@article{2ca59bab676747e78ef00d424f2d0174,
title = "Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus",
abstract = "Purpose: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. Methods: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. Results: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. Conclusion: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.",
keywords = "TNR, cerebral palsy, developmental disorder, exome sequencing, spastic tetraparesis",
author = "Matias Wagner and Jonathan L{\'e}vy and Sabine Jung-Klawitter and Somayeh Bakhtiari and Fabiola Monteiro and Reza Maroofian and Tatjana Bierhals and Maja Hempel and Monique Elmaleh-Berg{\`e}s and Kitajima, {Joao P.} and Kim, {Chong A.} and Salomao, {Julia G.} and Amor, {David J.} and Cooper, {Monica S.} and Laurence Perrin and Eva Pipiras and Axel Neu and Mohammad Doosti and Karimiani, {Ehsan G.} and Toosi, {Mehran B.} and Henry Houlden and Jin, {Sheng Chih} and Si, {Yue C.} and Rodan, {Lance H.} and Hanka Venselaar and Kruer, {Michael C.} and Fernando Kok and Hoffmann, {Georg F.} and Strom, {Tim M.} and Wortmann, {Saskia B.} and Tabet, {Anne Claude} and Thomas Opladen",
note = "Funding Information: We thank the patients and their families for participation in this study. We thank the Helmholtz-Zentrum Munich NGS core facility, especially Elisabeth Graf and as well as Gertrud Eckstein, Peter Lichtner, and Veronika Schwarzbauer for their excellent support. We also thank the Robert-Debr{\'e} University Hospital for its full support. We also thank Fikret Y{\"u}zg{\"u}len for referring his patient. We thank Martin Krenn for his revision of the manuscript. This study was partly funded by Dietmar Hopp Stiftung (St. Leon-Rot, Germany) and the CNRG (Centre National de G{\'e}notypage (JFDeleuze). Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",
year = "2020",
month = jun,
day = "1",
doi = "10.1038/s41436-020-0768-7",
language = "English",
volume = "22",
pages = "1061--1068",
journal = "Genetics in Medicine",
issn = "1098-3600",
number = "6",
}