Damaging Variants in HNRNPUL2 Result in a Novel HNRNP-Related Neurodevelopmental Disorder

The HNRNP genes, encoding for heterogeneous nuclear ribonuclear proteins, have been shown to have significant enrichment of damaging de novo variation among neurodevelopmental disorder cohorts. To date, there are nine HNRNP genes with well described neurodevelopmental disorder associations, collectively termed the HNRNP-Related Neurodevelopmental Disorders (RNDDs), and multiple candidate genes. Here, we have found evidence that damaging variants in HNRNPUL2, encoding heterogenous nuclear ribonucleoprotein U-like 2, contribute to HNRNP-RNDDs. Multiple studies have shown that damaging variants in HNRNPUL2 are significantly enriched among autism and NDD cohorts.

We describe HNRNPUL2-RNDD, consisting of global developmental delay, normal cognition to moderate intellectual disability, behavioral differences, growth delay, seizures, and incoordination. Highlighted by the number of cases identified in the SPARK cohort, autism spectrum disorder is observed in over half of individuals identified, and HNRNPUL2-RNDD has the highest autism prevalence among the HNRNP-RNDDs. Additional natural history study data is being collected utilizing the Geneial platform.

RNAseq on fibroblasts derived from one individual with a nonsense variant (p.Tyr214*) showed a significant reduction in HNRNPUL2 gene expression. Top dysregulated genes were enriched in pathways relevant to neuronal development, Wnt signaling, and parathyroid hormone response. Future RNAseq from induced neurons will likely show additional neurodevelopmental genes that are dysregulated.

Furthermore, a Drosophila model has been developed using a patient’s missense variant that shows loss-of-function (p.Glu707Ala).