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

doi:10.1183/23120541.00714-2022

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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.
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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.
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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.

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 variables	Clinical outcomes
Age at diagnosis	Median 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 cough	57 (83.8%)
Persistent rhinosinusitis	64 (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=28	Median −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 ID	Gene	RefSeq transcript	Variant (all homozygous)	Genomic location (GRCh38)	Exon/total	LOF	NMD (DECIPHER)	ACMG/AMP evidence	ACMG/AMP classification	ClinVar classification	Recorded in previous publications/similar population
0-1, 0-2, 0-8, 0-9, 0-11, 0-20, 0-21, 0-25, 0-31	CCDC39	NM_181426.1	c.1871_1872del; p.(Ile624Lysfs*3)	3: 180641995_180641996del	13/20	Yes	Yes	PVS1_very strong PM2_moderate PM3_moderate	Pathogenic	Pathogenic	One case from Saudi exome project [26]
0-35	CCDC39	NM_181426.1	c.2190del; p.(Glu731Asnfs*31)	3: 180619334del	16/20	Yes	Yes	PVS1_very strong PM2_moderate PM3_moderate	Pathogenic	Pathogenic	Algerian/Tunisian founder effect [27, 39]
0-6 (4 aff)	CCDC40	NM_017950.3	c.48A>G; p.(Gly16Gly)	17: 80038141A>G	2/20	No	na	PM2_moderate PM3_supporting PP1_strong	Likely pathogenic (may create splice enhancer)	Likely benign	No
0-36, 0-39	CCNO	NM_021147.5	c.381+5G>C	5: 55233138C>G	1/3	No	No	PM2_moderate PM3_moderate PP1_moderate PP3_supporting PP4_supporting	Likely pathogenic	Absent	No
0-16, 0-30, 0-40	DNAAF4 (DYX1C1)	NM_130810.3	c.384_390del; p.(Tyr128*)	15: 55491138_55491144del	5/10	Yes	Yes	PVS1_very strong PM2_moderate PM3_moderate	Pathogenic	Likely pathogenic	No
0-4, 0-15, 0-18, 0-26, 0-42	DNAAF11 (LRRC6)	NM_012472.4	c.436G>C; p.(Asp146His)	8: 132632957C>G	5/12	No	na	PS3_strong PM3_moderate PP1_strong	Pathogenic	Pathogenic	Two unrelated Palestinian families [28, 40]
0-23 (2 aff)	DNAH5	NM_001369.2	c.10050G>A; p.(Trp3350*)	5: 13766027C>T	59/79	Yes	Yes	PVS1_very strong PM2_moderate PM3_supporting	Pathogenic	Absent	No
0-24	DNAH11	NM_001277115.1	c.6727C>T; p.(Arg2243*)	7: 21710596C>T	41/82	Yes	Yes	PVS1_very strong PM3_moderate	Pathogenic	Pathogenic/likely pathogenic	[41]
0-7	DNAH11	NM_001277115.1	c.12646G>T; p.(Glu4216*)	7: 21892563G>T	77/82	Yes	Yes	PVS1_very strong PM2_moderate PM3_moderate	Pathogenic	Absent	No
0-22	DNAH11	NM_001277115.1	c.13240dup; p.(Thr4414Asnfs*34)	7: 21900057dup	81/82	Yes	Yes	PVS1_very strong PM2_moderate PM3_moderate	Pathogenic	Pathogenic	No
0-28	DNAH11	NM_001277115.1	c.13436_13440dup; p.(Tyr4481Leufs*7)	7: 21901139_21901143dup	82/82	Yes	No	PVS1_moderate PM2_moderate PM3_moderate	Likely Pathogenic	Absent	No
0-14, 0-19	DRC1	NM_145038.5	c.1521_1524del; p.(Glu508Alafs*4)	2: 26450009_26450012del	12/17	Yes	Yes	PVS1_strong PM2_moderate PM3_moderate	Likely Pathogenic	Absent	No
0-5	ODAD3 (CCDC151)	NM_145045.4	c.850C>T; p.(Gln284*)	19: 11426257G>A	7/13	Yes	Yes	PVS1_strong PM2_moderate PM3_supporting	Likely Pathogenic	Absent	No
0-29	RSPH4A	NM_001010892.3	c.367del; p.(Pro123Leufs*44)	6: 116616991del	1/6	Yes	Yes	PVS1_very strong PM2_moderate PM3_supporting	Pathogenic	Absent	No
0-37	RSPH4A	NM_001010892.3	c.72G>A; p.(Trp24*)	6: 116616695G>A	1/6	Yes	Yes	PVS1_very strong PM2_moderate PM3_supporting	Pathogenic	Absent	No
0-27, 0-32, 0-33	RSPH9	NM_152732.4	c.800_802del; p.(Lys268del)	6: 43670922_43670924del	5/5	No	na	PS3_strong PM2_supporting PM3_moderate PM4_supporting PP1_strong	Pathogenic	Pathogenic	Two Bedouin families; one Saudi family [29, 30, 42]
0-34	SPAG1	NM_172218.3	c.742C>T; p.(Arg248*)	8: 100187160C>T	8/19	Yes	Yes	PVS1_very strong PM2_moderate PM3_supporting PP1_supporting	Pathogenic	Absent	No
0-3	CCDC103	NM_213607.3	c.104G>C; p.(Arg35Pro)	17: 44901102G>C	2/4	No	na	PM2_moderate PM3_moderate PP3_supporting PP4_supporting	VUS (likely pathogenic)	VUS	No
0-10, 0-12	DNAH11	NM_001277115.1	c.563T>C; p.Met188Thr	7:21558869T>C	3/82	No	na	PM2_moderate PM3_moderate PP1_supporting	VUS	Absent	No
0-17	DNAL1	NM_031427.4	c.285_287del; p.(Glu97del)	14: 73687283_73687285del	6/8	No	No	PM2_moderate PM3_supporting PM4_supporting	VUS	VUS	No
0-13 (aff+aff father)**	RSPH9	NM_152732.4	c.760del; p.(Arg254Alafs*76)	6: 43670878del	5/5	Yes	No	PVS1_moderate PM2_moderate PM3_supporting	VUS	Absent	No

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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