Genetic spectrum and genotype-phenotype correlations in DNAH5-mutated primary ciliary dyskinesia: a systematic review.

Background: Primary ciliary dyskinesia (PCD), a rare ciliopathy disorder, is caused by variants in multiple genes, with DNAH5 being one of the most frequently implicated. However, the precise relationship between variant type or location in the DNAH5 gene and the clinical heterogeneity remains elusive. The present systematic review aims to provide critical insights into the impact of the molecular nature of DNAH5 variants on PCD phenotypes.

Methods: We enrolled all reported cases of PCD with biallelic pathogenic variants in the DNAH5 gene to date, and evaluated genotype-phenotype correlations in these patients, employing truncating (TV) and missense (MV) variant-carrying as grouping criteria.

Results: A total of 323 PCD patients with the DNAH5 variants were included, with 14.55% of these patients were diagnosed as Kartagener syndrome. Pediatric and adult patients exhibited distinct clinical features, including varying incidences of bronchiectasis, infertility, neonatal respiratory distress (NRD), ciliary ultrastructural defects distributions, and lung function (all p < 0.05). With regard to mutational patterns, truncating variants in DNAH5 were clustered in the 1200-3200 amino acid region, and were more prevalent in children compared to adult (p < 0.0001). Most missense variants are clustering in the linker, AAA + ATPase and AAA-lid domains. The most frequently observed mutation, c.10815delT, was prevalent in Europe and America, whereas c.8030G > A was more common in China and Asia. In terms of genotype-phenotype correlations, individuals with the TV/TV genotype exhibited a higher proportion of NRD and earlier onset compared to those with MV-carrying genotypes, both in overall population and in pediatric patients (all p < 0.05). Patients with the TV/TV genotype exhibited worse lung function compared to those with MV-carrying genotypes.

Conclusion: The study underscores the broad mutational spectrum and high phenotypic heterogenicity in DNAH5-related PCD patients. The presence of biallelic truncating variants may predispose patients to earlier disease onset and poorer lung function.