Genetic Prevalence of Thymidine Kinase 2-Related Mitochondrial Disease: Combined Approach Using Clinical Literature and Large-Scale Genomic Databases

Topic:

Translational Research

Poster Number: 123 S

Author(s):

Austin Larson, MD, Children's Hospital Colorado, Amina Kozaric, PhD, Genomenon, Kaja Zarakowska, UCB, Bulle, Switzerland, Prashant Dongre, MD, UCB Inc, Sarah Chang, PhD, UCB, Amar Mujkic, Genomenon, Mark Kiel, MD, PhD, Genomenon

Introduction: Thymidine kinase 2 deficiency (TK2d) is a rare, life-threatening mitochondrial disease caused by autosomal recessive mutations in the TK2 gene. Patients present with progressive proximal myopathy and respiratory weakness, with many losing the ability to walk, eat, and breathe independently. The first cases of TK2d were described in 2001, yet the prevalence of TK2d remains poorly understood. This study aimed to calculate the genetic birth prevalence of TK2d globally and in different populations.
Methods: We used the Mastermind Genomic Search Engine to identify all TK2 single-nucleotide variants (SNVs) and indels from the literature, followed by a semi-automated curation and expert review to classify variants according to the American College of Medical Genetics criteria. Included variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, and presumed pathogenic (e.g., loss-of-function variants). TK2d genetic prevalence was estimated from gnomAD v4 database allele frequencies assuming Hardy–Weinberg equilibrium.
Results: Limiting analysis to pathogenic and likely pathogenic variants gave a lower-bound TK2d global genetic prevalence of 0.34 per million pregnancies, while considering all selected variants increased the estimate to 2.82 per million pregnancies. The highest genetic prevalence and carrier frequency as assessed per million pregnancies were observed in the Admixed American (2.80 to 13.06), African/African American (0.36 to 8.27), South Asian (0.27 to 5.15), and Finnish (3.23 to 4.39) populations. The most common pathogenic variants globally were p.Ala139Thr, p.Arg183Trp, p.Ala139Val, p.His121Asn, and p.Thr108Met, however these differed in prevalence in the subpopulations.
Conclusion: TK2d genetic prevalence is estimated to be 0.34 to 2.82 per million pregnancies globally. These findings can inform healthcare planning by identifying at-risk populations and may provide data for evaluating the feasibility of TK2 inclusion in newborn screening programs. The higher estimated genetic prevalence in some populations emphasizes the importance of clinical awareness and early diagnostic testing.
Study funded by UCB.