The NEK10 gene encodes a kinase involved in the function and growth of cilia (PMID: 29581457, PMID: 31959991). Loss-of-function variants in this gene were first identified in patients with bronchiectasis and reduced ciliary motion in cultured bronchial epithelial cells (PMID: 31959991). These features are consistent with primary ciliary dyskinesia (PCD), a condition of impaired ciliary function characterized by neonates with respiratory distress, recurrent chest infections, wet cough, and abnormalities of abdominal situs in approximately half of affected individuals. Given the ciliary function of NEK10, this gene has been evaluated in this curation for gene-disease association with primary ciliary dyskinesia 44.
Individuals with phenotypes consistent with PCD (e.g. bronchiectasis, recurrent sinusitis, neonatal respiratory distress) who carried homozygous or compound heterozygous variants in NEK10 were first identified in 2020 (PMID: 31959991). The mutational spectrum of disease-causing variants suggests loss of function (LOF) as a mechanism of disease. However, missense and a non-canonical splice variants (p.Pro748Leu, p.Arg773Cys, c.1230+5G>C) have also been identified in the homozygous state. Variant-specific functional studies of cultured patient bronchial epithelial cells in an air-liquid interface reveal short airway cilia in imaging flow cytometry, supporting a deleterious effect. At the same time, many of the individuals in the literature were reported to have normal nasal nitric oxide measurements, normal electron microscopy of the cilia, and absence of abdominal situs abnormalities (PMID: 31959991, 32414360, 33875846, 35728977, 37998386).
Experimental evidence supporting this gene-disease relationship includes studies demonstrating that NEK10 protein localizes to motile cilia and interacts with other motile cilia proteins, as well as knockout/knockdown assays in cell culture and zebrafish models that result in ciliary abnormalities and can be rescued with exogenous NEK10 (PMID: 29581457, 31959991).
In summary, NEK10 has a Definitive association with primary ciliary dyskinesia 44 based on multiple genetic and experimental evidence data points. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Motile Ciliopathy GCEP on July 10, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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