency syndrome 2013: current state of the art. Seizure 22, 803–811 (2013).
    Article PubMed Google Scholar
  46. Farwell, K. D. et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet. Med. 17, 578–586 (2015).
    Article PubMed CAS Google Scholar
  47. Huppke, P. et al. Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. Nat. Commun. 8, 818 (2017).
    Article PubMed PubMed Central CAS Google Scholar
  48. Trujillano, D. et al. Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur. J. Hum. Genet. 25, 176–182 (2017).
    Article PubMed CAS Google Scholar
  49. Chilamakuri, C. S. et al. Performance comparison of four exome capture systems for deep sequencing. BMC Genomics 15, 449 (2014).
    Article PubMed PubMed Central CAS Google Scholar
  50. Ware, J. S., Samocha, K. E., Homsy, J. & Daly, M. J. Interpreting de novo variation in human disease using denovolyzeR. Curr. Protoc. Hum. Genet. 87, 7.25 (2015).
    Google Scholar
  51. Rubinstein, W. S. et al. The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency. Nucleic Acids Res. 41, D925–D935 (2013).
    Article PubMed CAS Google Scholar

Download references

Acknowledgements

We thank all patients and their families who participated in this study, as well as the teams who were involved in recruiting patients and gathering samples and data at the respective study sites. We thank L. Vissers and C. Gilissen for epilepsy and age phenotypes from the cohort of Lelieveld et al.23 and J. McRae for useful discussions on the DDD cohort7. We are grateful to members of the ATGU and the Institute for Human Genetics in Leipzig for insightful discussions. We thank J. Krause for support in figure design and helpful conversations. This work was supported by the Eurocores program EuroEPINOMICS, the Fund for Scientific Research Flanders (FWO), International Coordination Action (ICA) grant G0E8614N, and the University of Antwerp (research fund). H.O.H. was supported by stipends from the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 and the German Research Foundation (DFG): HE7987/1-1. H.S. was supported as a PhD fellow of the Fund for Scientific Research Flanders (1125416 N). I.H. and Y.G.W. were supported by DFG grants WE4896/3-1 and HE5415/6-1. R.G. received funding through the EU Seventh Framework Programme (FP7) under the project DESIRE grant N602531. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Author information

Author notes

  1. A list of members and affiliations appears at the end of the paper

Authors and Affiliations

  1. University of Leipzig Hospitals and Clinics, Leipzig, Germany
    Henrike O. Heyne, Rami Abou Jamra & Johannes R. Lemke
  2. Program in Medical and Population Genetics, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA
    Henrike O. Heyne, Tarjinder Singh, Jack A. Kosmicki, Aarno Palotie, Mark J. Daly & Dennis Lal
  3. Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig Hospitals and Clinics, Leipzig, Germany
    Henrike O. Heyne
  4. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
    Henrike O. Heyne, Tarjinder Singh, Jack A. Kosmicki, Mark J. Daly & Dennis Lal
  5. Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
    Hannah Stamberger, Peter De Jonghe, Tania Djémié, Arvid Suls & Sarah Weckhuysen
  6. Laboratory of Neurogenetics, Institute Born–Bunge, University of Antwerp, Antwerp, Belgium
    Hannah Stamberger, Peter De Jonghe, Tania Djémié, Arvid Suls & Sarah Weckhuysen
  7. Division of Neurology, University Hospital Antwerp, Antwerp, Belgium
    Hannah Stamberger, Peter De Jonghe, Tania Djémié, Arvid Suls & Sarah Weckhuysen
  8. Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey
    Hande Caglayan
  9. ‘Carol Davila’ University of Medicine Bucharest, Department of Clinical Neurosciences (No. 6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania
    Dana Craiu
  10. Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children’s Hospital–University of Florence, Florence, Italy
    Renzo Guerrini & Carla Marini
  11. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
    Katherine L. Helbig & Ingo Helbig
  12. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
    Bobby P. C. Koeleman & Carolien de Kovel
  13. Department of Pediatric Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
    Tarja Linnankivi
  14. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
    Patrick May
  15. Department of Neuropediatrics, University Medical Center Schleswig–Holstein, Christian–Albrechts University, Kiel, Germany
    Hiltrud Muhle, Manuela Pendziwiat, Johanna Jähn, Stefanie H. Müller, Ulrich Stephani & Ingo Helbig
  16. Danish Epilepsy Centre, Dianalund, Denmark
    Rikke S. Møller
  17. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
    Rikke S. Møller
  18. Department of Pediatric Neurology, University Hospital Giessen, Giessen, Germany
    Bernd A. Neubauer
  19. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa ‘G. Gaslini’ Institute, Genoa, Italy
    Pasquale Striano
  20. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA
    Sha Tang & Sitao Wu
  21. Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, MA, USA
    Annapurna Poduri
  22. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
    Niklas Schwarz & Yvonne G. Weber
  23. Department of Clinical and Experimental Epilepsy, NIHR, University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK
    Sanjay M. Sisodiya
  24. The Epilepsy Society, Chalfont-St-Peter Bucks, UK
    Sanjay M. Sisodiya
  25. Cologne Center for Genomics (CCG), Cologne, Germany
    Dennis Lal
  26. Department of Physiology and Pharmacology, Tel Aviv University Medical School, Ramat Aviv, Israel
    Zaid Afawi
  27. Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
    Carolien de Kovel
  28. Epilepsy Center, Department of Neurosurgery, University Hospital ‘St. Ivan Rilski’, Sofia, Bulgaria
    Petia Dimova
  29. Neurology Department, Medical Academy, Lithuanian University of Health Services, Kaunas, Lithuania
    Milda Endziniene
  30. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
    Dorota Hoffman-Zacharska
  31. Neuropediatrics Unit, University of Geneva, Geneva, Switzerland
    Christian Korff
  32. Folkhälsan Institute of Genetics, Helsinki, Finland
    Anna-Elina Lehesjoki
  33. Neuroscience Center, University of Helsinki, Helsinki, Finland
    Anna-Elina Lehesjoki
  34. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland
    Anna-Elina Lehesjoki
  35. Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
    Deb Pal & Shan Tang
  36. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
    Kaja Selmer
  37. Neurology Laboratory and Epilepsy Unit, Department of Neurology, IIS–Fundacion Jimenez Diaz, UAM, Madrid, Spain
    Jose Serratosa
  38. Centro Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
    Jose Serratosa
  39. Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
    Katalin Štěrbová
  40. Department of General Paediatrics, Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
    Steffen Syrbe
  41. Tallinn Children’s Hospital, Tallinn, Estonia
    Inga Talvik
  42. Department of Neuropediatrics, Christian-Albrechts-University, Kiel, Germany
    Sarah von Spiczak
  43. Northern German Epilepsy Center for Children & Adolescents, Schwentinental/OT, Raisdorf, Germany
    Sarah von Spiczak
  44. Laboratory of Genetics and Neuroscience, Institute of G. Gaslini, Genoa, Italy
    Federico Zara

Authors

  1. Henrike O. Heyne
    You can also search for this author inPubMed Google Scholar
  2. Tarjinder Singh
    You can also search for this author inPubMed Google Scholar
  3. Hannah Stamberger
    You can also search for this author inPubMed Google Scholar
  4. Rami Abou Jamra
    You can also search for this author inPubMed Google Scholar
  5. Hande Caglayan
    You can also search for this author inPubMed Google Scholar
  6. Dana Craiu
    You can also search for this author inPubMed Google Scholar
  7. Peter De Jonghe
    You can also search for this author inPubMed Google Scholar
  8. Renzo Guerrini
    You can also search for this author inPubMed Google Scholar
  9. Katherine L. Helbig
    You can also search for this author inPubMed Google Scholar
  10. Bobby P. C. Koeleman
    You can also search for this author inPubMed Google Scholar
  11. Jack A. Kosmicki
    You can also search for this author inPubMed Google Scholar
  12. Tarja Linnankivi
    You can also search for this author inPubMed Google Scholar
  13. Patrick May
    You can also search for this author inPubMed Google Scholar
  14. Hiltrud Muhle
    You can also search for this author inPubMed Google Scholar
  15. Rikke S. Møller
    You can also search for this author inPubMed Google Scholar
  16. Bernd A. Neubauer
    You can also search for this author inPubMed Google Scholar
  17. Aarno Palotie
    You can also search for this author inPubMed Google Scholar
  18. Manuela Pendziwiat
    You can also search for this author inPubMed Google Scholar
  19. Pasquale Striano
    You can also search for this author inPubMed Google Scholar
  20. Sha Tang
    You can also search for this author inPubMed Google Scholar
  21. Sitao Wu
    You can also search for this author inPubMed Google Scholar
  22. Annapurna Poduri
    You can also search for this author inPubMed Google Scholar
  23. Yvonne G. Weber
    You can also search for this author inPubMed Google Scholar
  24. Sarah Weckhuysen
    You can also search for this author inPubMed Google Scholar
  25. Sanjay M. Sisodiya
    You can also search for this author inPubMed Google Scholar
  26. Mark J. Daly
    You can also search for this author inPubMed Google Scholar
  27. Ingo Helbig
    You can also search for this author inPubMed Google Scholar
  28. Dennis Lal
    You can also search for this author inPubMed Google Scholar
  29. Johannes R. Lemke
    You can also search for this author inPubMed Google Scholar

Consortia

EuroEPINOMICS RES Consortium

Contributions

H.O.H. performed the analyses and drafted the manuscript. H.O.H. and J.R.L. conceived the study. H.O.H., J.R.L., M.J.D., T.S., D.L. and H.S. contributed to analysis concepts and methods. H.O.H., J.R.L., D.L., I.H., T.S., M.J.D., S.M.S., and S. Weckhuysen interpreted the results. T.S., H.S., R.A.J., H.C., D.C., P.D.J., R.G., K.L.H., B.P.C.K., J.A.K., D.L., T.L., P.M., H.M., R.S.M., B.A.N., A. Palotie, M.P., P.S., S.T., S. Wu, the EuroEPINOMICS RES Consortium, S.T., A. Poduri, Y.G.W., S. Weckhuysen, and I.H. provided patient data or analysis tools. All authors revised and approved the final manuscript.

Corresponding authors

Correspondence toHenrike O. Heyne or Johannes R. Lemke.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Figures

Supplementary Figures 1–10 and Supplementary Note

Reporting Summary

Supplementary Table 1

Description of cohorts analyzed in this study

Supplementary Table 2

List of all DNVmis, DNVtrunc, and DNVsynonymous of all NDD cohorts (n = 6,753) and controls (n = 1,911) analyzed in this study

Supplementary Table 3

List of 50 dominant and X-linked known EE genes

Supplementary Table 4

Genes with at least two DNVmis+trunc in NDDEE+uE (n = 1,942)

Supplementary Table 5

Genes with at least two DNVmis+trunc in all NDD (NDD EE+uE +woE, n = 6,753)

Supplementary Table 6

Significantly enriched HPO terms in 33 genes with DNV burden in NDD with epilepsy

Supplementary Table 7

Evaluating genes with at least two DNVmis+trunc in NDD with epilepsy for therapeutic consequences

Supplementary Table 8

Gene sets significantly enriched (odds raio > 1) or depleted (odds ratio < 1) for DNV in epilepsy compared to no epilepsy

Supplementary Table 9

DNV in epilepsy vs. no epilepsy

Supplementary Table 10

DNV in NDDuE vs. NDDEE

Supplementary Table 11

Diagnostic sequencing panels from 24 different academic and commercial providers

Supplementary Table 12

191 dominant/X-linked genes in sequencing panels from 24 different academic/commercial providers with three criteria for disease association in NDD with epilepsy (DNV burden, constraint, brain expression)

Supplementary Table 13

Evaluating 50 genes lacking features of DNV-enriched genes (DNV enrichment, constraint, brain expression) for published evidence for disease association using guidelines from the ClinGen Gene Curation Workgroup

Rights and permissions

About this article

Cite this article

Heyne, H.O., Singh, T., Stamberger, H. et al. De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet 50, 1048–1053 (2018). https://doi.org/10.1038/s41588-018-0143-7

Download citation