ADD3 is the γ-subunit of Adducin; a heterodimeric protein that provides structural support and maintains cytoskeletal interactions between actin and spectrin within neuronal structures.
ADD3 was first reported in relation to cerebral palsy, spastic quadriplegic, 3 in 2013 (Kruer et al., PMID:23836506). It is characterized by spastic quadriplegia/diplegia, cognitive impairment, speech impairment, strabismus, and borderline to true microcephaly in infancy. Other less common phenotypes include facial dysmorphisms, cataracts, and neuroimaging abnormalities; the latter including white matter hyperintensities, anomalies of the corpus callosum, and grey matter heterotopia. The aforementioned disease entities have been grouped together as one disease entity: Complex neurodevelopmental disorder with motor features (MONDO: 0100516).
Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 6 POINTS. 5 unique missense variants that have been reported in 5 probands in 3 publications (PMID: 23836506, 30369941, 29768408) are included in this curation. This gene-disease association is also supported by a Drosophila model, where knockdown resulted in impaired locomotion, deficient climbing ability, and lesions in the brain lamina and medulla (PMID: 23836506).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish a definitive relationship, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on August 15, 2022 (SOP Version 9).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.