NME5

Inheritance Pattern: AR

Disease ID:MONDO:0031054

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0031054

Submitter: ClinGen

The *NME5* gene was first reported in relation to primary ciliary dyskinesia in 2020 (Cho et al., PMID: 32185794). The specific disease entity, primary ciliary dyskinesia 48, without situs inversus (MONDO:0031054, OMIM #620032), is one of at least 40 different primary ciliary dyskinesias distinguished by a single monogenic cause. Affected patients have exhibited recurrent sinusitis and bacterial pulmonary infections, pneumonia, bronchiectasis, otitis media with hearing impairment, and respiratory motile cilia with absence of the central microtubular pair and/or other abnormalities of microtubule number. On the other hand, abnormalities of abdominal situs or of the inner and outer dynein arms have been absent. Due to the limited number of case reports available (PMID: 32185794, PMID: 32950024, PMID: 37957793), it is not yet clear whether other primary ciliary dyskinesia-related features such as infertility are present among affected cases. Patient iPSC-derived multiciliated epithelial cells exhibit ciliary beat frequencies that are higher and more variable than control cells, accompanied by impaired mucociliary clearance (PMID: 37296588). This curation has scored three suspected disease-causing *NME5* variants (one nonsense and two frameshift), which were reported in the homozygous or compound heterozygous state in three published probands (PMID: 32185794, PMID: 32950024, PMID: 37957793, PMID: 37998386). Two of the variants likely trigger nonsense-mediated decay, while the other is predicted to generate a C-terminally truncated protein product. 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. However, the limited number of patients and functional assays available has so far precluded a more thorough analysis of molecular mechanism. There is one unpublished case of a proband carrying homozygous NME5:c.436+3862_555+236del p.? variants that remove exon 5 (M. Legendre, personal communication 7/9/2026). This patient has sino-otopulmonary symptoms, low nasal NO, and central complex defects in 29% of the analyzed cilia (TEM). Please note that an urgent need remains for additional published case data to establish the spectrum of disease and evaluate the pathogenicity of other emerging variants in this locus. This gene-disease association is also supported by abundant biochemical evidence that *NME5* encodes a component of the radial spoke neck, a critical structure within the axoneme of respiratory cilia and sperm flagella (PMID: 21391306, PMID: 25789548, PMID: 22065640, PMID: 12169685, PMID: 14499630). The RSPH1, RSPH4A, and RSPH9 genes encoding other radial spoke components have each been associated with monogenic forms of primary ciliary dyskinesias, all of which similarly present with central microtubule complex and radial spoke defects (PMID: 23993197, PMID: 19200523, PMID: 19200523). Human tissues with the highest levels of *NME5* expression include tissue types known to contain multi-ciliated or flagellated cells, including the testes, fallopian tubes, and lungs (PMID: 23715323). Animal models of *NME5* loss-of-function have been identified in canines (PMID: 31479451) and generated in zebrafish (PMID: 32185794), mice (PMID: 21746835), and *Xenopus* embryos (PMID: 24424412). These models recapitulate features of the human patients such as abnormalities of motility and axonemal organization of respiratory motile cilia, reduced cilia-based flow rate, rhinitis, impaired nasal mucociliary clearance, recurrent bacterial infections, recurrent bronchitis, and bronchiectasis (PMID: 31479451, PMID: 32185794, PMID: 21746835, PMID: 24424412). In summary, the evidence linking *NME5* with primary ciliary dyskinesia 48 without situs inversus has reached a classification in the Moderate range. Additional genetic evidence from research and diagnostic settings will be required to reach a more definitive gene-disease association. This classification was approved by the ClinGen Motile Ciliopathy GCEP on July 9, 2026 (SOP Version 12).

Inheritance Pattern: Unknown

Disease ID:MONDO:0031054

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0031054

Submitter: PanelApp Australia