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High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy.

BACKGROUND: Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. METHODS AND RESULTS: We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. CONCLUSIONS: Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.

Pubmed ID: 22499950


  • Nakhleh N
  • Francis R
  • Giese RA
  • Tian X
  • Li Y
  • Zariwala MA
  • Yagi H
  • Khalifa O
  • Kureshi S
  • Chatterjee B
  • Sabol SL
  • Swisher M
  • Connelly PS
  • Daniels MP
  • Srinivasan A
  • Kuehl K
  • Kravitz N
  • Burns K
  • Sami I
  • Omran H
  • Barmada M
  • Olivier K
  • Chawla KK
  • Leigh M
  • Jonas R
  • Knowles M
  • Leatherbury L
  • Lo CW



Publication Data

May 8, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL071798
  • Agency: NHLBI NIH HHS, Id: R01 HL071798
  • Agency: NHLBI NIH HHS, Id: U54 HL096458
  • Agency: NHLBI NIH HHS, Id: U54-HL09645806
  • Agency: NHLBI NIH HHS, Id: ZO1-HL005701

Mesh Terms

  • Adolescent
  • Adult
  • Axonemal Dyneins
  • Breath Tests
  • Child
  • Child, Preschool
  • Ciliary Motility Disorders
  • Cytoskeletal Proteins
  • Female
  • Heart Defects, Congenital
  • Heterotaxy Syndrome
  • Humans
  • Infant
  • Male
  • Microscopy, Video
  • Middle Aged
  • Mutation
  • Nitric Oxide
  • Prevalence
  • Proteins
  • Respiratory System Abnormalities
  • Young Adult