Report of a novel recurrent homozygous variant c.620A>T in three unrelated families with thiamine metabolism dysfunction syndrome 5 and review of literature.

Introduction: Biallelic variants in thiamine pyrophosphokinase 1 ( TPK1 ) are known to cause thiamine metabolism dysfunction syndrome 5 (THMD5). This disorder is characterized by neuroregression, ataxia and dystonia with basal ganglia abnormalities on neuroimaging. To date, 27 families have been reported with THMD5 due to variants in TPK1 .

Methods: We ascertained three individuals from three unrelated families. Singleton exome sequencing was performed on all three individuals, followed by in silico mutagenesis of the mutant TPK protein. Additionally, we reviewed the genotypic and phenotypic information of 27 previously reported individuals with THMD5.

Results: Singleton exome sequencing revealed a novel homozygous variant c.620A>T p.(Asp207Val) in TPK1 (NM_022445.4) in all three individuals. In silico mutagenesis of the mutant protein revealed a decrease in protein stability and altered interactions with its neighboring residues compared to the wild-type protein. Thus, based on strikingly similar clinical and radiological findings compared to the previously reported individuals and with the support of in silico mutagenesis findings, the above-mentioned variant appears to be the probable cause for the condition observed in the affected individuals in this study.

Conclusion: We report a novel homozygous variant in TPK1 , which appears to be recurrent among the Indian population.