DRC1 – Primary Ciliary Dyskinesia

DRC1 has emerged as a key gene implicated in primary ciliary dyskinesia (PCD), a heterogeneous disorder of motile cilia characterized by chronic respiratory infections, bronchiectasis, and infertility. The evidence indicates that pathogenic variants in DRC1, including truncating mutations and large deletions affecting multiple exons, contribute to the disease phenotype in an autosomal recessive pattern (PMID:31270959).

Several independent case reports have identified recurrent variants, such as the truncating variant c.1296G>A (p.Trp432Ter), along with large exon deletions (exons 1–4), in patients with PCD. These findings are supported by familial segregation studies where affected relatives across multiple unrelated families have been demonstrated to carry the disease‐associated DRC1 variants (PMID:34851034; PMID:35873463).

In addition to case reports, multi‐patient studies confirm that DRC1 variants are a recurrent cause of PCD in Asian populations, with evidence of a founder effect as the identical deletion breakpoint in exons 1–4 has been reported in numerous Japanese and Korean patients (PMID:39152285; PMID:36747106). This founder mutation underscores the clinical relevance of DRC1 screening within these ethnic groups.

Genetic evidence is further strengthened by the documentation of segregation of the variants in families, with over 23 probands and additional affected relatives demonstrating concordant inheritance patterns (PMID:31270959). Functional studies in both patient-derived samples and animal models have revealed that loss of DRC1 function disrupts the nexin-dynein regulatory complex, leading to impaired ciliary beating and axonemal structural defects that mirror the human phenotype (PMID:34815526).

Moreover, experimental evidence from high-speed video microscopy and ultrastructural analyses via electron microscopy have validated that DRC1 deficiency results in decreased nasal nitric oxide production and abnormal ciliary motion, providing a mechanistic link between the genotype and the characteristic PCD clinical features (PMID:36856967).

In summary, the integration of robust genetic data, segregation analyses, and concordant functional studies provides strong support for the association between DRC1 and primary ciliary dyskinesia. This strong evidence base highlights the clinical utility of including DRC1 in diagnostic panels for PCD, particularly in populations with a high prevalence of the founder mutation.

References

• Molecular genetics & genomic medicine | 2019 | Recurring large deletion in DRC1 causing primary ciliary dyskinesia PMID:31270959
• American journal of medical genetics. Part A | 2022 | Expanded phenotype of primary ciliary dyskinesia related to DRC1 pathogenic variant PMID:34851034
• Frontiers in genetics | 2022 | Whole-Exome Sequencing-Based Copy Number Variation Analysis Identified a Novel DRC1 Homozygous Exon Deletion in a PCD Patient PMID:35873463
• Journal of human genetics | 2022 | DRC1 deficiency caused primary ciliary dyskinesia and MMAF in a Chinese patient PMID:34815526
• Journal of human genetics | 2024 | A 3000-year-old founder variant in the DRC1 gene causes primary ciliary dyskinesia in Japan and Korea PMID:39152285
• Journal of assisted reproduction and genetics | 2023 | Characterization of a DRC1 null variant associated with primary ciliary dyskinesia and female infertility PMID:36856967

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