Genotypic and phenotypic characteristics of ADGRV1 mutations in four children and functional validation in a...

Mutations in ADGRV1 can cause seizures, but the mechanism remains unclear. The zebrafish model can be used to assess the functions of human ADGRV1 and its variant alleles during embryonic development. In this study, we summarized the phenotypic and genotypic characteristics of four children with ADGRV1 variation and based on this, we validated the ADGRV1 loss phenotype in an adgrv1-knockout zebrafish model. We retrospectively analyzed the clinical and genotypic characteristics of four pediatric patients diagnosed as having ADGRV1 mutations at Children's Hospital Affiliated to Chongqing Medical University from April 2019 to February 2022. Moreover, we used the adgrv1-knockout zebrafish larvae model and performed morphological, behavioral, and neuroelectrophysiological testing. We found that of the four included children, two had epilepsy, one had paroxysmal kinesigenic dyskinesia, and one had febrile seizure plus. Three children had a history of febrile seizures, whereas two had a family history of febrile seizures. Three children had well-controlled clinical epilepsy seizures or motor disorders. Finally, one child with spontaneous mutation had epigenetic abnormalities and comprehensive developmental delay, one had language developmental delay, and two (paternal or maternal) had a good prognosis. Regarding the zebrafish model, the cas9-control and adgrv1-edited groups demonstrated significant differences in the interocular areas of the zebrafish observed in the open field and the maximum swimming velocity under light stimulus. In neuroelectrophysiological testing, epilepsy-related signals were observed in 2 of 26 adgrv1-edited group fish. We believe that, mutations in the ADGRV1 may lead to epileptic seizures and movement disorders. The patients usually have a history of febrile seizures or a family history. Through research using the zebrafish model, it has been found that ADGRV1 mutations can affect the expression of eye and the neuromotor development of zebrafish larvae. This might be one of the reasons for epileptic seizures caused by ADGRV1 gene mutations.