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 under-represented 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 recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized 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.

Cambridge Institute for Medical Research Keith Peters Building Cambridge Biomedical Campus Cambridge CB2 0XY UK

Center for Human Genetics Genetikum® 89231 Neu Ulm Germany

Center for Molecular Biomedicine Institute for Biophysics Friedrich Schiller Universität Jena 07745 Jena Germany

Centre for Medical Genetics Universitair Ziekenhuis Brussel 1090 Jette Brussels Belgium

CHU Nantes Service de Génétique Médicale Centre de Référence des Maladies Neuromusculaires AOC 44000 Nantes France

Davis and Davis Children's Hospital University of California Sacramento CA 95817 USA

Department of Anesthesiology and Intensive Care and CBBM Center of Brain Behavior and Metabolism University of Luebeck 23562 Luebeck Germany

Department of Biochemistry and Genetics MitoVasc Institute UMR CNRS 6015 INSERM U1083 CHU Angers 49055 Angers France

Department of Child Neurology PD Hinduja Hospital and Medical Research Centre Mumbai Maharashtra 400 016 India

Department of Clinical Chemistry University Hospital Zurich University of Zurich 8006 Zurich Switzerland

Department of Clinical Genetics and Genetic Counselling Mediscan Systems Chennai 600032 Tamilnadu India

Department of Genetics Hospital Infantil Doutor Juvêncio Mattos São Luis Maranhão 65015 460 Brazil

Department of Medical Genetics University Hospital Brno 625 00 Brno Czechia

Department of Molecular Biotechnology and Health Sciences Molecular Biotechnology Center 'Guido Tarone' University of Torino 10124 Turin Italy

Department of Neurology Faculty of Medicine Charles University Prague and Motol University Hospital 150 06 Prague Czechia

Department of Neurology Medical Faculty of the RWTH Aachen University 52074 Aachen Germany

Department of Neurology National Institute of Mental Health and Neurosciences Bengaluru 560 029 India

Department of Neurology University Hospital Evangelisches Klinikum Bethel University of Bielefeld 33617 Bielefeld Germany

Department of Neurology University of Iowa Carver College of Medicine Iowa City IA 52242 USA

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London WC1N 3BG UK

Department of Neuropediatrics Developmental Neurology and Social Pediatrics LMU Campus Innenstadt University of Munich 80337 Munich Germany

Department of Neurosciences and Behaviour Sciences Clinical Hospital of Ribeirão Preto University of São Paulo Ribeirão Preto 14015 130 Brazil

Department of Orthopedics and Trauma Surgery Medical University of Vienna 1090 Vienna Austria

Department of Paediatric Neurology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital 150 06 Praha Czechia

Department of Pediatric Genetics Amrita Institute of Medical Sciences and Research Center Cochin Kerala 682 041 India

Department of Pediatric Neurology and Developmental Medicine Dr von Hauner Children's Hospital University Hospital LMU Munich 80337 Munich Germany

Department of Pediatrics Government Medical College Kozhikode Kerala 673 008 India

Department of Pediatrics Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry 605 006 India

Department of Pedodontics Faculty of Dentistry Dicle University 21200 Diyarbakir Turkey

Division of Pediatric Neurology Seattle Children's Hospital University of Washington School of Medicine Seattle WA 98105 USA

Dr John T Macdonald Foundation Department of Human Genetics and John P Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami FL 33136 USA

Friedrich Baur Institute at the Department of Neurology LMU University Hospital LMU Munich 80336 Munich Germany

Genetics Department Hospital Universitario Dr José Eleuterio González Universidad Autónoma de Nuevo León 64460 Monterrey Nuevo León México

Genetics Department Sorbonne Université Paris Brain Institute APHP INSERM CNRS 75013 Paris France

Genomics Group Institute of Biomedical and Genetic Engineering Islamabad 44000 Pakistan

INSERM MMG U 1251 Marseille France Aix Marseille Univ 13385 Marseille France

Institute for Human Genetics and Genomic Medicine Medical Faculty RWTH Aachen University Hospital 52074 Aachen Germany

Institute for Paramedical Sciences Khyber Medical University Peshawar KPK 25100 Pakistan

Institute of Human Genetics School of Medicine Technical University of Munich 81675 Munich Germany

Institute of Human Genetics University Hospital Jena 07747 Jena Germany

Institute of Medical Genetics and Applied Genomics University of Tübingen 72076 Tübingen Germany

Institute of Neurophysiology Medical Faculty Uniklinik RWTH Aachen University 52074 Aachen Germany

JARA BRAIN Institute Molecular Neuroscience and Neuroimaging Research Centre Jülich GmbH and RWTH Aachen University 52056 Aachen Germany

Molecular Nociception Group Wolfson Institute for Biomedical Research University College London London WC1E 6BT UK

MVZ Humangenetik Bremen Limbach Genetics 28209 Bremen Germany

Neurologie Praxis für Neurologie und Schlafmedizin 53359 Rheinbach Germany

Neuromuscular Reference Centre Department of Neurology Antwerp University Hospital 2610 Antwerp Belgium

Neuromuscular Unit Department of Neurology Istanbul Faculty of Medicine Istanbul University 34093 Istanbul Turkey

Nuffield Department of Clinical Neuroscience University of Oxford Oxford OX3 9DU UK

Pediatría Clínica Premium 29601 Marbella Spain

Pediatric Neurology and Neurodevelopment Medanta The Medicity Gurgaon Haryana 122 001 India

Pediatric Neurology and Neurodevelopment Unit Department of Pediatrics Advanced Pediatric Centre Post Graduate Institute of Medical Education and Research Chandigarh 160 012 India

Pediatric Neurology Children's Hospital of the King's Daughters in Norfolk Norfolk VA 23507 USA

Peripheral Neuropathy Research Group Department of Biomedical Sciences Institute Born Bunge University of Antwerp 2160 Antwerp Belgium

Translational Neurosciences and Institute Born Bunge Faculty of Medicine and Health Sciences University of Antwerp 2610 Antwerp Belgium

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