NCKAP1 variants were first reported in connection to an autosomal dominant complex neurodevelopmental disorder in 2012 by a study identifying autism susceptibility genes (Iossifov et al., 2012 PMID: 22542183). Common phenotypes for individuals with NCKPA1-related neurodevelopmental disorder include ASD or autistic features, speech-language problems, childhood motor delay, and ID or learning disabilities (PMID: 33157009). Evidence of deleterious variants segregating with neuropsychiatric phenotypes such as repetitive behaviors, aggressive behaviors, and attention-deficit/hyperactivity disorder (ADHD) is reported. In addition to neurodevelopmental and neuropsychiatric disturbances, tall stature, obesity, gastrointestinal disturbances, hearing and visual impairment, and congenital heart defects are also observed in some patients.
Thirteen unique variants of different types (4 frameshift, 5 nonsense, 2 canonical splice sites, and 2 introns) reported in 14 probands have been included in this curation (Guo et al., 2020 PMID:33157009). The presumed mechanism of pathogenicity is loss-of-function. The maximum score for genetic evidence (12 pts.) has been reached.
This gene-disease relationship is further supported by functional alteration and mouse model data (Yakoto et al., 2007 PMID:17481396). The Nap1 knock down significantly hinders all aspects of cortical neuronal differentiation. In vivo Nap1 deficient neurons displayed significantly reduced axonal and dendritic process extension and branching. Furthermore, mouse model studies demonstrated that Nap1 plays an essential role in the final phenotypic differentiation of cortical neurons and facilitating neuronal cytoskeletal changes. It is likely that the observed phenotypes in patients with pathogenic NCKAP1 variants are the consequence of changes in neuronal function.
In summary, there is definitive evidence to support the relationship between NCKPA1 and autosomal dominant complex neurodevelopmental disorder. 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 expert panel on December 6th, 2023 (SOP Version 10).
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.