CCDC22 was first reported as a cause of syndromic X-linked intellectual disability in 2012 (Voineagu et al., PMID: 21826058) in a large Australian family. A missense variant affecting splicing and leading to decreased mRNA expression was identified in six affected males. In 2022, Rodgers et al. (PMID: 36073196) provided detailed phenotypic information for eight affected males in this family. Common features included global developmental delay, intellectual disability, typical facies, congenital heart disease, posterior fossa malformations, short stature, ectodermal abnormalities, and genital and skeletal anomalies. The clinical presentation is consistent with Ritscher-Schinzel syndrome 2, also known as cranio-cerebro-cardiac (3C) syndrome.
Since then, four additional variants (3 missense and 1 inframe deletion) have been reported in six individuals with similar features (PMIDs: 24916641, 33059814, 34020006, 36130690). Two of the missense variants were detected in families with two affected siblings each. Additional missense variants have been identified in large sequencing studies of individuals with intellectual disability or autism spectrum disorder (PMIDs: 19377476, 23563313, 25363768, 31906484); however, as clinical data of these individuals were not provided, these variants were not scored. CCDC22 is not significantly constrained for missense variants (Z = 1.29; gnomAD v2.1.1), but is intolerant to truncating variants (pLI = 1.0, LOEUF = 0.123). The mechanism of pathogenicity is not fully understood, but there is some evidence of loss of function (PMID: 21826058, 23563313, 24916641).
CCDC22 encodes a protein known as coiled-coil domain containing 22, which is a component of the Commander complex that plays a role in endosomal recycling. This gene-disease relationship is supported by alterations in patient-derived cells (PMIDs: 21826058, 23563313, 24916641, 31537807) and CCDC22 interactions with cullin proteins (CUL3, CUL4B) previously implicated in intellectual disability and other neurodevelopmental disorders.
In summary, there is moderate evidence to support the relationship between CCDC22 and Ritscher-Schinzel syndrome 2. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 7, 2023 (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).
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