Submission Details

Executive Summary DNAH7:

DNAH7, Primary Ciliary Dyskinesia 50 (MONDO:0957252), autosomal recessive

DNAH7 was first described as a Primary Ciliary Dyskinesia (PCD)-causing gene in 2022 (Gao et al. 2022, PMID: 35543642). The specific disease entity, Primary Ciliary Dyskinesia 50 (MONDO:0957252), (OMIM:610061), is one of at least 45 different primary ciliary dyskinesias distinguished by a single monogenic cause. Some of the most common patient phenotypes are: Absent inner dynein arms, Chronic sinusitis and Chronic bronchitis.

Seven variants: (2 types of genetic mutations: Frameshift (2) and Missense (5) that have been reported in 5 probands in 3 publications (PMIDs: 35543642, PMID: 34476482 and PMID: 37998386) are included in this curation.

Many of the family members of the probands were similarly genotyped and found to be heterozygous carriers. However, the phenotypic and affected status of those individuals were unknown.

Overall, the mechanism of pathogenicity appears to be loss of function as shown by the suspected disease-causing variants in the probands.

This gene-disease relationship is also supported by multiple forms of experimental evidence such as Expression A (Quantity: 1), Expression B (Quantity: 1) and Biochemical Function A (Quantity: 1). First, GTex data showed that DNAH6 is primarily expressed in fallopian tubes and lungs, which is consistent with PCD phenotypes (PMID: 23715323). Next, Zhang et al. 2002 demonstrated and recapitulated a phenotype that recurred in probands (PMID: 11877439). In Figure 2, cilia collected via nasal scrape from a control (A) and the PCD patient (B and C) were evaluated with electron microscopy. Both inner and outer dynein arms were observed in the cilia of the control. However, when the cilia of the PCD patient was examined, it was found that there was a near complete absence of inner arm structures. Wilken et al. 2024 found that DNAH7 is a component of the inner dynein arm of ciliary axonemes and CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex. DNAH7 and CCDC39 are both IDA components and are localized to the same region. Within the healthy control subjects, DNAH7 is localized throughout the entire length of ciliary axonemes (Figure 6B). However, it was found that in PCD individuals who had disease-causing variants in either CCDC39 or CCDC40 (Figure 6C,D), DNAH7 was absent from the ciliary axoneme. CCDC39 was classified as having a “definitive” relationship with PCD 14 by the Motile Ciliopathy GCEP. Refer to the curation for further details.

In conclusion, DNAH7 has a limited association with Primary Ciliary Dyskinesia 50. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time.

This classification was approved by the Motile Ciliopathy GCEP on February 13th, 2025 (SOP Version 10).