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Cyclin O (CCNO) has been robustly implicated in primary ciliary dyskinesia, a genetically heterogeneous disorder affecting the motile cilia of the respiratory tract. Multiple independent studies have identified deleterious variants of CCNO that lead to reduced cilia number and severe respiratory complications. The overall clinical validity of this gene‐disease association is classified as Strong due to the accumulation of case reports with clear autosomal recessive inheritance, familial segregation, and concordant clinical phenotypes (PMID:32464346, PMID:36157652).
The genetic evidence highlights an autosomal recessive mode of inheritance whereby affected individuals inherit biallelic pathogenic variants from heterozygous parents. Segregation analyses in several reports demonstrated that the variant alleles cosegregate with disease phenotypes in families, including cases where parents are heterozygous carriers and affected siblings share the same genotype (PMID:37220549).
A range of variant classes have been described in CCNO. Among these, frameshift mutations, such as the recurrent variant c.248_252dup (p.Gln88ArgfsTer8), have been reported in multiple independent case studies. This variant, which disrupts the coding sequence early in exon 1, has been observed in more than one study and is consistent with a loss-of-function mechanism driving the disease (PMID:32464346, PMID:38784318).
Functional studies further support the pathogenicity of CCNO mutations. In vitro models, including human induced pluripotent stem cells (hiPSCs) derived from a patient, have recapitulated the disease phenotype by demonstrating a marked reduction of multiciliated cells and decreased ciliation on the respiratory epithelium. These models provide essential evidence that links the genetic variant to the cellular dysfunction observed in primary ciliary dyskinesia (PMID:32464346).
Integrating the genetic and functional data provides a coherent narrative where multiple lines of evidence, ranging from detailed family segregation to robust in vitro functional assays, support the role of CCNO in primary ciliary dyskinesia. Although additional evidence exists beyond the ClinGen scoring maximum, the cumulative findings offer significant diagnostic utility by reinforcing the clinical use of genetic testing for CCNO mutations in cases of suspected primary ciliary dyskinesia.
Key Take‑home: The strong, multi‑faceted evidence linking CCNO mutations to primary ciliary dyskinesia facilitates precise diagnostic decision‑making and fosters the clinical translation of genetic findings into patient care.
Gene–Disease AssociationStrongMultiple independent case reports (including 1 proband from [PMID:32464346], 1 from [PMID:36157652], 1 from [PMID:37220549] and 2 affected siblings from [PMID:38222993]) demonstrate autosomal recessive inheritance, robust familial segregation, and highly concordant clinical phenotypes. Genetic EvidenceStrongDiverse loss-of-function variants in CCNO, particularly the recurrent c.248_252dup (p.Gln88ArgfsTer8), have been identified in multiple probands and families, reinforcing a causal role in primary ciliary dyskinesia. Functional EvidenceModerateIn vitro studies using hiPSC-derived models have shown reduced ciliation and recapitulated the cellular phenotype of primary ciliary dyskinesia, supporting a mechanistic link between CCNO mutations and the disease. |