HPCA was first reported in relation to autosomal recessive complex movement disorder with or without neurodevelopmental features in 2015 (Charlesworth et al., PMID: 25799108). This condition is characterized by dystonia, which can be generalized or localized; dysarthria; motor delay; intellectual disability; and involuntary movements/jerking. Seven variants (missense, nonsense, frameshift) that have been reported in at least eight probands across six publications (PMIDs: 25799108, 30145809, 33511595, 34077496, 36698997, 36704070) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function (PMID: 30145809). This gene-disease relationship is also supported by experimental evidence (mouse models, cell culture model, functional alteration evidence; PMIDs: 1280427, 15878804, 23142228, 33502045). Model evidence shows abnormal behavioral, reduced learning ability, and increased neurodegeneration in mutants. Expression-level data shows hippocampal expression of HPCA.
In summary, there is definitive evidence supporting the relationship between HPCA and autosomal recessive complex movement disorder with or without neurodevelopmental features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date 10/2/2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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