NME8

Inheritance Pattern: AR

Disease ID:MONDO:0012571

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012571

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0016575

Submitter: ClinGen

NME8 was first reported in relation to autosomal recessive primary ciliary dyskinesia (PCD) in 2007. Duriez et al. described a proband with clinical features consistent with PCD, including chronic respiratory infections with bronchiectasis, chronic sinusitis, serous otitis media, and laterality defects (situs ambiguous with the heart and liver located centrally). Ciliary beat frequency from respiratory epithelial cells was reported as normal, but transmission electron microscopy revealed abnormal ciliary ultrastructure in 66% of respiratory cilia, including shortened or absent outer dynein arms. The proband was compound heterozygous for a rare nonsense variant c.1277T>A (p.Leu426*) and a relatively common intronic variant c.271-27C>T present in approximately 2% of control alleles. Of note, these variants were identified using gene-targeted methods, and no broader genomic analysis was performed to exclude alternative genetic causes (PMID: 17360648). The NME8 gene product has two reported isoforms: a full-length isoform (TXNDC3fl) and a second isoform containing a 117-bp in-frame deletion in exon 7 (TXNDC3d7). Duriez et al. reported that individuals heterozygous for the c.271-27C>T variant exhibit reduced levels of the truncated TXNDC3d7 isoform relative to the full-length TXNDC3fl isoform compared with controls. Functional studies in HeLa cells similarly suggested that this intronic variant alters alternative splicing and results in reduced production of the truncated TXNDC3d7 isoform (PMID: 17360648). The closest paralog, NME9, also produces both a full-length isoform and a truncated isoform lacking exon 5, and previous work demonstrated that the truncated NME9 isoform binds microtubules with higher affinity. Because exon 5 of NME9 shares sequence similarity with exon 7 of NME8, Duriez et al. investigated microtubule binding of the two NME8 isoforms. Both isoforms were capable of binding microtubules, although the truncated TXNDC3d7 isoform showed somewhat higher affinity (PMID: 17360648). These experiments therefore indicate that microtubule interaction is not exclusive to the truncated isoform. Subsequent expression data have raised questions regarding the relevance of NME8 to motile airway cilia. Single-cell RNA sequencing data from the Human Protein Atlas indicate that NME8 expression is not detected in ciliated epithelial cells of the human airway. In addition, a transcriptomic analysis of differentiating human airway epithelial cells performed by Paff et al. (PMID: 29363216) examined the expression of 26 PCD genes before and after ciliogenesis. While most PCD genes were strongly upregulated during differentiation, NME8 was the only gene that showed no detectable expression throughout the experiment. Although there is experimental evidence that NME8 is expressed in tissues containing motile cilia, such as lung and testis (PMID: 23715323), organismal studies in mice and sea urchin indicate that NME8 orthologs are predominantly expressed in sperm. In sea urchin, the ortholog IC1 functions as one of the three intermediate chains of the sperm axoneme and is a component of the sperm outer dynein arm complex (PMID: 8970153; PMID: 12909633). In summary, the initial report suggested a potential relationship between altered NME8 splicing and PCD. However, the genetic evidence is limited to a single report with incomplete genomic investigation, and subsequent expression studies have not demonstrated NME8 expression in human airway ciliated cells. Together, these findings raise substantial uncertainty regarding the role of NME8 in motile airway cilia. Therefore, the gene–disease relationship between NME8 and autosomal recessive primary ciliary dyskinesia is currently considered disputed. This classification was approved by the ClinGen Motile Ciliopathy GCEP on March 12th 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0012571

Submitter: PanelApp Australia