Mitochondrial background and tissue-specific heteroplasmy in relation to clinical features of patients with diabetes

Introduction Mitochondrial diabetes is a rare syndromic form of monogenic diabetes whose clinical presentation resembles that of the more common, polygenic forms of diabetes. We characterized the mitochondrial genetic background, clinical spectrum and tissue-specific heteroplasmy in Polish patients with suspected monogenic diabetes. Methods Next-generation sequencing of mitochondrial DNA (mtDNA) was performed in 496 patients referred with suspected monogenic diabetes and negative nuclear DNA testing. The clinical analysis included 53 individuals from 31 families. In 30 m.3243A>G carriers, heteroplasmy was quantified in urine sediment and buccal swabs, and longitudinally, at two time points, in peripheral blood. Results Pathogenic mtDNA variants were identified in 21/496 patients (diagnostic yield 4.23%), most frequently m.3243A>G (17/21). Three further probands carried rare mitochondrial tRNA variants of uncertain clinical significance, two of them in MT-TL2 . No significant association between heteroplasmy in any tissue and specific clinical features was demonstrated, although statistical power was limited. A clear tissue hierarchy was observed (p < 0.0001): mean heteroplasmy was highest in urine sediment (60.7%), followed by buccal swabs (39.1%) and blood (21.6%). Blood heteroplasmy decreased with age by 0.58% per year (linear mixed-effects model, p < 0.0001). Conclusions Urine sediment appears to be the most informative material for assessing heteroplasmy. Analysis of blood alone may be insufficient to establish the genetic basis of mitochondrial diabetes, particularly in older patients. The recurrent identification of rare MT-TL2 variants in patients with diabetes warrants further functional studies of this gene. These findings have direct implications for diagnostic algorithms, genetic counseling, and clinical follow-up.