Journal article
Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies
Brain (London, England : 1878), Vol.146(12), pp.4880-4890
12/01/2023
DOI: 10.1093/brain/awad328
PMCID: PMC10689924
PMID: 37769650
Abstract
Abstract Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally underrepresented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognised entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognised mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.
Details
- Title: Subtitle
- Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies
- Creators
- Annette Lischka - RWTH Aachen UniversityKatja Eggermann - RWTH Aachen UniversityChristopher J Record - National Hospital for Neurology and NeurosurgeryMaike F Dohrn - RWTH Aachen UniversityPetra Laššuthová - University Hospital in MotolFlorian Kraft - RWTH Aachen UniversityMatthias Begemann - RWTH Aachen UniversityDaniela Dey - RWTH Aachen UniversityThomas Eggermann - RWTH Aachen UniversityDanique Beijer - Dr. John T. Macdonald FoundationJana Šoukalová - University Hospital BrnoMatilde Laura - National Hospital for Neurology and NeurosurgeryAlexander M Rossor - National Hospital for Neurology and NeurosurgeryRadim Mazanec - University Hospital in MotolJonas Van Lent - University of AntwerpPedro J Tomaselli - Universidade de São PauloMartin Ungelenk - Jena University HospitalKarlien Y Debus - Friedrich Schiller University JenaShawna M E FeelyDieter Gläser - GenetikumSujatha Jagadeesh - Fetal Care Research FoundationMadelena MartinGeeta M Govindaraj - Government Medical CollegePratibha Singhi - Medanta The MedicityRevanth Baineni - Jawaharlal Institute of Post Graduate Medical Education and ResearchNiranjan Biswal - Jawaharlal Institute of Post Graduate Medical Education and ResearchMarisol Ibarra-RamírezMaryse Bonduelle - Universitair Ziekenhuis BrusselBurkhard Gess - RWTH Aachen UniversityJuan Romero SánchezRenu Suthar - Post Graduate Institute of Medical Education and ResearchVrajesh Udani - P. D. Hinduja Hospital and Medical Research CentreAtchayaram Nalini - National Institute of Mental Health and NeurosciencesGopikrishnan Unnikrishnan - National Institute of Mental Health and NeurosciencesWilson Marques JuniorSandra Mercier - Génétique Médicale & Génomique FonctionelleVincent Procaccio - Université d'AngersCéline Bris - Université d'AngersBeena Suresh - Fetal Care Research FoundationVaishnavi Reddy - Fetal Care Research FoundationMariola Skorupinska - National Hospital for Neurology and NeurosurgeryNathalie Bonello-PalotFanny Mochel - Institut de Psychiatrie et Neurosciences de ParisGeorg Dahl - Children's Hospital of The King's DaughtersKarthika Sasidharan - Government Medical CollegeFiji M Devassikutty - Government Medical CollegeSheela Nampoothiri - Amrita Institute of Medical Sciences and Research CentreMaria J Rodovalho DoriquiWolfgang Müller-FelberKatharina Vill - Technical University of MunichTobias B Haack - University of TübingenAndreas Dufke - University of TübingenMichael Abele - Tierärztliche Praxis für NeurologieRolf Stucka - Friedrich Baur StiftungSaima Siddiqi - Institute of Biomedical and Genetic EngineeringNoor UllahStephanie SprangerDeborah Chiabrando - University of TurinBehiye S Bolgül - Dicle UniversityYesim Parman - Istanbul UniversityPavel Seeman - University Hospital in MotolAngelika Lampert - RWTH Aachen UniversityJörg B Schulz - RWTH Aachen UniversityJohn N Wood - University College LondonJames J Cox - University College LondonMichaela Auer-GrumbachVincent Timmerman - University of AntwerpJonathan de Winter - University of AntwerpAndreas C Themistocleous - University of OxfordMichael Shy - University of IowaDavid L Bennett - University of OxfordJonathan Baets - University of AntwerpChristian A Hübner - Jena University HospitalEnrico LeipoldStephan Züchner - University of MiamiMiriam Elbracht - RWTH Aachen UniversityArman Çakar - Istanbul UniversityJan Senderek - Friedrich Baur StiftungThorsten Hornemann - University Hospital of ZurichC Geoffrey WoodsMary M Reilly - National Hospital for Neurology and NeurosurgeryIngo Kurth - RWTH Aachen University
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.146(12), pp.4880-4890
- DOI
- 10.1093/brain/awad328
- PMID
- 37769650
- PMCID
- PMC10689924
- NLM abbreviation
- Brain
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- DOI: 10.13039/501100001659, name: Deutsche Forschungsgemeinschaft, award: KU 1587/6-1, SE 1839/2-1; DOI: 10.13039/501100001823, name: Ministry of Education, Youth and Sports; name: Czech Republic; DOI: 10.13039/501100002428, name: Austrian Science Fund; DOI: 10.13039/501100001711, name: Swiss National Science Foundation; DOI: 10.13039/501100004410, name: Scientific and Technological Research Council of Turkey; name: European Joint Programme on Rare Diseases; name: European Union's Horizon 2020; name: Interdisciplinary Centre for Clinical Research, award: IZKF TN1-1/IA 532001, IZKF TN1-2/IA 532002, IZKF TN1-9/IA 532009; name: German Federal Ministry of Education and Research, award: 13GW0656; DOI: 10.13039/501100000265, name: Medical Research Council, award: MR/R011737/1; DOI: 10.13039/100004440, name: Wellcome Trust, award: 200183/Z/15/Z, 200183/Z/15/Z; DOI: 10.13039/501100012041, name: Versus Arthritis, award: 21950; DOI: 10.13039/501100000272, name: NIHR; DOI: 10.13039/501100018956, name: Cambridge Biomedical Research Centre, award: BRC-1215-20014; DOI: 10.13039/501100000276, name: Department of Health and Social Care; DOI: 10.13039/100007372, name: Association Belge contre les Maladies Neuromusculaires; name: Senior Clinical Researcher; DOI: 10.13039/501100003130, name: Research Fund - Flanders, award: 1805021N; DOI: 10.13039/501100007660, name: University of Antwerp; DOI: 10.13039/501100007601, name: Horizon 2020, award: 779257; name: European Commission Horizon 2020, award: ID633491; DOI: 10.13039/501100004963, name: European Union’s Seventh Framework Program, award: FP7/2007-2013; name: International Diabetic Neuropathy Consortium; name: Novo Nordisk Foundation Challenge Programme, award: NNF14OC0011633; DOI: 10.13039/100014013, name: UKRI; DOI: 10.13039/501100012041, name: Versus Arthritis, award: MR/W002388/1; DOI: 10.13039/501100001659, name: German Research Foundation, award: LE-2338/3-1; DOI: 10.13039/501100000691, name: Academy of Medical Sciences Starter, award: SGL022\\1086; DOI: 10.13039/501100002426, name: Fondazione Telethon ETS, award: GMR22T1076; name: International Centre for Genomic Medicine in Neuromuscular Diseases, award: MR/S005021/1
- Language
- English
- Electronic publication date
- 09/28/2023
- Date published
- 12/01/2023
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984473779802771
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