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Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia

Alex Gileles-Hillel, Hagar Mor-Shaked, David Shoseyov, Joel Reiter, Reuven Tsabari, Avigdor Hevroni, Malena Cohen-Cymberknoh, Israel Amirav, Shuli Brammli-Greenberg, Amjad Horani, Eitan Kerem, Oded Breuer
ERJ Open Research 2020 6: 00213-2020; DOI: 10.1183/23120541.00213-2020
Alex Gileles-Hillel
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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  • ORCID record for Alex Gileles-Hillel
Hagar Mor-Shaked
2Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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David Shoseyov
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Joel Reiter
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Reuven Tsabari
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Avigdor Hevroni
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Malena Cohen-Cymberknoh
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Israel Amirav
3Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Pediatric Pulmonology Unit, Tel Aviv, Israel
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Shuli Brammli-Greenberg
4The Department of Management, Policy and Health Economics, School of Public Health, The Hebrew University of Jerusalem, Israel
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Amjad Horani
5Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
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Eitan Kerem
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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Oded Breuer
1Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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  • For correspondence: odedbreuer@gmail.com
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    FIGURE 1

    Study population and the results of whole-exome sequencing (WES) analysis. nNO: nasal nitric oxide; TEM: transmission electron microscopy; PCD: primary ciliary dyskinesia. #: meeting inclusion criteria (see main text).

Tables

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  • TABLE 1

    Characteristics of patients evaluated for primary ciliary dyskinesia

    All patientsPositiveNegativeInconclusive
    Subjects483684
    Age at assessment years median (range)10.0 (1–37)12.1 (1.0–37)9.6 (1–23)6.5 (4–10)
      0–5 years13 (27%)7 (21%)4 (50%)2 (50%)
      5–18 years27 (56%)22 (61%)3 (38%)2 (50%)
      >18 years8 (17%)7 (21%)1 (13%)0 (0%)
    Male21 (44%)14 (39%)5 (63%)2 (50%)
    Consanguinity34 (71%)32 (76%)2 (50%)4 (100%)
    Ethnicity
     Jewish13 (27%)7 (19%)4 (50%)2 (50%)
     Arabic35 (73%)29 (81%)4 (50%)2 (50%)
     Other
    Bronchiectasis46 (96%)34 (94%)7 (88%)4 (100%)
    Associated conditions#11 (23%)10 (28%)1 (13%)0 (0%)
    Neonatal respiratory distress15 (31%)13 (36%)0 (-%)2 (50%)
    Diagnostic assessment performed
     nNO measurement48 (100%)36 (100%)8 (100%)4 (100%)
     TEM for ciliary structure41 (85%)31 (86%)6 (75%)4 (100%)

    nNO: nasal nitric oxide; TEM: transmission electron microscopy. #: situs abnormalities or retinitis pigmentosa.

    • TABLE 2

      Primary ciliary dyskinesia causing genes in our cohort and the related prevalence of situs abnormalities and neonatal distress, and associated findings by transmission electron microscopy (TEM) and nasal nitric oxide (nNO) measurements

      Gene (n=34)LocusSitus abnormalitiesNeonatal respiratory distressTEMnNO ppb mean (range)
      DNAAF3 (n=2)19q1301ODA+IDA46 (32–60)
      DNAH11 (n=9)7p15–2113Normal41.8 (10–79)
      DNAI1 (n=4)9p21–p1311Normal/short ODA34.5 (20–70)
      DNAI2 (n=3)17q25.112Normal/orientation/ODA+ IDA41.3 (30–47)
      DYX1C1 (DNAAF4) (n=1)15q2110Short ODA+IDA55
      HYDIN (n=3)16q2201Normal59.6 (19–90)
      LRRC50 (DNAAF1) (n=2)16q2422ODA+IDA65
      LRRC6 (n=6)8q2442ODA+IDA81.9 (12–328)
      MCIDAS (n=2)5q1100Absence of ciliary cells57 (54–60)
      RSPH4A (n=1)6q2200Normal38
      RSPH9 (n=1)6p2101Normal48

      ODA: outer dynein arm; IDA: inner dynein arm.

      • TABLE 3

        Diagnostic accuracy of nasal nitric oxide (nNO), transmission electron microscopy (TEM) and genetic evaluation for diagnosis of primary ciliary dyskinesia

        nNO <77 nL·min−1nNO <30 nL·min−1TEMWES
        All subjects, including unresolved diagnosis (n=57)48484148
        Sensitivity (95% CI)100 (89.1–100)93.8 (79.2–99.2)62.2 (44.8–77.5)94.4 (81.3–99.3)
        Specificity (95% CI)50.0 (21.1–78.9)75.0 (42.8–94.5)85.7 (57.2–98.2)100 (73.5–100)
        ROC area (95% CI)0.75 (0.60–0.90)0.84 (0.71–0.98)0.74 (0.62–0.86)0.97 (0.93–1.0)

        WES: untargeted whole-exome sequencing; ROC: receiver operating characteristic.

        • TABLE 4

          Diagnostic accuracy of nasal nitric oxide (nNO)

          nNO <77 nL·min−1nNO <77 nL·min−1 and WES
          ≤5 years>5 yearsAll
          All subjects, including unresolved diagnosis (n=48)
           Sensitivity (95% CI)100 (47.8–100)100 (87.2–100)100 (89.1–100)93.8 (79.2–99.2)
           Specificity (95% CI)33.3 (4.3–77.7)66.7 (22.3–95.7)50.0 (21.1–78.9)100 (73.5–100)
           ROC area (95% CI)0.67 (0.46–0.87)0.83 (0.63–1.00)0.75 (0.60–0.90)0.97 (0.93–1.0)
          Subjects with unresolved diagnosis excluded (n=40)
           Sensitivity (95% CI)100 (47.8–100)100 (87.2–100)100 (89.1–100)93.8 (79.2–99.2)
           Specificity (95% CI)50.0 (6.8–93.2)100 (39.8–100)75 (34.9–96.8)100 (63.1–100)
           ROC area (95% CI)0.75 (0.47–1.0)1.00.88 (0.72–1.0)0.97 (0.93–1.0)

          WES: untargeted whole-exome sequencing; ROC: receive operating characteristic.

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          Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
          Alex Gileles-Hillel, Hagar Mor-Shaked, David Shoseyov, Joel Reiter, Reuven Tsabari, Avigdor Hevroni, Malena Cohen-Cymberknoh, Israel Amirav, Shuli Brammli-Greenberg, Amjad Horani, Eitan Kerem, Oded Breuer
          ERJ Open Research Oct 2020, 6 (4) 00213-2020; DOI: 10.1183/23120541.00213-2020

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          Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
          Alex Gileles-Hillel, Hagar Mor-Shaked, David Shoseyov, Joel Reiter, Reuven Tsabari, Avigdor Hevroni, Malena Cohen-Cymberknoh, Israel Amirav, Shuli Brammli-Greenberg, Amjad Horani, Eitan Kerem, Oded Breuer
          ERJ Open Research Oct 2020, 6 (4) 00213-2020; DOI: 10.1183/23120541.00213-2020
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