DNAH14 was first described in relation to primary ciliary dyskinesia in 2021 (PMID: 33577779, Guan et al. 2021). The proband phenotype included productive cough, bronchiectasis, chronic sinusitis, otitis media, decreased nasal nitric oxide, and absent or shortened inner and outer dynein arms (PMID: 33577779). A second monogenic proband with respiratory phenotypes characteristic of primary ciliary dyskinesia was subsequently reported in the 2024 (PMID: 39004944). DNAH14 variants have separately been asserted in the literature in relation to neuro-developmental disorders (PMID: 35438214). Per the recommendations of the ClinGen Lumping & Splitting Working Group, the Motile Ciliopathy GCEP recommended to focus specifically on the relationship between DNAH14 variants and primary ciliary dyskinesia as a split curation, in order to dispute the current assertion for this gene-disease relationship.
The first asserted proband was a 5-year old male harboring two DNAH14 variants; NM_001367479.1:c.5120del (p.Gly1707ValfsTer12) and NM_001367479.1:c.4255-22_4255-21dup (described in the study as c.4172 _c.4173insAT (p.R1391Rfs∗26)). This proband was not scored due to skepticism around the potential pathogenicity of the second variant, which is intronic in the canonical transcript and not predicted to disrupt DNAH14 splicing. The second asserted proband in the literature was an 8-year old female harboring the NM_001367479.1:c.7792del (p.Thr2598LeufsTer19) variant in the homozygous state (PMID: 39004944). Collectively, the probands from this curation harbored frameshift or intronic variants in DNAH14.
This gene-disease relationship is supported by limited experimental evidence indicating that DNAH14 encodes an axonemal dynein heavy chain (PMID: 8812413) and is predominantly expressed in testis, as well as to a lesser degree in ovary and pituitary tissue (PMID: 23715323).
In conclusion, DNAH14 has a disputed association with primary ciliary dyskinesia due to the limited number of published human probands, absence of sufficient support for the pathogenicity of their variants, and the current lack of published experimental data. This classification was approved by the Motile Ciliopathy GCEP on May 8th, 2025 (SOP Version 11).
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