CCDC40 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of motile cilia characterized by chronic respiratory infections, laterality defects, and infertility. The coiled-coil domain-containing protein 40 (CCDC40) is essential for assembly of inner dynein arms (IDA) and 96 nm axonemal ruler structures in respiratory and sperm flagellar cilia. Loss-of-function mutations in CCDC40 disrupt IDA formation and microtubular organization, causing the PCD phenotype.

Biallelic CCDC40 variants have been reported in ≥23 unrelated probands from 14 families, including consanguineous and outbred pedigrees, all showing autosomal recessive segregation (8 families; 43 patients)(PMID:22693285; 9 patients)(PMID:31765523). Truncating alleles predominate, with recurrent frameshift and nonsense mutations such as c.901C>T (p.Arg301Ter) and founder splicing variants.

CCDC40-related PCD is invariably inherited in an autosomal recessive manner. Segregation analysis in multiple families confirms co-segregation of biallelic CCDC40 alleles with disease. Case series and reports describe additional affected sibships and multiplex pedigrees, supporting a robust genetic association.

The variant spectrum includes 30+ truncating mutations (nonsense, frameshift, splice), a small number of missense changes, deep-intronic splice-disrupting deletions, and complex indels. Founder alleles such as c.248delC recur in diverse populations, and novel missense variants are occasionally reported in isolated MMAF ± PCD cases.

Functional studies demonstrate complete absence of IDA heavy chains and microtubular disorganization on transmission electron microscopy, rigid ciliary beating by high-speed video analysis, and loss of inner arm markers by immunofluorescence (e.g., DNAH2) in patient cells (PMID:25619595; PMID:35449766). Induced pluripotent stem cell models retain CCDC40 mutations, offering platforms for mechanistic and rescue experiments (PMID:30296669), and Xenopus models clarify genomic structure for target validation (PMID:40415903).

No studies dispute the CCDC40–PCD link. All reported variants confer loss of function, consistent with a haploinsufficiency mechanism requiring biallelic inactivation.

In summary, extensive genetic and experimental evidence establishes a definitive association between CCDC40 and autosomal recessive PCD. CCDC40 testing is clinically indicated in patients with IDA defects, respiratory disease, laterality anomalies, and infertility, enabling accurate diagnosis, genetic counseling, and potential gene-based therapies.

Key Take-home: Biallelic loss-of-function CCDC40 variants definitively cause autosomal recessive PCD with inner dynein arm defects, situs inversus, bronchiectasis, and infertility.

References

• Journal of Medical Genetics • 2012 • Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia PMID:22693285
• Pediatric Pulmonology • 2020 • Genotype and phenotype evaluation of patients with primary ciliary dyskinesia: First results from Turkey PMID:31765523
• The Clinical Respiratory Journal • 2016 • CCDC40 mutation as a cause of primary ciliary dyskinesia: a case report and review of literature PMID:25619595
• Pharmacogenomics and Personalized Medicine • 2022 • Novel Compound Heterozygous Variants in CCDC40 Associated with Primary Ciliary Dyskinesia and Multiple Morphological Abnormalities of the Sperm Flagella PMID:35449766
• Stem Cell Research • 2018 • Generation of the induced pluripotent stem cell line UHOMi001-A from a patient with mutations in CCDC40 gene causing Primary Ciliary Dyskinesia (PCD) PMID:30296669
• microPublication Biology • 2025 • Genomic Complexity of ccdc40 in Xenopus : Implications for CRISPR Targeting and Disease Modeling PMID:40415903

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