Submission Details

The ZMYND10 gene was first reported in relation to primary ciliary dyskinesia in 2013 (Zariwala et al., PMID: 23891469, Moore et al., PMID: 23891471). The specific disease entity, primary ciliary dyskinesia 22 (MONDO:0014192, OMIM #615444), is one of at least 45 different primary ciliary dyskinesias (PCD) distinguished by a single monogenic cause. Affected patients can have onset of symptoms at birth and reported cases have been diagnosed with PCD either in infancy or in childhood. Frequent features among reported patients are chronic wet cough from early childhood, neonatal respiratory distress, sinusitis, otitis media, bronchiectasis, and decreased nasal nitric oxide. Approximately 50% of cases exhibit situs inversus or heterotaxy. Cilia are largely or completely immotile. Adult patients can exhibit decreased fertility. Biopsies of the airway epithelium show ciliary ultrastructure with absent or abnormal outer and inner dynein arms, although one reported case with a PCD-associated phenotype and homozygous missense variant has been found to exhibit normal ciliary ultrastructure (PMID: 23891469, and personal communication with the authors). This finding emphasizes the clear need for additional case reports to establish the full extent of outer and inner dynein arm defects in ZMYND10-related disease.

This curation has scored eleven suspected deleterious ZMYND10 variants (two missense, six frameshift, and three nonsense), which were collectively reported in twelve probands in three publications (PMID: 23891471, PMID: 23891469, PMID: 26139845). All of the probands harbored biallelic variants confirmed to be present in trans. Nine probands harbored variants in the homozygous state, four of whom were reported to be from consanguineous parents. Three others probands harbored ZMYND10 variants in the compound heterozygous state. The molecular mechanism appears to be biallelic loss-of-function with an autosomal recessive mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product. More genetic evidence was available (PMID: 26824761) but was not included as the maximum for this category of evidence had already been reached. Large families with segregation data were not found for inclusion in this gene curation. Please note that the genetic evidence scored in this curation has relied heavily on the best-characterized ZMYND10 variants from the literature, while an urgent need remains for additional published data to evaluate the pathogenicity of many other emerging variants.

This gene-disease relationship is also supported by experimental evidence that high levels of ZMYND10 expression in humans (PMID: 23715323) and mice (PMID: 23891471) are specific to tissues known to harbor multi-ciliated cells. ZMYND10 expression also increases dramatically when cultured human bronchial epithelial cells are subjected to conditions that stimulate ciliogenesis (PMID: 17413031). Biochemical studies indicate that the ZMYND10 protein interacts with the chaperone molecules FKBP8 and HSP90, functioning as a required chaperone during cytoplasmic pre-assembly of dyneins (PMID: 29916806). Animal models lacking Zmynd10 exhibit destabilization of dynein arm components (PMID: 29916806). ZMYND10 also physically interacts with the protein product of the LRRC6 / DNAAF11 gene, which harbors variants known to cause another form of PCD (PMID: 23891471). Drosophila, zebrafish, and medaka models with biallelic silencing or deletion of the respective genes orthologous to ZMYND10 recapitulate cellular and organ-level features of the human disease state (PMID: 23891469, PMID: 23891471, PMID: 28823919). Mouse models in particular exhibit absent outer and inner dynein arms, situs inversus totalis, mucopurulent nasal plugs, and reduced motility of cilia and sperm (PMID: 29916806). Rescue experiments have demonstrated the potential of a wild-type transgene from Drosophila, medaka, or mouse to rescue phenotypes of endogenous Zmynd10 disruption in various model organisms (PMID: 28823919, PMID: 23891471).

In summary, ZMYND10 is definitively associated with primary ciliary dyskinesia 22. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Motile Ciliopathy GCEP on February 7th, 2022 (SOP Version 9).