Dilated cardiomyopathy in the structure of a familial form of TOP3A-related Bloom-like syndrome

Bloom-like syndrome is a rare autosomal recessive disorder caused by nucleotide variants in the TOP3A gene. It is characterized by clinical manifestations similar to Bloom syndrome, including a characteristic facial phenotype and physical development delay, but diff ers in the more frequent development of a dilated cardiomyopathy. These syndromes belong to the group of hereditary diseases associated by impaired DNA repair. Given the existence of isolated clinical cases with a predominant description of characteristic physical development delay, a detailed description of the course of dilated cardiomyopathy is signifi cant for understanding the disease and optimizing medical treatment.

Here is a description of the clinical course and features of the child’s management with a homozygous mutation c.2264_2265delinsT in the TOP3A gene, examined at the cardiology department of the National Medical Research Center of Children’s Health of the Ministry Health of the Russian Federation. An analysis of anamnesis data, including family history, results of clinical, laboratory, instrumental diagnostic methods, and molecular genetic testing performed using Sanger direct sequencing technology, was conducted.

A literature review of patients with mutations in the TOP3A gene was conducted. The presented clinical case demonstrates the importance of timely diagnosis of the disease, the high frequency of cardiac manifestations, particularly the steadily progressive and fatal course of dilated cardiomyopathy.

In childhood, dilated cardiomyopathy can be a dominant and life-threatening manifestation of TOP3A-associated Bloom-like syndrome. Given the risk of a sudden and aggressive course of dilated cardiomyopathy, identifying mutations in the TOP3A gene in children with physical development delay and a characteristic «bird-like» facies has important prognostic value. Improving the prognosis requires early diagnosis, including prenatal diagnosis in high-risk families, the development of pathogenetic therapy, and a multidisciplinary approach to patient management.

1. German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28(8):743‒753. doi: 10.1002/humu.20501

2. Martin CA, Sarlós K, Logan CV, et al. Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Human Genet. 2018;103(3):456. doi: 10.1016/j.ajhg.2018.08.012

3. Wang Y, Lyu YL, Wang JC. Dual localization of human DNA topoisomerase III alpha to mitochondria and nucleus. Proc Natl Acad Sci USA. 2002;99(19):12114‒12119. doi: 10.1073/pnas.192449499

4. Wang Y, Kaiser S, Martin-Gonzalez J, et al. Functional analysis of pathological mutations in DNA topoisomerase 3A. Cell Rep. 2025;44(6):115764. doi: 10.1016/j.celrep.2025.115764

5. Saha LK, Pommier Y. TOP3A coupling with replication forks and repair of TOP3A cleavage complexes. Cell Cycle. 2024;23(2):115‒130. doi: 10.1080/15384101.2024.2314440

6. Menger KE, Chapman J, Díaz-Maldonado H, et al. Two type I topoisomerases maintain DNA topology in human mitochondria. Nucleic Acids Res. 2022;50(19):11154‒11174. doi: 10.1093/nar/gkac857

7. Nicholls TJ, Nadalutti CA, Motori E, et al. Topoisomerase 3α is required for decatenation and segregation of human mtDNA. Mol Cell. 2018;69(1):9‒23.e6. doi: 10.1016/j.molcel.2017.11.033

8. Primiano G, Torraco A, Verrigni D, et al. Novel TOP3A variant associated with mitochondrial disease: expanding the clinical spectrum of topoisomerase III alpha-related diseases. Neurol Genet. 2022;8(4):e200007. doi: 10.1212/NXG.0000000000200007

9. Jiang W, Jia N, Guo C, et al. Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder. Biochim Biophys Acta Mol Basis Dis. 2021;1867(6):166106. doi: 10.1016/j.bbadis.2021.166106

10. Erdinc D, Rodríguez-Luis A, Fassad MR, et al.; Genomics England Research Consortium. Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability. EMBO Mol Med. 2023;15(5):e16775. doi: 10.15252/emmm.202216775

11. Savostyanov KV, Namazova-Baranova LS, Basargina EN, et al. The new genome variants in Russian children with genetically determined cardiomyopathies revealed with massive parallel sequencing. Annals of the Russian Academy of Medical Sciences. 2017;72(4):242‒253]. doi: 10.15690/vramn872 EDN: ZFOURX

12. Kostrova I, Aliomarova P, Dzhamolodinova E, et al. Bloomlike syndrome. A clinical case. In: Conference on Orphan and Pediatric Endocrine Diseases with International Involvement “Implementation of Scientifi c Achievements to the Practice of a Pediatric Endocrinologist”. Moscow; 2021. (In Russ.)]. doi: 10.14341/ISAPPE-2021-20

13. Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):124. doi: 10.1038/s41392-024-01839-8

14. Liu Y, Huang Y, Xu C, et al. Mitochondrial dysfunction and therapeutic perspectives in cardiovascular diseases. Int J Mol Sci. 2022;23(24):16053. doi: 10.3390/ij ms232416053