CAMTA1 was first reported in relation to cerebellar dysfunction with variable cognitive & behavioral abnormalities in 2011 (Mikhail et.al, PMID: 22031302). Probands are characterized by cerebellar ataxia, global developmental delay, speech delay, hypotonia, dysmorphism, behavioral abnormalities (ADHD, OCD, autistic features) and movement disorders such as tremors and myotonic dystonia. Less common phenotypes include epilepsy, GERD, velopharyngeal insufficiency, constipation, strabismus & nystagmus. Inheritance of variants is primarily de novo. Twenty one variants (missense, nonsense, frameshift, CNV: deletions & duplications) in 22 probands in 7 publications (PMIDs: 22031302, 33131045, 33677721, 30838254, 22693284, 24738973, 32157189) have been included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism of pathogenicity appears to be haploinsufficiency, but a dominant negative mechanism could not be ruled out (PMID:22693284).
This gene-disease relationship is also supported by experimental evidence..Both constitutive deletion of Camta1 and conditional deletion in the G nervous system causes severe ataxia with Purkinje cell degeneration and cerebellar atrophy in mice, partially recapitulating the consequences of haploinsufficiency of the human CAMTA1 locus (PMID: 25049392).
In summary, there is definitive evidence to support the relationship between CAMTA1 and cerebellar dysfunction with variable cognitive and behavioral abnormalities. 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 Intellectual Disability and Autism Gene Curation Expert Panel on May 16, 2023 (SOP 9).
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