title: High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th St, Pittsburgh, PA 15201, USA.
authors.forename: Nader
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authors.lastname: Nakhleh
authors.forename: Richard
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authors.lastname: Francis
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Giese
authors.forename: Xin
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authors.lastname: Tian
authors.forename: You
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authors.lastname: Li
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Hisato
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authors.lastname: Khalifa
authors.forename: Safina
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authors.lastname: Kureshi
authors.forename: Bishwanath
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authors.lastname: Chatterjee
authors.forename: Steven L
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authors.lastname: Swisher
authors.forename: Patricia S
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authors.lastname: Connelly
authors.forename: Mathew P
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authors.lastname: Daniels
authors.forename: Ashok
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authors.lastname: Srinivasan
authors.forename: Karen
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authors.lastname: Kuehl
authors.forename: Nadav
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authors.lastname: Kravitz
authors.forename: Kimberlie
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authors.forename: Iman
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authors.lastname: Sami
authors.forename: Heymut
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authors.forename: Michael
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authors.lastname: Barmada
authors.forename: Kenneth
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authors.lastname: Olivier
authors.forename: Kunal K
authors.initials: KK
authors.lastname: Chawla
authors.forename: Margaret
authors.initials: M
authors.lastname: Leigh
authors.forename: Richard
authors.initials: R
authors.lastname: Jonas
authors.forename: Michael
authors.initials: M
authors.lastname: Knowles
authors.forename: Linda
authors.initials: L
authors.lastname: Leatherbury
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
mesh_terms: D000293:Adolescent; D000328:Adult; D056444:Axonemal Dyneins / Q000235:genetics; D001944:Breath Tests; D002648:Child; D002675:Child, Preschool; D002925:Ciliary Motility Disorders / Q000453:epidemiology* / Q000235:genetics; D003598:Cytoskeletal Proteins; D005260:Female; D006330:Heart Defects, Congenital / Q000453:epidemiology* / Q000235:genetics; D059446:Heterotaxy Syndrome / Q000453:epidemiology* / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D018715:Microscopy, Video; D008875:Middle Aged; D009154:Mutation; D009569:Nitric Oxide / Q000032:analysis; D015995:Prevalence; D011506:Proteins / Q000235:genetics; D015619:Respiratory System Abnormalities / Q000453:epidemiology* / Q000235:genetics; D055815:Young Adult
chemical_list: C556026:CCDC39 protein, human; C556028:CCDC40 protein, human; D003598:Cytoskeletal Proteins; C425071:DNAI1 protein, human; D011506:Proteins; D009569:Nitric Oxide; D056444:Axonemal Dyneins; C465433:DNAH11 protein, human