A PNPLA6 variant case report with a novel combination of heterozygous variants

PNPLA6 (patatin-like phospholipase domain-containing protein 6) encodes neuropathy target esterase (NTE), an essential enzyme involved in membrane lipid metabolism and neuronal maintenance. Here we present a case of a 51-year-old male with motor and cognitive delays since birth who was able to acquire some skills but then experienced motor regression. The patient has cognitive impairment, cerebellar ataxia, peripheral neuropathy, hypogonadism, and hair anomalies but no chorioretinal dystrophy or spasticity. Whole genome sequencing was initially performed for diagnostic purposes and revealed two missense variants in PNPLA6 : p.(S1127C) and p.(D1077G). The biallelic PNPLA6 variants are typically associated with one of five major neurodegenerative syndromes, however, the clinical features in this case do not fully align with the diagnostic criteria for any of these established disorders. p.(S1127C) is a likely pathogenic variant. The p.(D1077G) variant has not been previously reported in the literature and is of uncertain significance. However, in silico analysis supports that it deleteriously affects protein structure/function. Both variants are inherited in an autosomal recessive pattern and the compound heterozygous state in our patient possibly resulted in a mixed phenotype. There is a growing perspective that PNPLA6 -associated disorders fall under a pleiotropic spectrum of disease influenced by the activity of neuropathy target esterase (NTE) where the NTE activity level defines phenotypic expression among PNPLA6 disorders.