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

Autor:	Mascarenhas S; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal., Yeole M; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal., Rao LP; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal., do Rosario MC; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal., Majethia P; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal., Nair KV; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal., Sharma S; Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi., Barala PK; Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi., Puri RD; Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi., Pal S; Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi., Siddiqui S; Department of Neuroimaging and Interventional Radiology, STAR Institute of Neurosciences, STAR Hospitals, Hyderabad, India., Shukla A; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal.
Jazyk:	angličtina
Zdroj:	Clinical dysmorphology [Clin Dysmorphol] 2024 Oct 01; Vol. 33 (4), pp. 160-166. Date of Electronic Publication: 2024 Jul 16.
DOI:	10.1097/MCD.0000000000000490
Abstrakt:	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. (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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