Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant

Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called ‘Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities’ (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband–parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.