KIDINS220 was first reported in relation to autosomal dominant spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) in 2016 (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: SINO (OMIM: 617296) & ventriculomegaly and arthrogryposis (VENARG OMIM:619501). The split curation for autosomal recessive VENARG has been curated separately.
11 variants (missense, nonsense, frameshift) that have been reported in at least 17 probands in 9 publications (PMID: 27005418, 29667355, 30542205, 31130284, 31630374, 31618753, 33763417, 36368352, 37642312) are included in this curation. The mechanism of pathogenicity appears to be gain-of-function.
This gene-disease relationship is also supported by experimental evidence (expression-level evidence, functional alteration evidence, mouse model; PMID: 19449316, 33763417). Expression-level evidence shows high expression in the hippocampus, especially in the dentate gyrus. Functional alteration analysis supports that KIDINS220 impairs adipocyte differentiation. A mouse model shows that mutating KIDINS220 reduces dendritic complexity and increases spine elimination.
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy GCEP on October 21st, 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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