Relevance to Autism

De novo damaging missense variants (defined by CADD score 25) in the CLCN4 gene were identified in two ASD probands from the Autism Sequencing Consortium (Kosmicki et al., 2017), while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CLCN4 as an ASD candidate gene with a q-value 0.1. Mutations in the CLCN4 gene are also responsible for Raynaud-Claes syndrome (OMIM 300114), an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development; behavioral problems are frequently observed in individuals with this syndrome, and autistic features have been reported in a subset of affected individuals (Claes et al., 1997; Palmer et al., 2018). Palmer et al., 2022 assembled a collection of 90 rare CLCN4 missense variants in 90 families that included detailed clinical and segregation data for 43 families that included 22 males and 33 females; autism spectrum disorder (or autistic behavior) was observed in 54.5% of all males and 40% of females with de novo variants in this study, while functional assessment of the electrophysiological properties of these 59 variants in Xenopus oocytes identified variants with either loss-of-function or toxic gain-of-function effects.

Molecular Function

Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons.

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Model Summary

The homozygous Clcn4 knockout mouse model is viable and shows complete ablation of the transcript, with no compensation or increased expression of Clcn3 or Clcn5. This model shows reduced spine density in hippocampal neurons. Male pups have a deficit in righting response. Female and male adult mice show phenotypes consistent with autism, including decreased sociability, decreased preference for social novelty, and increased digging behavior. The haploinsufficient heterozygote model also shows increased digging behavior. Chronic treatment with risperidone rescues all behavioral deficits in the homozygous knockout.

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