Whole-exome sequencing identification of novel DNAH5 mutations in a young patient with primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by structural and/or functional impairment of cilia throughout the whole body. Early diagnosis of PCD is important for the prevention of long‑term sequelae, however early diagnosis is a challenge due to the phenotypic heterogeneity of PCD. In the current study, the patient with PCD was diagnosed at nine years old following several efforts to control intractable airway symptoms. The patient experienced a chronic productive cough beginning in early childhood and had multiple episodes of pneumonia and otitis media with effusion and sinusitis. No situs inversus or other heterotaxias were reported. Serial chest X‑rays exhibited persistent atelectasis and bronchiectasis in the right middle lobe. When the patient was nine years old, electron microscopy of his cilia and genetic analysis were conducted. Electron microscopy of a biopsy specimen from the nasal mucosa indicated loss of the outer dynein arms. Whole‑exome analysis of the genome demonstrated the presence of compound heterozygous mutations in DNAH5: NM_001369.2:c.5983C>T, p.Arg1995X in exon 36 and NM_001369.2:c.9101delG, p.Gly3034ValfsX22 in exon 54; neither of which have been previously reported in the literature in a Japanese patient. Notably, this case is, to the best of our knowledge, the first reported case of PCD caused by the DNAH5 mutation in a Japanese patient.

Figure 1.

Family pedigree. The parents of the proband, his two younger sisters and his younger brother present with no respiratory illness.

Figure 2.

Serial chest X-rays of the patient. X-ray images at (A) one, (B) three, (C) seven and (D) nine years of age.

Figure 3.

High resolution computed tomography scan of lung at nine years old shows atelectasis and bronchiectasis in the right middle lobe.

Figure 4.

Otological observations for the proband. Bilaterally, the eardrums were retracted (A, right; B, left). (C) The pure-tone audiogram indicated bilateral conductive hearing loss. (D) The tympanogram was type B bilaterally.

Figure 5.

Rhinological observations for the proband. The nasal cavities were observed to be bilaterally filled with mucopurulent nasal secretions (A, right; B, left). Nose X-ray indicates (C) bilateral opacification of the maxillary sinuses and (D) clear agenesis of the frontal sinuses.

Figure 6.

Electron microscopy for the proband. In the proband, (A) the central microtubules are unclear, (B) the outer dynein arms are shortened, (C) however the inner dynein arms are present. (D) In the control specimen, the inner and outer dynein arms were evident.

Figure 7.

Whole-exome analysis of proband genomic DNA observed compound heterozygous mutations in DNAH5: NM_001369.2:c.5983C>T, p.Arg1995X in exon 36; and NM_001369.2:c.9101delG, p.Gly3034ValfsX22 in exon 54. (A) Sanger sequencing confirmed the two mutations in the proband. (B) The father of the proband carried only the former mutation, whereas the mother (C) carried only the latter. These finding were compatible with the normal autosomal inheritance pattern of compound heterozygous mutations.