Submission Details

The DNAI2 gene was initially reported as a candidate gene linked to primary ciliary dyskinesia 9 (PCD 9) in 1999 and 2000 (Pennarun et al., PMID: 10577904, PMID:11153919). The specific disease entity, primary ciliary dyskinesia 9 (PCD 9) (MONDO: 0012906, OMIM # 612444), is part of a larger group of primary ciliary dyskinesias (PCD) and one of at least 50 monogenic causes of PCD.

The onset of the symptoms and signs of the disease can occur at birth (Rocca MS et al., PMID:33167880), and the median age of diagnosis is 15 years old (Loges et al., PMID:18950741). The clinical features among well-characterized newborn patients with DNAI2 pathogenic mutations include neonatal respiratory distress, such as tachypnea or mild hypoxemia, requiring supplemental oxygen for a few hours to days after birth. In early childhood and later life, recurrent pneumonia is common. Otitis and rhinosinusitis are also reported. Approximately 50% of patients exhibit situs inversus or another form of reversed organ laterality and heterotaxy, in some cases including congenital transposition of the great vessels, pyloric stenosis, and other cardiac abnormalities. Patients can also be characterized by chronic sinusitis, as well as bronchiectasis in older individuals. Normal pressure hydrocephalus has been described in PCD (PMID: 31004071, PMID: 11912187, PMID: 31383820). Most men and women with PCD 9 have impaired and/or decreased fertility.

Additional diagnostic features include impaired or absent ciliary movement and radiological findings of bronchiectasis, mucous plugging, atelectasis, and lobar collapse. Nasal nitric oxide levels are very low or absent in these patients. However, among diagnostic features of PCD associated with pathogenic DNAI2 variants is exhibiting ciliary ultrastructure with an absence or shortening of outer dynein arms.

This curation has scored five different suspected deleterious DNAI2 variants (one deleting exons 7-9, one nonsense variant in exon 7, one nonsense variant in exon 10, one splicing variant causing skipping of exon 11, and one splicing variant disrupting exon 4), which were collectively reported in 3 publications (PMID:18950741, PMID:23261302, PMID:33167880). All probands harbored biallelic homozygous variants that were confirmed to be trans. 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.

This gene-disease relationship is also supported by experimental evidence. High levels of DNAI2 expression in humans are specific to tissues that harbor multi-ciliated cells, particularly the testis and trachea (PMID: 11153919 and PMID: 18950741). Loss of DNAI2 from the cilia of patients harboring other forms of PCD has been described and supports the functional role of DNAI2 in outer dynein arm assembly complexes throughout all respiratory ciliary axonemes and sperm (PMID: 18950741). Biochemical studies of the Chlamydomonas ortholog of DNAI2 indicate that the protein product is an intermediate dynein chain positioned at the base of the alpha-beta dimer of the outer dynein arms (PMID: 2147183). This is consistent with the ultrastructural defect characteristic of human patients. The protein also interacts with the Chlamydomonas ortholog of DNAI1 (2147183), a related intermediate dynein chain associated in humans with variants that cause PCD 1. Human patient phenotypes such as ciliary immotility and the absence of outer dynein arms are recapitulated by the Chlamydomonas model of DNAI2 loss of function (PMID:7698982) . Histopathology, infertility and lung damage phenotypes are recapitulated by mouse models of DNAI2 loss of function (PMID: 30387321). In addition, fish mutants with dnai2 loss-of-function exhibit a defect in outer dynein arms in the cilia axoneme, resulting in aberrant ciliary motility along with reversed organ laterality and situs inversus (PMID: 20709053). These phenotypic features are consistent with the pathogenicity of DNAI2 loss of function variants in PCD 9 patients.

In summary, DNAI2 is definitively associated with primary ciliary dyskinesia 9. This has been repeatedly demonstrated in both clinical diagnostic and research settings and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 11, 2022 (SOP Version 9).