TNR was first reported in relation to autosomal recessive neurodevelopmental disorder, non-progressive with spasticity and transient opisthotonus (NEDSTO) in 2012 (Dufresne et al., PMID: 22730557). Individuals with variants in TNR can present with features such as gross motor delay (specifically in walking), axial hypotonia, peripheral spasticity, opisthotonus, and varying degrees of intellectual disability. Other phenotypes can include speech delay and brain myelination anomalies.
Ten variants (missense, frameshift, nonsense, large deletion) that have been reported in 16 probands in 3 publications (PMIDs: 22730557, 28334938, 32099069) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function (PMID: 22730557). This gene-disease relationship is also supported by experimental evidence such as a mouse model and expression-level evidence (PMIDs: 8626505, 12882316, 15034584). The mouse model shows that TNR-deficient mice have atypical behavior, structural brain anomalies, and impaired learning/memory. Expression-level data from healthy human tissue shows that the gene is expressed specifically in the brain.
In summary, there is definitive evidence supporting the relationship between TNR and autosomal recessive NEDSTO. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on January 2, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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