Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity.

Tenascin-R (TNR) is an extracellular matrix glycoprotein that is essential for the formation of perineuronal nets in the central nervous system and is critical for neurite outgrowth, synaptic plasticity, and neural stem cell proliferation and differentiation. Biallelic TNR variants were reported to cause neurodevelopmental disorders with developmental delay, hypotonia, spasticity, and a variety of motor abnormalities. Here, we describe two Japanese siblings sharing novel compound heterozygous TNR missense variants (NM_003285.3:c.[1783 G > A];[3766 C > T] p.[(Asp595Asn)];[(Arg1256Cys)]) identified by exome and Sanger sequencing. The elder brother had dystonia, while the younger sister was asymptomatic except for adult-onset restless legs syndrome. Their development and intellect were normal. A total of 15 patients, including 13 previously reported patients, showed diverse phenotypic variability and severity, even among individuals sharing the same variants, indicating variable expressivity and reduced penetrance possibly influenced by genetic or environmental modifiers. Our findings extend the clinical spectrum of TNR-related disease and highlight the need for further accumulation of clinical cases and functional studies to understand genotype-phenotype correlations and the pathogenesis of diseases.