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Neurogenetics
Original research
National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy
  1. Davide Mei1,
  2. Simona Balestrini1,2,
  3. Elena Parrini1,
  4. Antonio Gambardella3,
  5. Grazia Annesi4,
  6. Valentina De Giorgis5,6,
  7. Simone Gana7,
  8. Maria Teresa Bassi8,
  9. Claudio Zucca9,
  10. Maurizio Elia10,
  11. Luigi Vetri10,
  12. Barbara Castellotti11,
  13. Francesca Ragona12,
  14. Mario Mastrangelo13,14,
  15. Francesco Pisani14,15,
  16. Giuseppe d'Orsi16,
  17. Massimo Carella16,
  18. Dario Pruna17,
  19. Sabrina Giglio18,
  20. Carla Marini19,
  21. Elisabetta Cesaroni19,
  22. Antonella Riva20,21,
  23. Marcello Scala20,21,
  24. Laura Licchetta22,
  25. Raffaella Minardi22,
  26. Ilaria Contaldo23,
  27. Maria Luigia Gambardella23,
  28. Alberto Cossu24,25,
  29. Jacopo Proietti24,25,
  30. Gaetano Cantalupo24,25,
  31. LICE Collaborative Group,
  32. Marina Trivisano26,
  33. Angela De Dominicis26,
  34. Nicola Specchio26,
  35. Laura Tassi27,
  36. Renzo Guerrini1,2
    1. 1Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCSS, Florence, Italy
    2. 2University of Florence, Florence, Italy
    3. 3Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi Magna Graecia, Catanzaro, Italy
    4. 4Institute for Biomedical Research and Innovation, National Research Council, Cosenza, Italy
    5. 5Brain and Behavioral Sciences Department, University of Pavia, Pavia, Italy
    6. 6Childhood and Adolescence Epilepsy Center, Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, ERN EpiCARE Full Member, Pavia, Italy
    7. 7Neurogenetics Research Center, IRCCS Mondino Foundation, ERN EpiCARE Full Member, Pavia, Italy
    8. 8Laboratory of Genetics, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Bosisio Parini, Italy
    9. 9Clinical Neurophysiology Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
    10. 10Oasi Research Institute - IRCCS, Troina, Italy
    11. 11Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    12. 12Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    13. 13Department of Women/Child Health and Urological Sciences, Sapienza University of Rome, Rome, Italy
    14. 14Unit of Child Neurology and Psychiatry-Department of Neurosciences/Mental Health, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Rome, Italy
    15. 15Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
    16. 16Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
    17. 17Child Neurology and Epileptology, S. Michele Hospital, ASL Cagliari, Cagliari, Italy
    18. 18Medical Genetics, R. Binaghi Hospital, ASL Cagliari, Cagliari, Italy
    19. 19Child neurology and psychiatric unit, Pediatric Hospital G. Salesi; AOU delle Marche, Ancona, Italy
    20. 20IRCCS Istituto Giannina Gaslini, Full Member of European Reference Network EpiCARE, Genova, Italy
    21. 21Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
    22. 22IRCCS Istituto delle Scienze Neurologiche di Bologna, IRCCS Istituto Delle Scienze Neurologiche di Bologna, Full member of the ERN EpiCARE, Bologna, Italy
    23. 23Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
    24. 24UOC Neuropsichiatria Infantile, Ospedale della Donna e del Bambino c/o Ospedale Civile Maggiore, AOUI Verona, Full member of ERN EpiCARE, Verona, Italy
    25. 25Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
    26. 26Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of ERN EpiCARE, Rome, Italy
    27. 27Claudio Munari Epilepsy Surgery Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
    1. Correspondence to Professor Renzo Guerrini; renzo.guerrini{at}meyer.it

    Abstract

    Background We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period.

    Methods Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs.

    Results We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0–75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%).

    Conclusion Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.

    • Epilepsy
    • Genomics

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. The authors affirm that all data necessary for confirming the conclusions of the article are present within the article, figures, tables and supplemental material dataset (excluding patients’ sensitive information).

    https://doi.org/10.1136/jmg-2024-110328

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      Data availability statement

      All data relevant to the study are included in the article or uploaded as supplementary information. The authors affirm that all data necessary for confirming the conclusions of the article are present within the article, figures, tables and supplemental material dataset (excluding patients’ sensitive information).

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      Footnotes

      • Collaborators LICE Collaborative Group: Elena Cellini, Valentina Cetica, Dalila De Vita, Claudia Mandorlini, Daniela Pucatti, Domenico Rutigliano, Simona Virdò (Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy), Francesco Fortunato, Monica Gagliardi, Mariagrazia Talarico (Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi Magna Graecia, Catanzaro), Enza Maria Valente (Neurogenetics Research Center, IRCCS Mondino Foundation, ERN EpiCARE Full Member, Pavia, Italy) (Department of Molecular Medicine, University of Pavia, Pavia, Italy), Elena Tartara, Carlo Andrea Galimberti (Epilepsy Center, IRCCS Mondino Foundation, ERN EpiCARE Full Member, Pavia, Italy), Ludovica Pasca (Brain and Behavioral Sciences Department, University of Pavia, Pavia, Italy), Fabiana Mambretti (Laboratory of Genetics, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy), Paolo Bonanni, Marta De Rinaldis (Clinical Neurophysiology Unit, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Italy), Francesco Calì, Mirella Vinci, Antonino Musumeci (Oasi Research Institute—IRCCS, Troina, Italy), Giuliana Messina, Cinzia Gellera, Tiziana Granata, Elena Freri, Roberta Solazzi, Laura Canafoglia (Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy), Giacomina Ricciardi, Rossella Bove (Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy), Orazio Palumbo, Pietro Palumbo, Mario Benvenuto (Fondazione IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Foggia, Italy), Carola Adragna (Child Neuropsychiatry, A. Cao Hospital, Cagliari University, Cagliari, Italy), Silvia Cossu (Child Neurology and Epileptology, S. Michele Hospital, ASL Cagliari, Cagliari, Italy), Sabrina Siliquini, Silvia Cappanera (Child Neurology and Psychiatric Unit, Pediatric Hospital G. Salesi; AOU delle Marche, Ancona, Italy), Michele Iacomino, Francesca Madia (IRCCS Istituto Giannina Gaslini, Full Member of European Reference Network EpiCARE, Genova, Italy), Pasquale Striano, Federico Zara (IRCCS Istituto Giannina Gaslini, Full Member of European Reference Network EpiCARE, Genova, Italy) (Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy), Francesca Bisulli, Lorenzo Muccioli (IRCCS Istituto delle Scienze Neurologiche di Bologna, Full member of the ERN EpiCARE, Bologna, Italy) (Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy), Tommaso Pippucci (IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy), Domenica Immacolata Battaglia (Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy) (Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy), Michela Quintiliani, Marco Perulli, Chiara Veredice (Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy), Francesca Darra (UOC Neuropsichiatria Infantile, Ospedale della Donna e del Bambino c/o Ospedale Civile Maggiore, AOUI Verona, Full member of ERN EpiCARE, Verona, Italy) (Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy), Anna Ludovica Ghobert, Elena Fiorini, Elena Fontana (UOC Neuropsichiatria Infantile, Ospedale della Donna e del Bambino c/o Ospedale Civile Maggiore, AOUI Verona, Full member of ERN EpiCARE, Verona, Italy), Alessandra Terracciano (Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy).

      • Contributors Conceptualisation: DM, SB, LT, and RG; Data curation, formal analysis, resources: DM, SB, EP, AG, GA, VDG, SG, MTB, CZ, ME, LV, BC, FR, MM, FP, Gd’O, MC, DP, SG, CM, EC, AR, MS, LL, RM, IC, MLG, AC, JP, GC, LICE Collaborative Group (EC, VC, DDV, CM, DP, DR, SV, FF, MG, MT, EMV, ET, CAG, LP, FM, PB, MDR, FC, MV, AM, GM, CG, TG, EFr, RS, LC, GR, RB, OP, PP, MB, CA, SCo, SS, SCa, MI, FM, PS, FZ, FB, LM, TP, DIB, MQ, MP, CV, FD, ALG, EFi, EFo, AT), MT, ADD, NS, LT and RG; Writing-original draft: DM; all authors critically reviewed the manuscript and approved the final version for publication. RG is the guarantor of the study.

      • Funding This study was supported, in part, by funds from the ‘Current Research Annual Funding’ of the Italian Ministry of Health. This work was supported by the Italian Ministry of Health Ricerca Finalizzata RF-2019-12370059 (to DM) and RF-2019-12370491 (to BC); the Regione Toscana under the Call for Health 2018 (grant DECODE-EE) (to RG) and the ‘Brain Project’ by Fondazione Cassa di Risparmio di Firenze (to RG). This work was partially supported by PNRR funding M6/C2_CALL 2022 (to MM) and by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022) (to FD, RG, NS, PS, MT and FZ).

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      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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