#689 First report of kidney failure in PEX6-related peroxisomal disorder

Abstract Background and Aims Peroxisomes are semiautonomous subcellular organelles involved in key metabolic pathways. Biallelic pathogenic variants in any of the 14 currently known PEX proteins are responsible for a genetically heterogeneous group of multi-organ disorders named as peroxisome biogenesis disorders (PBDs). Main symptoms of PBDs spectrum include retinopathy, sensorineural hearing loss, enamel hypoplasia, liver dysfunction and neurologic disorders and prognosis ranges from relatively mild form to lethal outcome regarding to involved genes and/or pathogenic variant. PEX1 and PEX6 biallelic variants together account for up to 70% of Zellweger syndrome disorder (ZSD), a subset of PBDs. We present here for the first time evidence of renal involvement in the clinical spectrum of ZSD, previously confined to anecdotal observations of isolated kidney cysts. Method We conducted a detailed clinical, genetic, and biochemical evaluation of a 60-year-old female proband referred for kidney failure (KF) of unknown origin, as well as her extended family with similar clinical histories. Results The proband presented with a history of progressive sensorineural hearing loss from age 2, retinopathy from age 20, amelogenesis imperfecta requiring full dental extraction by age 28, proteinuric chronic kidney disease (CKD) diagnosed at 17 years (eGFR 67 mL/min/1.73 m²) and bland urinary sediment. No kidney biopsy was performed. She reached KF by age 50 and received a kidney transplant at age 51. There were no cardiac or liver disorder. Previously, two next-generation sequencing (NGS) panels targeting Usher syndrome-associated genes were inconclusive, as was a panel analyzing over 300 kidney disease-associated genes. Ultimately, an NGS retinal dystrophy panel covering 230 genes identified a biallelic missense variant in PEX6 (c.659G>T, p.Gly220Val). The variant was unanimously predicted to be pathogenic by in silico tools (Phred CADD score 26, Alpha Missense likely pathogenic). Clinical and biochemical findings, such as elevated pipecolic acid and a slight increase in very-long-chain fatty acids (VLCFA), confirmed the suspected diagnosis and supported its classification as ACMG class IV. The familial history was notable. Her sister, who died young from an unknown cause, had a history of albuminuria, sensorineural hearing loss and pigmentary retinopathy. Two paternal ninth degree male cousins presented with proteinuria at age 2 and 23, progressing to CKD reaching KF at age 25 and 40, respectively. Both exhibited severe childhood-onset sensorineural hearing loss, pigmentary retinopathy, and amelogenesis imperfecta. A kidney biopsy in the first cousin at age 20 showed nonspecific glomerulosclerosis and interstitial fibrosis. He died by suicide at age 58. Segregation genetic analysis in the second cousin revealed the same biallelic variant PEX6 c.659G>T. Browsing the Genomics England 100KG database revealed no additional cases of PBD associated with kidney failure. Conclusion This study provides the first evidence of kidney involvement with progression to KF within the spectrum of PBDs. The phenotypic consistency among distantly related individuals and the absence of alternative pathogenic variants support a direct link between the PEX6 variant and the renal phenotype. This case highlights the importance of regular re-evaluation of KF of unknown cause, including after kidney transplantation, and underscores the critical role of comprehensive genetic analysis in uncovering previously unrecognized disease associations.