Submission Details

KLHL20 was first reported in relation to autosomal dominant (AD) neurodevelopmental disorder in 2022 (Sleyp et al., PMID: 36214804). Phenotypic features in individuals with heterozygous KLHL20 variants include developmental delay, intellectual disability (ranging from mild to severe), epilepsy (including febrile seizures and infantile spasms), autism spectrum disorder (ASD), hyperactivity, behavioral abnormalities, and subtle dysmorphic features. One individual was reported with West syndrome characterized by infantile spasms, hypsarrhythmia, and early-onset developmental delay (Kuroda et al., PMID: 38513146). Onset of seizures and developmental symptoms occur in infancy or early childhood. Brain MRI findings were reported as unremarkable or nonspecific in available cases.

At least 15 affected individuals with five unique heterozygous missense variants have been reported in the literature (Sleyp et al., PMID: 36214804; Kuroda et al., PMID: 38513146). These variants occurred de novo in all cases where parental testing was performed. A recurrent missense variant, p.Gly357Arg, was observed in 11 individuals, and three other individuals carried different de novo missense variants (p.Gly396Asp, p.Ser410Leu, and p.Gly423Arg), all located within the highly conserved kelch-repeat domain of KLHL20. An additional individual with West syndrome carried a novel missense variant (p.Ser405Asn) also within the same functional domain (Kuroda et al., PMID: 38513146). All reported variants cluster within the substrate-binding kelch-type β-propeller domain of KLHL20, which is essential for its function as a substrate adaptor for the CUL3-based E3 ubiquitin ligase complex.

Functional studies of KLHL20 outside of these reports have demonstrated its involvement in neurite outgrowth, autophagy, and synaptic development, suggesting a critical role in neuronal function and brain development. Although in vivo models of the specific variants have not been reported, the observed variant clustering within the functional domain, recurrence of specific variants, and de novo status support a likely dominant-negative or gain-of-function mechanism.

In summary, there is moderate genetic evidence supporting the relationship between KLHL20 and autosomal dominant neurodevelopmental disorder. This relationship is based on consistent clinical findings across multiple unrelated individuals with de novo missense variants in a key functional domain. Further functional studies and replication of the gene-disease association in additional cohorts will strengthen this classification.This classification was approved by the ClinGen Epilepsy GCEP on the meeting date June 17, 2025 (SOP Version 11).