CCDC103 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal motility of respiratory and sperm cilia, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility (PMID:26123568). Transmission electron microscopy (TEM) typically reveals absence of inner and outer dynein arms (IDA/ODA) consistent with loss-of-function in axonemal assembly.

A homozygous CCDC103 c.461A>C (p.His154Pro) variant was first identified in an Irish Traveller family with three affected siblings, segregating with classic PCD phenotypes and laterality defects (PMID:26123568). The same variant was later reported in a professional athlete presenting isolated total sperm immotility without respiratory symptoms, confirming pleiotropic ciliary dysfunction (PMID:36777727).

Additional biallelic CCDC103 variants, including novel missense and frameshift alleles, have been reported in at least two unrelated patients with absent dynein arms on TEM (PMID:31273583). High-throughput sequencing in 161 multiethnic families detected CCDC103 mutations in South Asian patients (36% of that subgroup), reinforcing its role across populations (PMID:31879361). In pediatric and adult cohorts from China and India, CCDC103 ranks among the top 13 genes with biallelic pathogenic variants in confirmed PCD cases (PMID:32502479; PMID:39004944).

Functional studies demonstrate that CCDC103 deficiency disrupts dynein arm preassembly: TEM and immunofluorescence show complete loss of IDA/ODA in respiratory and sperm axonemes of p.His154Pro homozygotes (PMID:26123568; PMID:36777727). Expression profiling confirms reduced CCDC103 mRNA and protein levels, and reveals tissue-specific oligomerization states critical for cilia and flagella stability (PMID:31273583).

No studies to date have refuted the association or reported unaffected homozygotes, and all identified variants concord with an autosomal recessive mechanism. While additional candidate PCD genes continue to emerge, CCDC103 remains a core diagnostic target in gene panels.

CCDC103 is definitively associated with autosomal recessive PCD, supporting its use in genetic diagnostics, carrier screening and personalized management of ciliary motility disorders.

References

• BMC medical genetics • 2015 • A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder PMID:26123568
• Frontiers in genetics • 2023 • Case report: The CCDC103 variant causes ultrastructural sperm axonemal defects and total sperm immotility in a professional athlete without primary ciliary diskinesia PMID:36777727
• Journal of assisted reproduction and genetics • 2019 • Characterization of CCDC103 expression profiles: further insights in primary ciliary dyskinesia and in human reproduction PMID:31273583
• Journal of medical genetics • 2020 • Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort PMID:31879361
• The Journal of pediatrics • 2020 • Clinical and Genetic Spectrum of Children with Primary Ciliary Dyskinesia in China PMID:32502479
• Clinical genetics • 2024 • Genetics of 67 patients of suspected primary ciliary dyskinesia from India PMID:39004944

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