New Gene-Disease Link May Help Diagnose Rare Neurodevelopmental Disorders

Families may face prolonged searches for answers when the underlying genetic cause has not yet been linked to a defined syndrome. Establishing clear gene-disease relationships can reduce uncertainty and guide clinical evaluation. New findings now identify a previously unrecognized genetic form of neurodevelopmental disorder.

University of Otago (Dunedin, New Zealand) researchers identified ELAVL2 variants as the cause of a previously undefined neurodevelopmental disorder and delineated its clinical features. The work, published in The American Journal of Human Genetics, classifies an ELAVL2-related neurodevelopmental disorder characterized by prominent cognitive, behavioral, and neurological features. The study involved an international collaboration between teams at Otago and in the Netherlands.

Investigators used international gene databases to assemble individuals worldwide who harbored ELAVL2 alterations and shared clinical presentations, including developmental delay and intellectual disability. Functional analyses showed that some variants change the gene’s biological activity, consistent with ELAVL2 haploinsufficiency underlying the disorder. By linking genotype with phenotype, the team established ELAVL2 as a disease gene and formalized the entity as an ELAVL2-related neurodevelopmental disorder.

According to the study authors, the work has already provided answers for 15 individuals and families who participated in the research. The discovery offers a structured basis for case recognition and variant interpretation in clinical genetics. The researchers indicate that ongoing investigations are examining additional members of the ELAVL gene family for similar roles in neurodevelopment and disease.

“Neurodevelopment depends on precise orchestration of the dosage, location and timing of gene expression. Before the study, the gene ELAVL2 was known to have an important role in helping influence brain development, but no one had connected it with a genetic condition. We have now discovered variants in this gene are the cause of a previously undefined neurodevelopmental disorder. The work has helped provide answers for 15 individuals and families who were part of the research and has the potential to help many more,” said Dr. Meghan Mulligan, of the Department of Biochemistry.

“Our discovery not only helps those whānau involved in the study—who now have an answer as to the cause of their family member's neurological condition—but also opens up a new diagnostic pathway for other families with rare and previously unexplained neurodevelopmental disorders. Diagnostic labs globally will be able to use our findings to help other families searching for an answer and potentially receive a genetic diagnosis in a much shorter time frame,” added Mulligan.

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