Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

Haploinsufficiency of ELAVL2, which encodes an RNA-binding protein, disrupts post-transcriptional regulation of gene expression in the neuron.

RNA-binding proteins regulate gene expression and several have been implicated in brain function and behaviour. The authors report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, a gene not previously linked to Mendelian disease, 13 of them identified through GeneMatcher: two structural, five nonsense and six missense variants, supporting haploinsufficiency as the primary mechanism. The phenotype combines developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability and difficulty with socialisation; three further variants, each previously reported in a different large cohort study, were included for follow-up investigations. Common variants in ELAVL2 are also significantly associated in the general population with intelligence, motor development, sleep-related traits and sociability, and Drosophila loss-of-function models provide independent evidence for a conserved role in seizure-like behaviour, sensory processing and sleep. Molecular studies confirm that some missense variants are deleterious and lower protein levels.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The case is complete — de novo variants, matchmaking replication, population-level evidence, an animal model, molecular proof — and it is this accumulation, more than the number of patients, that convinces. In practice ELAVL2 is already covered by any exome: what changes is not detection but annotation, a de novo truncating variant in a child with a neurodevelopmental disorder, autism and sleep problems now becoming interpretable. The caveat concerns missense variants, only some of which were tested functionally — the others will remain VUS until a higher-throughput assay becomes available.

Analysis by Dr Thibaut Benquey