KIDINS220 was first reported in relation to autosomal dominant VENARG (ventriculomegaly and arthrogryposis) in 2017 (Mero et al., PMID: 28934391). This condition is associated with ventriculomegaly, cerebellar hypoplasia, and other brain anomalies; as well as joint contractures and congenital heart disease. VENARG is neonatal lethal, and features of the condition have been evident in ultrasounds of affected probands earlier than 12 weeks gestation. The gene is also associated with autosomal dominant SINO (spastic paraplegia, intellectual disability, nystagmus, and obesity), an assertion first made in 2016 by Josifova et al (PMID: 27005418). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: VENARG (OMIM:619501) & SINO (OMIM: 617296). The split curation for autosomal dominant SINO has been done separately. 5 variants (in-frame deletion, frameshift, splicing) that have been reported in at least 8 probands in 4 publications (PMIDs: 28934391, 32909676, 33205811, 36588759) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models, expression analysis; PMIDs: 19449316, 22048169, 34002021, 35140204). Mouse analysis indicates expression of KIDINS220 within the brain, specifically in the pyramidal neurons and hippocampus. Mouse models indicate ventriculomegaly, reduced dendritic complexity, memory issues, and abnormal heart morphology in mutants. In summary, there is definitive evidence supporting the relationship between KIDINS220 and autosomal dominant VENARG. 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 Prenatal GCEP on the meeting date 9/4/2024 (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.