Friedreich’s Ataxia: Is It a True Single Gene Disease?

Friedreich’s ataxia (FRDA) is the most common form of hereditary ataxia. The disease affects multiple organs and manifests with progressive ataxia, scoliosis, cardiomyopathy, and diabetes. FRDA is believed to occur due to a mutation in a single gene, frataxin (FXN), despite its incomplete genotype-phenotype correlation. FXN encodes an essential mitochondrial protein regulating cellular energy production and iron homeostasis. To gain novel insights into FRDA molecular underlining, this study examined, postmortem, a putative link between phenotypic features and genetic mutations in an FRDA body donor. A 34-year-old female with reported FRDA and comorbidities such as heart failure and type I diabetes was evaluated using a multimodal approach. External examination revealed cavovarus foot deformity, and MRI showed levoscoliosis. Histological examination of the interventricular septum demonstrated cardiac hypertrophy, while examination of the cerebellar dentate nucleus revealed a significant loss of large neuronal cells. These findings were consistent with the FRDA diagnosis and prompted a search for additional genes potentially contributing to the disease. Whole exome sequencing (WES) using the Illumina next-generation sequencing (NGS) platform revealed 77 genes with rare (minor allele frequency, MAF ≤ 0.01) and 67 with low-frequency (0.01 ELF2, SYNE1, ZNF512B, CLCN1, HSPG2, NEB, OBSCN, and BMP10 (rare variants); ARMC9, GRID2IP, VWA5B1, MYO18B, and SGCD (low-frequency variants). These genes, together with FXN, may contribute to the phenotypic variability and multisystem manifestations of FRDA, thereby pointing toward its polygenic underlining.