KLHL20

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*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).

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: LiferaOmics

ClinGen KLHL20- AD complex neurodevelopmental disorder Genetic evidence – Published (AR scope): No scorable published cases of biallelic (autosomal recessive) KLHL20 variants causing neurodevelopmental disorder were identified in the current literature review. Available published human data primarily describe heterozygous (autosomal dominant) de novo missense variants, which are outside the scope of this AR GDR. Published (AD context; not scored for AR): PMID: 36214804 – Reports 14 individuals with de novo heterozygous missense variants in KLHL20 associated with complex neurodevelopmental disorder (intellectual disability, seizures, autism spectrum disorder, dysmorphic features). Evidence supports an autosomal dominant mechanism with recurrent missense clustering. As this represents monoallelic/dominant evidence, it is not scorable under the autosomal recessive model. Case-level = 0 (AR scope); segregation = 0; case-control = 0 PMID: 35982160 – Large-scale exome/genome sequencing study identifying KLHL20 among genes enriched for de novo heterozygous variants in autism spectrum disorder cohorts. Association-level evidence under a dominant model and not applicable to AR scoring. Case-level = 0 (AR scope); segregation = 0; case-control = 0 AD-context evidence total (not scored for AR) = 0 Published genetic evidence total = 0/12 Genetic evidence – Our cases: Family 1 – One proband. Case-level (predicted loss-of-function variant in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = (1.5 − 0.5) = 1.0; segregation = 0; case-control = 0; Family 1 total = 1.0 Our cases total = 1.0/12 Total genetic evidence (published AR + our cases) 1.0/12 Experimental evidence – Published: Although the dominant KLHL20 literature discusses functional relevance to neurodevelopment, ClinGen has not formally scored this experimental evidence. Given the absence of AR-specific functional validation and in alignment with ClinGen’s approach (experimental evidence mentioned but not scored), no experimental points are assigned for the AR GDR. Experimental evidence total = 0/6 Overall score Genetic evidence = 1.0 Experimental evidence = 0 Overall score = 1.0

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics