Two novel heterozygous HPDL variants in a Chinese family with a neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities.

Recent studies have shown that homozygous and compound heterozygous variants in the 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene contribute to a novel early onset neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), a severe neurodevelopmental disorder characterized by impaired psychomotor development in infancy. Using whole-exome sequencing and Sanger sequencing, we identified and verified a novel compound heterozygous variant in HPDL, c.502 T > C (p.Cys278Arg)/c.833G > A (p.Gly278Asp), which may lead to lethal NEDSWMA, with individual differences in severity. We systematically summarized the clinical characteristics of the patients and their family members and analyzed the genetic characteristics such as homozygosity, conservatism, and pathogenicity of the variants by various prediction methods. Further in vitro functional experiments showed that the identified variants inhibited the proliferative capacity but not apoptosis of SH-SY5Y cells by altering HPDL expression at the mRNA and protein levels and negatively affecting endogenous CoQ10 secretion. Our study further contributes to the assessment of genotype-phenotype correlations, and firstly provides new insights for elucidating specific pathogenesis mechanisms and identifying precision-targeted therapies.