DTYMK – Mitochondrial DNA Depletion Syndrome

Biallelic loss‐of‐function variants in DTYMK have been reported in siblings presenting with congenital hypotonia, microcephaly, and severe intellectual disability characteristic of mitochondrial DNA depletion syndrome. In a quartet family, two affected sibs carried compound heterozygous variants c.295G>A (p.Ala99Thr) and c.287_320del (p.Asp96fs) in trans, with biochemical evidence of mitochondrial DNA depletion in the more severely affected child ([PMID:31271740]). The inheritance is autosomal recessive with segregation of variants in unaffected parents and two affected siblings (affected_relatives=2). Functional assays of recombinant TMPK harboring patient variants demonstrated complete loss of kinase dimerization and catalytic activity, and patient‐derived fibroblasts lacked mitochondrial TMPK activity, consistent with a loss‐of‐function mechanism ([PMID:34926941]).

Although only a single family (two probands) has been described to date, the concordant genetic segregation and robust functional data support a Limited clinical validity for DTYMK in mitochondrial DNA depletion syndrome. Clinical testing should include DTYMK in gene panels for early‐onset mitochondrial disorders. Key Take-home: DTYMK loss‐of‐function causes autosomal recessive mitochondrial DNA depletion syndrome and should be considered in neonatal hypotonia with microcephaly.

References

• Clinica chimica acta; international journal of clinical chemistry • 2019 • Deoxythymidylate kinase, DTYMK, is a novel gene for mitochondrial DNA depletion syndrome. PMID:31271740
• ACS omega • 2021 • Biochemical Characterizations of Human TMPK Mutations Identified in Patients with Severe Microcephaly: Single Amino Acid Substitutions Impair Dimerization and Abolish Their Catalytic Activity. PMID:34926941

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