Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Annette Lischka, Katja Eggermann, Christopher J Record, Maike F Dohrn, Petra Laššuthová, Florian Kraft, Matthias Begemann, Daniela Dey, Thomas Eggermann, Danique Beijer, Jana Šoukalová, Matilde Laura, Alexander M Rossor, Radim Mazanec, Jonas Van Lent, Pedro J Tomaselli, Martin Ungelenk, Karlien Y Debus, Shawna M E Feely, Dieter GläserSujatha Jagadeesh, Madelena Martin, Geeta M Govindaraj, Pratibha Singhi, Revanth Baineni, Niranjan Biswal, Marisol Ibarra-Ramírez, Maryse Bonduelle, Burkhard Gess, Juan Romero Sánchez, Renu Suthar, Vrajesh Udani, Atchayaram Nalini, Gopikrishnan Unnikrishnan, Wilson Marques Junior, Sandra Mercier, Vincent Procaccio, Céline Bris, Beena Suresh, Vaishnavi Reddy, Mariola Skorupinska, Nathalie Bonello-Palot, Fanny Mochel, Georg Dahl, Karthika Sasidharan, Fiji M Devassikutty, Sheela Nampoothiri, Maria J Rodovalho Doriqui, Wolfgang Müller-Felber, Katharina Vill, Tobias B Haack, Andreas Dufke, Michael Abele, Rolf Stucka, Saima Siddiqi, Noor Ullah, Stephanie Spranger, Deborah Chiabrando, Behiye S Bolgül, Yesim Parman, Pavel Seeman, Angelika Lampert, Jörg B Schulz, John N Wood, James J Cox, Michaela Auer-Grumbach, Vincent Timmerman, Jonathan de Winter, Andreas C Themistocleous, Michael Shy, David L Bennett, Jonathan Baets, Christian A Hübner, Enrico Leipold, Stephan Züchner, Miriam Elbracht, Arman Çakar, Jan Senderek, Thorsten Hornemann, C Geoffrey Woods, Mary M Reilly, Ingo Kurth

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.

Original languageEnglish
JournalBrain : a journal of neurology
Volume146
Issue number12
Pages (from-to)4880-4890
Number of pages11
ISSN0006-8993
DOIs
Publication statusPublished - 01.12.2023

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