Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice

Abstract TBCK‐related encephalopathy is a rare pediatric neurodegenerative disorder caused by biallelic loss‐of‐function variants in the TBCK gene. After receiving anecdotal reports of neurologic phenotypes in both human and mouse TBCK heterozygotes, we quantified if TBCK haploinsufficiency causes a phenotype in mice and humans. Using the tbck +/− mouse model, we performed a battery of behavioral assays and mTOR pathway analysis to investigate potential alterations in neurophysiology. We conducted as well a phenome‐wide association study (PheWAS) analysis in a large adult biobank to determine the presence of potential phenotypes associated to this variant. The tbck +/− mouse model demonstrates a reduction of exploratory behavior in animals with significant sex and genotype interactions. The concurrent PheWAS analysis of 10,900 unrelated individuals showed that patients with one copy of a TBCK loss‐of‐function allele had a significantly higher rate of acquired toe and foot deformities, likely indicative of a mild peripheral neuropathy phenotype. This study presents an example of what may be the underappreciated occurrence of mild neurogenic symptoms in heterozygote individuals of recessive neurogenetic syndromes.