Association of ABHD12 Variants with the Spectrum of PHARC Syndrome Phenotypes

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts) syndrome is a rare neurodegenerative inherited disorder characterized by a spectrum of these clinical phenotypes. Due to the considerable heterogeneity in the age of onset of the different clinical features and the similarities with other conditions, it is often misdiagnosed. Variants in the ABHD12 gene have been identified as a genetic cause of PHARC syndrome and are predicted to result in loss-of-function or severely reduced protein synthesis. ABHD12 (α/β-hydrolase domain-containing protein 12) is responsible for the breakdown of very-long-chain lysophosphatidylserines (VLC-lyso-PS). When ABHD12 is dysfunctional, VLC-lyso-PS accumulates in the brain, producing inflammation. In this study, the clinical phenotypes of five patients with molecularly confirmed ABHD12 pathogenic variants from Moorfields Eye Hospital together with those of 64 patients reported in the literature were analyzed to investigate genotype-phenotype correlations. We report a novel variant c.985del p.(His329Thrfs*57) associated with PHARC syndrome. Moreover, patients with two null variants in ABHD12 manifest more of the clinical features of PHARC syndrome than those with at least one missense variant. Our study shows the importance of a complete clinical and genetic diagnosis to enable accurate diagnosis and genetic counselling for affected individuals.