Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22–49-fold) risk of neuropathy (rs2032930 and rs2032931 of recQ-mediated genome instability protein 2 (RMI2) gene), rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07–0.08-fold) risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p = 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus (p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant relationship between rs91778 and cold perception threshold (p = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.

The pathogenesis of diabetic neuropathy involves complex interactions between metabolic and genetic factors. This study aimed to identify novel genetic variants associated with neuropathy risk in type 2 diabetes through reanalysis of whole-exome sequencing data. We identified seven new SNPs with significant associations, including intronic variants in TTN, PLCB1, CCNI, and CDC34 and a 5′-upstream variant in BTG2. These variants are implicated in muscle elasticity, neurotransmission, endothelial regeneration, and apoptosis resistance, suggesting multifaceted genetic contributions to neuropathy development. These findings enhance our understanding of diabetic neuropathy and may support future advances in risk stratification and therapy development.

Az 55 éves férfibeteg, akinek a kórelőzményében magas vérnyomás, illetve asthma bronchiale szerepel, átmeneti nem-invazív légzési támogatást (NIV) szükségessé tevő cardialis decompensatio miatt került kardiológiai osztályos felvételre. Panaszai hátterében az elvégzett vizsgálatok során takotsubo cardiomyopathia igazolódott. Szív MRI-vizsgálat mellékleleteként egy 6 cm-es mellékvese daganatot írtak le, a hormonvizsgálatok pheochromocytomát igazoltak. A beteg laparoszkópos adrenelectomián esett át, amely után tünetei megszűntek, és a 24 órás gyűjtött vizeletben a katekolaminszintek normalizálódtak. Genetikai vizsgálat szukcinát-dehidrogenáz komplex, B alegység (SDHB) mutációt igazolt, amely később a beteg 25 éves, tünetmentes fiánál is kimutatható volt. A pheochromocytoma ritka, hormontermelő daganat, amely súlyos szív-ér rendszeri tüneteket okozhat. Az SDHB mutációhoz agresszív lefolyás is társulhat, ezért szoros, életen át tartó követés és családi genetikai szűrés elengedhetetlen.

Diabetic neuropathy is a common and multifactorial complication of type 2 diabetes, in which genetic susceptibility is increasingly recognized as a contributing factor. This study (cross-sectional case–control) aimed to investigate the associations between previously identified genetic variants and clinically relevant neurophysiological and symptomatic parameters. A total of 48 individuals with type 2 diabetes (24 with neuropathy and 24 without) were included. Neuropathy was assessed using standardized neurological, sensory, and cardiovascular autonomic function tests. Genetic variants were selected in a prior discovery analysis of this same cohort and re-tested here, precluding independent validation. Associations between genetic variants and clinical parameters were assessed through group-based comparisons using Mann–Whitney U tests and Fisher’s exact test, correlation analysis using Spearman’s rank correlation, permutation-based testing to improve robustness, and multivariable linear regression adjusted for age and sex to account for potential demographic confounding (q < 0.1). Mann–Whitney U test analysis identified several associations between genetic variants and neuropathy-related clinical parameters. In the Mann–Whitney U test analysis, only the rs6682221 variant remained significantly associated with heat detection threshold in the left hand after false discovery rate correction (p = 0.000150; q = 0.02736), although this association did not remain significant in the complementary permutation analysis based on median differences. Spearman’s rank correlation analysis identified a significant positive association between rs6682221 allele burden and heat detection threshold in the left hand, which remained significant after permutation correction (r = 0.552, p = 0.000086, q = 0.016). Multivariable regression adjusted for age and sex revealed several independent associations between selected variants and sensory neuropathy-related parameters. These findings should be considered exploratory, as all analyses were performed within the original discovery cohort and no independent validation cohort was available. Independent replication and functional studies are required before any clinical relevance can be inferred.