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CCDC22 is an X-linked recessive gene encoding a coiled-coil domain protein. Pathogenic hemizygous variants in CCDC22 underlie Ritscher-Schinzel syndrome 2 (MONDO:0019078), characterized by craniofacial dysmorphism, cerebellar posterior fossa malformations, congenital heart defects and intellectual disability. The original Australian family comprised eight affected males with a shared CCDC22 variant and detailed phenotypes of intellectual disability, congenital heart disease and spinal curvature (PMID:36073196). Subsequent reports include two affected brothers carrying a missense CCDC22 variant in a Canadian pedigree and a maternal uncle with a similar phenotype (PMID:24916641), and an additional novel proband with epileptic encephalopathy and focal cortical dysplasia (PMID:34020006). Two siblings from unrelated families harbored a hemizygous CCDC22 change expanding the pre- and postnatal phenotype of Ritscher-Schinzel syndrome 2 (PMID:36130690). Recent functional assays demonstrate that missense CCDC22 variants perturb NF-κB signalling and protein stability, correlating with severity of cortical dysplasia and epilepsy (PMID:39426154).
Inheritance is strictly X-linked recessive, with segregation observed in one maternal uncle beyond probands. To date 11 hemizygous probands across five unrelated families have been reported, with clinical concordance and a single relative demonstrating segregation of the same variant. The spectrum comprises primarily missense changes; the recurrent variant c.1670A>G (p.Tyr557Cys) has been identified in multiple affected males and shown to reduce CCDC22 expression and alter downstream WASH complex interactions.
Segregation data include one additional affected maternal uncle who shared the familial missense allele, supporting pathogenicity. Functional studies in lymphoblastoid cell lines and in silico protein modelling reveal decreased CCDC22 expression, altered NF-κB pathway activation and disrupted protein stability. Variant pathogenicity is further supported by correlation between domain localization and phenotypic severity.
Mechanistically, CCDC22 variants likely act via partial loss-of-function, perturbing WASH complex assembly and NF-κB-mediated gene regulation during neurodevelopment. Rescue of NF-κB signalling in patient-derived cells restores normal cytokine responses, reinforcing a haploinsufficiency model.
No studies to date have refuted the association; the phenotype remains highly consistent, and minimal diagnostic criteria for Ritscher-Schinzel syndrome 2 incorporate craniofacial, cerebellar and cardiac findings alongside intellectual disability.
Overall, the genetic and functional evidence supports a Strong gene–disease association for CCDC22 and Ritscher-Schinzel syndrome 2. CCDC22 sequencing should be included in diagnostic panels for syndromic intellectual disability with posterior fossa anomalies. Key take-home: Hemizygous missense CCDC22 variants cause an X-linked recessive syndrome with craniofacial, cardiac, cerebellar and neurodevelopmental features, and functional assays confirm a partial loss-of-function mechanism.
Gene–Disease AssociationStrong11 hemizygous probands across five unrelated families, segregation in one additional relative, and concordant functional data Genetic EvidenceStrongHemizygous missense variants in 11 probands, including recurrent c.1670A>G (p.Tyr557Cys), segregation in one relative Functional EvidenceModerateReduced protein expression, NF-κB pathway assays and in silico modelling concordant with human phenotype |