Genetics and pathophysiology of neurodevelopmental Disorders

Genetics and pathophysiology of neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) are a group of diseases that result from abnormalities during brain development that impair brain function. NDDs include intellectual disability and autism-spectrum disorders, which affect 1.5-2% of children or young adults, and might be associated to movement disorders (MD). More than 1,000 genes are known to be involved in monogenic forms of NDD, coding for proteins involved in different cellular processes, with others yet to be identified. Identifying the genes involved in NDD and MD and characterising the consequences of variants occurring in these genes is essential for families to obtain accurate molecular diagnosis and genetic counselling. The gene identities are also critical for researchers to understand the mechanisms important for brain development and  for applicability of potential therapies. The genotype/phenotype correlations and natural history of patients with these different genetic forms are not always well described, and little is known about the pathophysiological mechanisms involved. It is our hope that this knowledge will improve the patient outcomes and to help to develop novel therapeutic approaches.

The team is therefore interested in identifying new genes and new molecular mechanisms involved in NDD and MD, in studying genotype/phenotype correlations and the natural history of patients, and in dissecting the pathophysiological mechanisms involved in certain frequent genetic mutations (fragile X syndrome, DYRK1A syndrome, etc). In the context of Fragile X syndrome, the team is involved in the development of a gene therapy strategy in collaboration with Lysogene SA. The team works in close interaction at the local level with different research teams from IGBMC and other research centers in Strasbourg and with clinical services from the University Hospital of Strasbourg thus favouring translational application of the research results. The team has also numerous national (IBPS, CRBM, etc) and international collaborations (Sick Children, DGIST, etc) and participates to different research and hospital networks on NDD.

Current projects

Identification of the genes and molecular mechanisms involved in NDD

Project leader : Amélie Piton

  • Identification of new genes involved in X-linked and autosomal DLD.
  • Development of genomic and functional tools to interpret variants of unknown significance
  • Investigation of the molecular and cellular mechanisms involved in frequent forms of monogenic NDT (e.g. DYRK1A syndrome, AGO1).

We are carrying out genetic and genomic analyses to identify the genetic causes of NDDs (in particular intellectual disabilities and autism spectrum disorders) and we are seeking to identify the molecular mechanisms involved in these disorders, which are still poorly understood. Using various genomic approaches (targeted DNA sequencing, exome and whole genome sequencing, as well as RNA sequencing), we have identified several new genes involved in NDDs (e.g. BRPF1, DDX6, NOVA2, AGO1). We are also developing functional tools to better interpret variants of unknown significance, which represent a major problem in medical genetics. Using cellular models (human neuronal precursors, cortical neurons, cerebral organoids), we are more specifically dissecting the pathophysiological mechanisms of certain frequent monogenic forms of NDD, affecting proteins involved in the regulation of gene expression at transcriptional or post-transcriptional level (e.g. DYRK1A, AGO1).


Identification of the genes involved in Movement Disorders

Project leader : Mathieu Anheim, Christine Tranchant

  •  We are carrying out genetic and genomic analyses to identify the genetic causes of movement disorders (MD)


Genotype/phenotype correlation and natural history of NDD

Project leaders: Jean-Louis Mandel & Pauline Burger

To better characterise the clinical manifestations and natural history of rare neurodevelopmental diseases, we have built a participatory online database to collect clinical information specific to each monogenic form of ID directly from families (Genida project: More than 1,000 families are registered and active.


Pathophysiological mechanisms and therapeutic approaches for Fragile X syndrome

Project leader: Hervé Moine

  • Characterising and understanding the pathophysiological mechanisms involved in Fragile-X syndrome using cell and mouse models (Fmrp, Dgkk).
  • Preclinical testing of innovative therapeutic approaches for Fragile X syndrome

Using cellular models as well as in vivo approaches with mouse models (KO or use of AAV for inactivation or expression of mutant proteins), we are further investigating the mechanisms by which the absence of the RNA-binding protein FMRP, involved in post-transcriptional regulation, leads to Fragile X syndrome (the most common monogenic cause of ID). In particular, we have identified that the mRNA encoding diacylglycerol kinase kappa (DGKK) is a primary target of FMRP mRNA and are currently testing it as a therapeutic target for Fragile-X syndrome, in collaboration with Lysogene.


Lab members:


Researchers & collab. clinicians


PITON   Amélie

MANDEL Jean-Louis

ANHEIM Mathieu


WIRTH Thomas



Engineers & technicians



BURGER Pauline

DROUOT Nathalie

SKORY Valérie

LAMOUCHE Jean-Baptiste


Postdoc fellows



PhD students


BAER Sarah




Selection of recent publications

- Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B). Wirth T, Clément G, Delvallée C, Bonnet C, Bogdan T, Iosif A, Schalk A, Chanson JB, Pellerin D, Brais B, Roth V, Wandzel M, Fleury MC, Piton A, Calmels N, Namer IJ, Kremer S, Tranchant C, Renaud M, Anheim M.Mov Disord.2023 Jul 20. doi: 10.1002/mds.29560. Online ahead of print. PMID: 37470282

- GenIDA: an international participatory database to gain knowledge on health issues related to genetic forms of neurodevelopmental disorders. Burger P, Colin F, Strehle A, Mazzucotelli T, Collot N, Coutelle R, Durand B, Bouman A, Landau Prat D, Kleefstra T, Parrend P, Piton A, Koolen DA, Mandel JL.J Neural Transm (Vienna). 2023 Mar;130(3):459-471. doi: 10.1007/s00702-022-02569-3. Epub 2022 Nov 27. PMID: 36436153

- SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice. El Chehadeh S, Han KA, Kim D, Jang G, Bakhtiari S, Lim D, Kim HY, Kim J, Kim H, Wynn J, Chung WK, Vitiello G, Cutcutache I, Page M, Gecz J, Harper K, Han AR, Kim HM, Wessels M, Bayat A, Jaén AF, Selicorni A, Maitz S, de Brouwer APM, Silfhout AV, Armstrong M, Symonds J, Küry S, Isidor B, Cogné B, Nizon M, Feger C, Muller J, Torti E, Grange DK, Willems M, Kruer MC, Ko J*, Piton A*, Um JW*. Nat Commun. 2022 Jul 15;13(1):4112. doi: 10.1038/s41467-022-31566-z. PMID: 35840571

- The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA. Coutelle R, Boedec M, Vermeulen K, Kummeling J, Koolen DA, Kleefstra T, Fournier C, Colin F, Strehle A, Geneviève D, Burger P, Mandel JL.BMC Psychiatry. 2022 Aug 25;22(1):572. doi: 10.1186/s12888-022-04213-6. PMID: 36008773 Free PMC article.

- Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study. Bogdan T, Wirth T, Iosif A, Schalk A, Montaut S, Bonnard C, Carre G, Lagha-Boukbiza O, Reschwein C, Albugues E, Demuth S, Landsberger H, Einsiedler M, Parratte T, Nguyen A, Lamy F, Durand H, Fahrer P, Voulleminot P, Bigaut K, Chanson JB, Nicolas G, Chelly J, Cazeneuve C, Koenig M, Bund C, Namer IJ, Kremer S, Calmels N, Tranchant C, Anheim M.J Neurol. 2022 Dec;269(12):6354-6365. doi: 10.1007/s00415-022-11253-1. Epub 2022 Jul 23. PMID: 35869996

- De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability. Schalk A, Cousin MA, Dsouza NR, Challman TD, Wain KE, Powis Z, Minks K, Trimouille A, Lasseaux E, Lacombe D, Angelini C, Michaud V, Van-Gils J, Spataro N, Ruiz A, Gabau E, Stolerman E, Washington C, Louie R, Lanpher BC, Kemppainen JL, Innes M, Kooy F, Meuwissen M, Goldenberg A, Lecoquierre F, Vera G, Diderich KEM, Sheidley B, El Achkar CM, Park M, Hamdan FF, Michaud JL, Lewis AJ, Zweier C, Reis A, Wagner M, Weigand H, Journel H, Keren B, Passemard S, Mignot C, van Gassen K, Brilstra EH, Itzikowitz G, O'Heir E, Allen J, Donald KA, Korf BR, Skelton T, Thompson M, Robin NH, Rudy NL, Dobyns WB, Foss K, Zarate YA, Bosanko KA, Alembik Y, Durand B, Tran Mau-Them F, Ranza E, Blanc X, Antonarakis SE, McWalter K, Torti E, Millan F, Dameron A, Tokita M, Zimmermann MT, Klee EW, Piton A*, Gerard B. J Med Genet. 2022 Oct;59(10):965-975. doi: 10.1136/jmedgenet-2021-107751. Epub 2021 Dec 15. PMID: 34930816

- De novo truncating NOVA2 variants affect alternative splicing and lead to heterogeneous neurodevelopmental phenotypes. Scala M, Drouot N, MacLennan SC, Wessels MW, Krygier M, Pavinato L, Telegrafi A, de Man SA, van Slegtenhorst M, Iacomino M, Madia F, Scudieri P, Uva P, Giacomini T, Nobile G, Mancardi MM, Balagura G, Galloni GB, Verrotti A, Umair M, Khan A, Liebelt J, Schmidts M, Langer T, Brusco A, Lipska-Ziętkiewicz BS, Saris JJ, Charlet-Berguerand N, Zara F, Striano P, Piton A.Hum Mutat. 2022 Sep;43(9):1299-1313. doi: 10.1002/humu.24414. Epub 2022 Jun 8. PMID: 35607920

- De Novo Mutation in TMEM151A and Paroxysmal Kinesigenic Dyskinesia. Wirth T, Méneret A, Drouot N, Rudolf G, Lagha Boukbiza O, Chelly J, Tranchant C, Piton A, Roze E, Anheim M. Mov Disord.2022 May;37(5):1115-1117. doi: 10.1002/mds.29023. PMID: 35587630 Free PMC article. No abstract available.

- Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes. Durand B, Schaefer E, Burger P, Baer S, Schroder C, Mandel JL, Piton A, Coutelle R. Clin Genet. 2022 Oct;102(4):296-304. doi: 10.1111/cge.14190. Epub 2022 Jul 25. PMID: 35821609

- Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder. Courraud J, Chater-Diehl E, Durand B, Vincent M, Del Mar Muniz Moreno M, Boujelbene I, Drouot N, Genschik L, Schaefer E, Nizon M, Gerard B, Abramowicz M, Cogné B, Bronicki L, Burglen L, Barth M, Charles P, Colin E, Coubes C, David A, Delobel B, Demurger F, Passemard S, Denommé AS, Faivre L, Feger C, Fradin M, Francannet C, Genevieve D, Goldenberg A, Guerrot AM, Isidor B, Johannesen KM, Keren B, Kibæk M, Kuentz P, Mathieu-Dramard M, Demeer B, Metreau J, Steensbjerre Møller R, Moutton S, Pasquier L, Pilekær Sørensen K, Perrin L, Renaud M, Saugier P, Rio M, Svane J, Thevenon J, Tran Mau Them F, Tronhjem CE, Vitobello A, Layet V, Auvin S, Khachnaoui K, Birling MC, Drunat S, Bayat A, Dubourg C, El Chehadeh S, Fagerberg C, Mignot C, Guipponi M, Bienvenu T, Herault Y, Thompson J, Willems M, Mandel JL, Weksberg R, Piton A.Genet Med. 2021 Nov;23(11):2150-2159. doi: 10.1038/s41436-021-01263-1. Epub 2021 Aug 3. PMID: 34345024 Free article.

- De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder. Mattioli F, Hayot G, Drouot N, Isidor B, Courraud J, Hinckelmann MV, Mau-Them FT, Sellier C, Goldman A, Telegrafi A, Boughton A, Gamble C, Moutton S, Quartier A, Jean N, Van Ness P, Grotto S, Nambot S, Douglas G, Si YC, Chelly J, Shad Z, Kaplan E, Dineen R, Golzio C, Charlet-Berguerand N, Mandel JL, Piton A.Am J Hum Genet.2020 Apr 2;106(4):438-452. doi: 10.1016/j.ajhg.2020.02.013. Epub 2020 Mar 19. PMID: 32197073 Free PMC article.

Collaborations and networks

  • Strasand:
  • FHU Neurogenycs:
  • Filière de santé Anddi-Rares
  • Filère de santé Defiscience
  • Juliette Godin, Yann Herault, Izabela Sumara, Nicolas Charlet Berguerand (IGBMC)
  • Hélène Dollfus, Elise Schafer, Salima El Chehadeh (Service de Génétique Médicale, Hôpitaux Universitaire de Strasbourg)
  • Vincent Laugel & Anne de St Martin (Département de Neuropédiatrie, Hôpitaux Universitaire de Strasbourg)
  • Carmen Schroder & Romain Coutelle (Service de Pédo-Psychiatrie, Hôpitaux Universitaire de Strasbourg)
  • Mathieu Anheim, Christine Tranchant (Service de Neurologie, Hôpitaux Universitaire de Strasbourg)
  • Nicolas Vitale (INCI, Strasbourg)
  • Olivier Manzoni (INMED, Marseille)
  • Barbara Bardoni (IMPC, Nice)
  • Alexandra Benchoua (Istem, Evry, France)
  • Dominique Weil & Marianne Bénard (IBPS, Paris)
  • Pierre Parrend (iCube, CNRS and U. of Strasbourg)
  • Damien Sanlaville, Gaetan Lesca (Hospices Civils de Lyon)
  • Fréderic Laumonnier (INSERM, Tours)
  • Rosanna Weksberg & Eric Chater-Diehl (Sick Children Hospital, Toronto, Canada)
  • Michael Lombardo, Simon Baron-Cohen (Cambridge Neuroscience, UK)
  • Victor Ambros (University of Massachusetts Medical School, USA)
  • David Koolen, Tjitske Kleefstra (Radboud University, Nijmegen, Holland)
  • Christel Depienne (Institut für Humangenetik; Essen Germany)
  • Ji-Won Um (Department of Brain and Cognitive Sciences, Daegu, Corea)
  • Vera Kalscheuer (Max Planck Institute for Molecular Genetics, Berlin, Germany)

Funding and partners

  • CNRS
  • Université de Strasbourg
  • Faculté de médecine
  • IUF
  • ANR
  • SATT Conectus
  • Jerome Lejeune Foundation
  • Fondation pour la Recherche Médicale
  • Agence de Biomédecine
  • Fondations Maladies Rares
  • Fondation de France


10 years of the Unistra Réseau Alumni: emphasis on sharing research

On March 24, the 10th anniversary evening of the University of Strasbourg Alumni Network will focus on solidarity and the transmission of knowledge in…

Read more

Awards and recognitions

  • Prix de thèse - Jeune Chercheur Jérôme Lejeune (2021) : J. Courraud
  • Prix de thèse - Jeune Chercheur Jérôme Lejeune (2017) : F. Mattioli
  • Prix de thèse - Société de Biologie de Strasbourg (2016): A. Quartier
  • Prix de Thèse - Chancellerie des Universités de Paris (2017) : L. Broix
  • Jeune Chercheur Jérôme Lejeune " (2015) : R.Tabet
  • Prix de Thèse - Société des Amis des Universités de l'Académie de Strasbourg (2015) : C. Redin
  • Prix Christian Nezelof (2014) : C. Redin
  • Junior member, Institut Universitaire de France (2018-2022): A. Piton
  • Installation grant FRM new team (2016): H. Moine
  • Maurice Nicloux price Société Française Biochimie et Biologie Moléculaire (1992): H Moine
  • Membre de l’ Académie des Sciences (1999): JL. Mandel
  • Membre de l’Académie Nationale de Médecine (2009): JL. Mandel
  • Chevalier de la légion d’honneur (2008): JL. Mandel
  • Prix Plasticité Neuronale - Fondation IPSEN (2014) : JL. Mandel
  • Prix Klaus Joachim Zülch Foundation Reemtsma / Max Planck Society (2001) : JL Mandel
  • Prix de la Fondation GPA - Académie des sciences (1988) : JL Mandel
  • Membre de l'organisation européenne de biologie moléculaire (EMBO) : JL Mandel
  • Prix de médecine Louis-Jeantet - Fondation Louis-Jeantet  (1999) : JL Mandel
  • Prix Mauro Baschirotto - Société Européenne de Génétique Humaine (1998) : JL Mandel
  • Prix Richard Lounsbery  (1994): JL Mandel
  • Prix International San Remo Société Italienne de Génétique Humaine (1992) : JL Mandel
  • European Molecular Biology Organization (EMBO) (1982) : JL Mandel
  • Prix de la Fondation GPA - Académie des sciences (1988) : : JL Mandel
  • Prix scientifique - Fondation NRJ - Institut de France (2014) : J. Chelly
  • Prix de la recherche – Inserm (2010): J. Chelly
  • Médaille d'argent - CNRS (2002), médaille de Bronze - CNRS (1992) : J. Chelly
  • Grand prix - EDF (2001) : J. Chelly
  • Grand prix de la recherche "Sciences du vivant" - Fondation Bettencourt Schueller (2009) : J. Chelly
  • Prix de la recherche médicale et scientifique - FRM(1999) : J. Chelly
  • Prix Carré-Bessault - Académie des sciences (1992) : J Chelly


Translational medecine and neurogenetics - Rare diseases