The CACNA1D gene encodes the alpha-1D subunit of voltage-dependent calcium channels, which mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including hormone or neurotransmitter release, and gene expression. CACNA1D was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without aldosteronism in 2013 (Scholl et al., PMID: 23913001). This condition is characterized by developmental delay, intellectual disability, autism spectrum disorder, hypotonia and seizures (PMIDs: 32666275, 37122292). Other reported features include endocrine abnormalities such as primary aldosteronism and congenital hyperinsulinemic hypoglycemia, facial dysmorphisms, heart defects, and self-injurious behavior. CACNA1D has also been reported in relation to autosomal recessive sinoatrial node dysfunction and deafness; this disease has been curated separately.
Nine missense variants reported in 11 probands in ten publications (PMIDs: 22495309, 22542183, 23913001, 25533962, 28318089, 28472301, 28726809, 32583268, 36208199, 37122292) are included in this curation. Most of the reported variants are de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is gain of function (PMIDs: 23913001, 37122292).
This gene-disease relationship is also supported by the biochemical function of CACNA1D, as seven other genes encoding alpha subunits of voltage-gated calcium channels have also been implicated in neurodevelopmental disorders, including CACNA1A, CACNA1B, CACNA1C, CACNA1E, CACNA1G, CACNA1H, and CACNA1I.
In summary, there is definitive evidence supporting the relationship between CACNA1D and autosomal dominant complex neurodevelopmental disorder with or without aldosteronism. This has been repeatedly demonstrated in both 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 September 4, 2024 (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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