Submission Details

Primary ciliary dyskinesia (PCD) is a clinically and genetically heterogeneous group of diseases resulting from variants in genes involved in the transport, assembly, and function of motile cilia (PMID 33304404). The HYDIN gene was first reported to cause PCD5 in humans in 2012 (PMID 23022101). Major parts of the gene are duplicated in the HYDIN2 pseudogene which might confound genetic diagnosis. Ciliary defects of the respiratory epithelium in the reported patients result in otitis media, sinusitis, recurrent chest infection and progressive airway destruction. Male infertility due to dysfunctional sperm tails is also reported (PMID 23022101). Absence of the situs inversus phenotype characteristic of other forms of PCD reflects the underlying defect in central pair (CP) apparatus, which is considered irrelevant to the nodal cilium that establishes the left-right body asymmetry (PMID 31545650). Deficiency of the CP-apparatus-associated protein HYDIN results in lack of the C2b projection of the central pair with reduced beating amplitudes of respiratory cilia and stiff sperm flagella (PMID 23022101). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and autosomal recessive mode of inheritance to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, the asserted disease associated with HYDIN variants, primary ciliary dyskinesia 5 (MONDO:0012088), was curated as a single entity. Ten splice site, nonsense and frameshift variants were reported in 5 publications (PMIDS 23022101, 23849777, 31089940, 31545650, 26139845). The disease consistently segregates in 1 German and 3 Faroe Islander families, and provides a scorable genetic evidence for segregation analysis of the autosomal recessive disease (PMID 23022101). Experimental evidence also supports this gene disease association. HYDIN expression in ciliated epithelial tissues relevant to PCD was identified in multiple papers (PMIDs 23715323, 12719380). The biochemical function of HYDIN protein in the axonemal central pair and its functional alteration in patient cells are consistent with a critical role in motile cilia structure and function (PMID 23022101). Abnormal ciliary structure and function were also evident in Hydin mutant mice (PMID 18250199). Similarly, Hydin knockdown causes flagellar paralysis in Chlamydomonas (PMID 17296796). In summary, HYDIN is definitively associated with autosomal recessive primary ciliary dyskinesia 5. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on February 10th, 2022 (SOP Version 8).