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Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare <jats:italic>CLCN4<\/jats:italic> missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in <jats:italic>Xenopus<\/jats:italic> oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15\/59) of variants demonstrated LOF, characterized by a \u201cshift\u201d of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with <jats:italic>CLCN4<\/jats:italic>-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.<\/jats:p>","DOI":"10.1038\/s41380-022-01852-9","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T12:03:43Z","timestamp":1668600223000},"page":"668-697","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition"],"prefix":"10.1038","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1844-215X","authenticated-orcid":false,"given":"Elizabeth 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