Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterized by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognized to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in DNAH11.
In order to test further for mutant DNAH11 as a cause of PCD, we sequenced DNAH11 in patients with a PCD clinical phenotype, but no known genetic etiology.
We sequenced 82 exons and intron/exon junctions in DNAH11 in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer ± inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, we sequenced DNAH11 in 13 patients with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.
Of the 58 unrelated PCD patients with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; plus, 2 PCD patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or Ioss-of-function splice-site mutations.
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.