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The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

Nisreen Rumman, Mahmoud R. Fassad, Corine Driessens, Patricia Goggin, Nader Abdelrahman, Adel Adwan, Mutaz Albakri, Jagrati Chopra, Regan Doherty, Bishara Fashho, Grace M. Freke, Abdallah Hasaballah, Claire L. Jackson, Mai A. Mohamed, Reda Abu Nema, Mitali P. Patel, Reuben J. Pengelly, Ahmad Qaaqour, Bruna Rubbo, N. Simon Thomas, James Thompson, Woolf T. Walker, Gabrielle Wheway, Hannah M. Mitchison, Jane S. Lucas
ERJ Open Research 2023 9: 00714-2022; DOI: 10.1183/23120541.00714-2022
Nisreen Rumman
1Pediatric Department, Makassed Hospital, East Jerusalem, Palestine
2Caritas Hospital, Bethlehem, Palestine
3Al-Quds University, School of Medicine, East Jerusalem, Palestine
18Joint first authors
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  • ORCID record for Nisreen Rumman
Mahmoud R. Fassad
4Genetics and Genomic Medicine Department, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
5Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
18Joint first authors
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Corine Driessens
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
8NIHR Applied Research Collaboration Wessex, University of Southampton, Southampton, UK
18Joint first authors
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Patricia Goggin
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
9Biomedical Imaging Unit, University of Southampton Faculty of Medicine, Southampton, UK
18Joint first authors
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Nader Abdelrahman
10Internal Medicine Department, Makassed Hospital, East Jerusalem, Palestine
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Adel Adwan
3Al-Quds University, School of Medicine, East Jerusalem, Palestine
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Mutaz Albakri
10Internal Medicine Department, Makassed Hospital, East Jerusalem, Palestine
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Jagrati Chopra
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
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Regan Doherty
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
9Biomedical Imaging Unit, University of Southampton Faculty of Medicine, Southampton, UK
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Bishara Fashho
2Caritas Hospital, Bethlehem, Palestine
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Grace M. Freke
4Genetics and Genomic Medicine Department, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
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Abdallah Hasaballah
11Rantisi Hospital, Gaza, Palestine
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Claire L. Jackson
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
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Mai A. Mohamed
4Genetics and Genomic Medicine Department, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
12Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Ash Sharqiyah, Egypt
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Reda Abu Nema
13Al-Mustaqbal Medical Center, Hebron, Palestine
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Mitali P. Patel
4Genetics and Genomic Medicine Department, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
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Reuben J. Pengelly
14Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
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Ahmad Qaaqour
10Internal Medicine Department, Makassed Hospital, East Jerusalem, Palestine
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Bruna Rubbo
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
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N. Simon Thomas
14Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
15Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK
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James Thompson
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
9Biomedical Imaging Unit, University of Southampton Faculty of Medicine, Southampton, UK
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Woolf T. Walker
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
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Gabrielle Wheway
14Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
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Hannah M. Mitchison
17Genetics and Genomic Medicine Research and Teaching Department, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
19Joint senior authors
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Jane S. Lucas
6Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
7Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
19Joint senior authors
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  • For correspondence: jlucas1@soton.ac.uk
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  • FIGURE 1
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    FIGURE 1

    Venn diagram representing the variability of symptoms characteristic of primary ciliary dyskinesia (n=67; insufficient data for one member of cohort): situs inversus, neonatal respiratory distress, chronic wet cough and rhinosinusitis.

  • FIGURE 2
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    FIGURE 2

    Range of homozygous gene variants identified in 45 genetically diagnosed Palestine primary ciliary dyskinesia patients. Per gene, each different block represents a different variant, as listed in table 2. Numbers within the blocks indicate the number of patients per mutation.

  • FIGURE 3
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    FIGURE 3

    Diagnostic outcomes in the Palestinian primary ciliary dyskinesia (PCD) population. Nasal nitric oxide (nNO) and PCD genes with pathogenic mutations are reported according to transmission electron microscopy (TEM) findings. Two patients with a genetic diagnosis did not have TEM conducted (RSPH9 and DNAH5). VUS: variants of unknown significance. All scale bars=200 nm.

Tables

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  • TABLE 1

    Demographics and clinical characteristics of participants in the primary ciliary dyskinesia (PCD) cohort, i.e. those with definite diagnosis of PCD based on transmission electron microscopy and/or genetic testing

    Clinical variablesClinical outcomes
    Age at diagnosisMedian 10.0 years; range 3 months–40.0 years
    Female  27 (39.7%)
    Situs inversus 29 (42.6%)
    Consanguinity (n=60) 65 (92.6%)
    Congenital heart disease# (n=67)8 (11.9%)
    Neonatal respiratory symptoms (n=67)57 (85.1%)
    Persistent wet cough57 (83.8%)
    Persistent rhinosinusitis64 (94.1%)
    Conductive hearing loss and/or otitis media with effusion (glue ear)50 (73.5%)
    Finger clubbing (n=67)13 (19.4%)
    nNO (nL·min−1) (n=36)Median 14.5; range 5–62.5
    FEV1 z-score (n=28)Median −1.90 (−5.0–1.32)
    FVC z-score (n=28)Median −1.72 (−5.64–0.57)
    BMI z-score n=28Median −0.36 (−3.03–2.57)

    n=68 unless otherwise stated. BMI: body mass index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; nNO: nasal nitric oxide.

    #Atrial septal defect n=2; right isomerism with complex cardiac defects n=1; situs ambiguous with complex cardiac defects n=1; subaortic membrane n=1; ventricular septal defect n=3.

    • TABLE 2

      Pathogenicity classifications for all identified variants in known primary ciliary dyskinesia (PCD) genes

      Study IDGeneRefSeq transcriptVariant (all homozygous)Genomic location (GRCh38)Exon/totalLOFNMD (DECIPHER)ACMG/AMP evidenceACMG/AMP classificationClinVar classificationRecorded in previous publications/similar population
      0-1, 0-2, 0-8, 0-9, 0-11, 0-20, 0-21, 0-25, 0-31CCDC39NM_181426.1c.1871_1872del; p.(Ile624Lysfs*3)3: 180641995_180641996del13/20YesYesPVS1_very strong
      PM2_moderate
      PM3_moderate
      PathogenicPathogenicOne case from Saudi exome project [26]
      0-35CCDC39NM_181426.1c.2190del; p.(Glu731Asnfs*31)3: 180619334del16/20YesYesPVS1_very strong
      PM2_moderate
      PM3_moderate
      PathogenicPathogenicAlgerian/Tunisian founder effect [27, 39]
      0-6 (4 aff)CCDC40NM_017950.3c.48A>G; p.(Gly16Gly)17: 80038141A>G2/20NonaPM2_moderate
      PM3_supporting
      PP1_strong
      Likely pathogenic (may create splice enhancer)Likely benignNo
      0-36, 0-39CCNONM_021147.5c.381+5G>C5: 55233138C>G1/3NoNoPM2_moderate
      PM3_moderate
      PP1_moderate
      PP3_supporting
      PP4_supporting
      Likely pathogenicAbsentNo
      0-16, 0-30, 0-40DNAAF4 (DYX1C1)NM_130810.3c.384_390del; p.(Tyr128*)15: 55491138_55491144del5/10YesYesPVS1_very strong
      PM2_moderate
      PM3_moderate
      PathogenicLikely pathogenicNo
      0-4, 0-15, 0-18, 0-26, 0-42DNAAF11 (LRRC6)NM_012472.4c.436G>C; p.(Asp146His)8: 132632957C>G5/12NonaPS3_strong
      PM3_moderate
      PP1_strong
      PathogenicPathogenicTwo unrelated Palestinian families [28, 40]
      0-23 (2 aff)DNAH5NM_001369.2c.10050G>A; p.(Trp3350*)5: 13766027C>T59/79YesYesPVS1_very strong
      PM2_moderate
      PM3_supporting
      PathogenicAbsentNo
      0-24DNAH11NM_001277115.1c.6727C>T; p.(Arg2243*)7: 21710596C>T41/82YesYesPVS1_very strong
      PM3_moderate
      PathogenicPathogenic/likely pathogenic[41]
      0-7DNAH11NM_001277115.1c.12646G>T; p.(Glu4216*)7: 21892563G>T77/82YesYesPVS1_very strong
      PM2_moderate
      PM3_moderate
      PathogenicAbsentNo
      0-22DNAH11NM_001277115.1c.13240dup; p.(Thr4414Asnfs*34)7: 21900057dup81/82YesYesPVS1_very strong
      PM2_moderate
      PM3_moderate
      PathogenicPathogenicNo
      0-28DNAH11NM_001277115.1c.13436_13440dup; p.(Tyr4481Leufs*7)7: 21901139_21901143dup82/82YesNoPVS1_moderate
      PM2_moderate
      PM3_moderate
      Likely PathogenicAbsentNo
      0-14, 0-19DRC1NM_145038.5c.1521_1524del; p.(Glu508Alafs*4)2: 26450009_26450012del12/17YesYesPVS1_strong
      PM2_moderate
      PM3_moderate
      Likely PathogenicAbsentNo
      0-5ODAD3 (CCDC151)NM_145045.4c.850C>T; p.(Gln284*)19: 11426257G>A7/13YesYesPVS1_strong
      PM2_moderate
      PM3_supporting
      Likely PathogenicAbsentNo
      0-29RSPH4ANM_001010892.3c.367del; p.(Pro123Leufs*44)6: 116616991del1/6YesYesPVS1_very strong
      PM2_moderate
      PM3_supporting
      PathogenicAbsentNo
      0-37RSPH4ANM_001010892.3c.72G>A; p.(Trp24*)6: 116616695G>A1/6YesYesPVS1_very strong
      PM2_moderate
      PM3_supporting
      PathogenicAbsentNo
      0-27, 0-32, 0-33RSPH9NM_152732.4c.800_802del; p.(Lys268del)6: 43670922_43670924del5/5NonaPS3_strong
      PM2_supporting
      PM3_moderate
      PM4_supporting
      PP1_strong
      PathogenicPathogenicTwo Bedouin families; one Saudi family [29, 30, 42]
      0-34SPAG1NM_172218.3c.742C>T; p.(Arg248*)8: 100187160C>T8/19YesYesPVS1_very strong
      PM2_moderate
      PM3_supporting
      PP1_supporting
      PathogenicAbsentNo
      0-3CCDC103NM_213607.3c.104G>C; p.(Arg35Pro)17: 44901102G>C2/4NonaPM2_moderate
      PM3_moderate
      PP3_supporting
      PP4_supporting
      VUS (likely pathogenic)VUSNo
      0-10, 0-12DNAH11NM_001277115.1c.563T>C; p.Met188Thr7:21558869T>C3/82NonaPM2_moderate
      PM3_moderate
      PP1_supporting
      VUSAbsentNo
      0-17DNAL1NM_031427.4c.285_287del; p.(Glu97del)14: 73687283_73687285del6/8NoNoPM2_moderate
      PM3_supporting
      PM4_supporting
      VUSVUSNo
      0-13 (**aff+aff father)RSPH9NM_152732.4c.760del; p.(Arg254Alafs*76)6: 43670878del5/5YesNoPVS1_moderate
      PM2_moderate
      PM3_supporting
      VUSAbsentNo

      Study ID indicates family number and each family has a single affected child with a positive genetic diagnosis, except where ‘aff’ is shown, indicating that there is more than one affected child in the family (number of affected individuals is shown in these cases). Family 0-13 is the only family with an affected parent in addition to affected children. Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER), American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) and ClinVar classifications indicate likelihood that variants cause protein loss of function, transcript nonsense-mediated decay (NMD), in addition to showing their predicted pathogenic, likely pathogenic or variants of unknown significance (VUS) status. LOF: loss of function; na: not applicable (i.e. cannot be done for missense variants).

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      The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum
      Nisreen Rumman, Mahmoud R. Fassad, Corine Driessens, Patricia Goggin, Nader Abdelrahman, Adel Adwan, Mutaz Albakri, Jagrati Chopra, Regan Doherty, Bishara Fashho, Grace M. Freke, Abdallah Hasaballah, Claire L. Jackson, Mai A. Mohamed, Reda Abu Nema, Mitali P. Patel, Reuben J. Pengelly, Ahmad Qaaqour, Bruna Rubbo, N. Simon Thomas, James Thompson, Woolf T. Walker, Gabrielle Wheway, Hannah M. Mitchison, Jane S. Lucas
      ERJ Open Research Mar 2023, 9 (2) 00714-2022; DOI: 10.1183/23120541.00714-2022

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      The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum
      Nisreen Rumman, Mahmoud R. Fassad, Corine Driessens, Patricia Goggin, Nader Abdelrahman, Adel Adwan, Mutaz Albakri, Jagrati Chopra, Regan Doherty, Bishara Fashho, Grace M. Freke, Abdallah Hasaballah, Claire L. Jackson, Mai A. Mohamed, Reda Abu Nema, Mitali P. Patel, Reuben J. Pengelly, Ahmad Qaaqour, Bruna Rubbo, N. Simon Thomas, James Thompson, Woolf T. Walker, Gabrielle Wheway, Hannah M. Mitchison, Jane S. Lucas
      ERJ Open Research Mar 2023, 9 (2) 00714-2022; DOI: 10.1183/23120541.00714-2022
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