Abstract
Background/Objectives: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, its role in human neurodevelopment remains unknown. We delineate a novel neurodevelopmental disorder caused by de novo missense variants in KLHL20.
Methods: Patients were ascertained by investigators through GeneMatcher. Deep phenotyping of patients with de novo missense variants in KLHL20 was performed.
Results: We studied 14 patients with de novo missense variants in KLHL20, delineating a novel genetic syndrome with patients having mild to severe intellectual disability, epilepsy, autism spectrum disorder and attention deficit hyperactivity disorder. Associated clinical features were spasticity, dystonia, strabismus, distal joint laxity, pectus excavatum, scoliosis, kyphosis, vascular anomalies, brachycephaly and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients ((NM_014458.4]: c.1069G>A, p.Gly357Arg). All missense variants clustered in the Kelch-type 3-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. Protein structure analysis revealed that two out of four missense variants destabilize the interaction of KLHL20 with DAPK1, a substrate associated with upregulated expression in the brain of patients with temporal lobe epilepsy.
Conclusion: Our findings implicate KLHL20 in a novel neurodevelopmental disorder characterized by intellectual disability, epilepsy, autism spectrum disorder and attention deficit hyper- activity disorder.