VPS13D-related disorders: a severe case, review, and genotype-phenotype correlation

Background: VPS13D-related disorders are autosomal recessive genetic disorders characterized by movement disorders primarily including ataxia and spasticity, mainly accompanying developmental delay, seizures, and neuroimaging abnormalities. VPS13D-related spectrum disorder (VSD) may better reflect the characteristics of the disease. So far, the relationship of VPS13D genotype and phenotype of VSD has not been established.

Methods: We analyzed clinical data and collected DNA samples from a severe patient and his healthy parents. Whole exome sequencing was performed by next-generation sequencing. We presented a review of all cases with VSD to establish genotype-phenotype correlation.

Results: The patient had compound heterozygous mutations (c.9785T>C, p.L3262P; c.8687C>T, p.T2896M) in VPS13D gene, maternally and paternally inherited, respectively. The p.L3262P is a novel mutation. The individual presented with ataxia, dystonia, developmental delay, epilepsy and neuroimaging abnormalities, including bilateral caudate and putamen, cerebellum, and right temporal lobe, which are the first detailed imaging study reported in VSD to date. We first report that the patient has achieved significant improvement through active treatment. We first summarize genotype-phenotype correlation of VSD, highlighting that the severity of the phenotype is mainly due to the mutations affecting important domains of VPS13D protein or special severe missense mutations.

Conclusions: Neuroimaging analysis is helpful to the etiology study of VSD. Active treatment of VSD is still meaningful. Important VPS13D regions correlated with severe phenotype need to be further studied.