DiagnosisClinical DiagnosisThe diagnosis of primary ciliary dyskinesia (PCD) is based on the presence of a characteristic clinical phenotype that may include (but is not limited to) the following: Chronic sinopulmonary disease Chronic cough and sputum production Chronic wheeze and air trapping Obstructive lung disease on lung function tests Persistent colonization with pathogens commonly found in individuals with PCD Chest radiograph with chronic abnormalities Sinus radiograph with chronic abnormalities Chronic otitis media Neonatal respiratory distress Chronic nasal congestion dating from the newborn period Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) or heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures, often categorized clinically as asplenia [predominant bilateral right-sidedness, or right isomerism] or polysplenia [predominant bilateral left-sidedness, or left isomerism]) [Zhu et al 2006]. Digital clubbing TestingSpecific ciliary ultrastructural defects identified by transmission electron microscopy. This diagnostic test for primary ciliary dyskinesia requires a biopsy of the respiratory epithelium, typically obtained by brushing or scraping the inferior surface of the nasal turbinate or brushing the bronchial surface via bronchoscopy [MacCormick et al 2002, Chilvers et al 2003]. The dynein arm defects are often specific for the gene in which mutation is causative (see Table 2). The most prevalent of the defined ultrastructural defects in primary ciliary dyskinesia are (Figure 1):FigureFigure 1. Cross section of the cilia
A. Schematic diagram of a cilium revealing '9+2' arrangement of nine peripheral microtubule doublets surrounding a central microtubule pair
B. Representative electron microscopic image of a normal (more...)Shortening and/or absence of dynein arms (inner, outer, or both) (~90%); Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (~10%). Note: (1) Expertise in evaluation of ciliary ultrastructure is needed to distinguish primary (genetic) defects from acquired defects that result from exposure to different environmental and infectious agents. (2) Classic Kartagener syndrome with situs inversus, chronic sinusitis, and bronchiectasis in which no apparent ultrastructural defects are observed has been reported. It is now known that some families with classic Kartagener syndrome have biallelic mutations in DNAH11 (locus name CILD7). Other tests under evaluation as screening or supportive tests for PCD, particularly when ciliary ultrastructure is normal: High-speed videomicroscopy of ciliary motility. Evaluation of ciliary beat frequency and ciliary beat pattern requires high-speed videomicroscopy of freshly obtained ciliary biopsies that are maintained in culture media under controlled conditions. Specific immotility/dysmotility patterns associated with PCD can be identified [Chilvers et al 2003, Toskala et al 2005]. Measurement of nasal nitric oxide production. Nitric oxide (NO), produced by the respiratory cells, is present in much higher concentrations in the upper airway than in the lower airway. For unknown reasons, individuals with PCD have very low nasal NO production that is approximately one-tenth of control values. Although measurement of nasal NO has promise as a screening test for PCD, better definition of normative NO values, particularly in young children, and definition of range of NO values in appropriate disease controls are needed. Mucociliary clearance analysis of radiolabeled particles. Mucociliary clearance has been measured by assessing clearance of radiolabeled particles from the nasal passages or from the lower airways [Coren et al 2002, De Boeck et al 2005, Marthin et al 2007]. For these studies, an aerosol containing radiolabeled particles is inhaled and then a gamma camera is used to track deposition and clearance of these insoluble particles.Immunofluorescent staining of ciliary biopsy. Immunofluorescent assays using antibodies specific to the ciliary components can be used to decipher the specific ciliary ultrastructural defect. For example, patients with outer dynein arm (ODA) defects (as per electron microscopic analysis and/or presence of biallelic mutations in ODA-related genes such as DNAH5 or DNAI2) show absence of ciliary staining using anti-DNAH5 or anti-DNAI2 antibodies [Fliegauf et al 2005, Loges et al 2008]. Similarly, inner dynein arm(IDA) defects and dynein regulatory complex defects can be ascertained using IDA specific anti-DNALI1 and nexin related anti-GAS8/GAS11 antibodies respectively [Becker-Heck et al 2011, Merveille et al 2011]. Semen analysis. Sperm count is typically normal, but sperm are immotile or motility is severely limited [Afzelius 2004]. In some reports, up to 50% of males with PCD are fertile [Munro et al 1994]. Molecular Genetic Testing Genes. The seventeen genes known to be associated with PCD, followed by locus name are: DNAI1 / CILD1, DNAAF3 / CILD2, DNAH5 / CILD3, HYDIN / CILD5, NME8 (previously TXNDC3) / CILD6, DNAH11 / CILD7, DNAI2 / CILD9, DNAAF2 (previously known as KTU, PF13, or C14orf104) / CILD10, RSPH4A / CILD11, RSPH9 / CILD12, DNAAF1 (previously known as LRRC50) / CILD13, CCDC39 / CILD14, CCDC40 / CILD15, DNAL1 / CILD16, CCDC103 / CILD17, HEATR2 / CILD18, and LRRC6 / CILD19. Evidence for additional locus heterogeneity. More than one third of individuals with well-characterized PCD do not have an identifiable mutation in any of the seventeen known genes. Other loci implicated in PCD for which no disease-related genes have been identified include the following:CILD4. 15q13.1-q15.1CILD8. 15q24-q25Table 1. Summary of Molecular Genetic Testing Used in Primary Ciliary DyskinesiaView in own windowGene Symbol / Locus Name % of All PCDTest MethodMutations DetectedTest AvailabilityDNAI1 / CILD1 2%-9% ^{1Sequence analysis of select exons 2 / sequence analysisSequence variants 3ClinicalDNAAF3 / CILD2 Unknown 4Sequence analysisClinical DNAH5 / CILD3 15%-21% 5Sequence analysis of select exons 6 / sequence analysisClinicalDeletion / duplication analysis 7Exonic or whole-gene deletions 8DNAAF1 (LRRC50) / CILD13 4%-5% 9Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 7Exonic or whole-gene deletions 10NME8 (TXNDC3) / CILD6 Unknown 11Sequence analysisSequence variants 3ClinicalDNAH11 / CILD7 6% 12ClinicalDNAI2 / CILD9 2% 13ClinicalDNAAF2 (C14orf104, KTU, PF13) / CILD10 <2% 14ClinicalRSPH4A / CILD11 Unknown 15ClinicalRSPH9 / CILD12 Unknown 16ClinicalCCDC39 / CILD14 2%-10% 17ClinicalCCDC40 / CILD15 1%-8% 18ClinicalDNAL1 / CILD16 Unknown 19Clinical CCDC103 / CILD17Unknown 20Clinical LRRC6 / CILD193% 21Clinical HYDIN / CILD5Unknown 22Research onlyHEATR2 / CILD18Unknown 231. Biallelic mutations account for approximately 2% [Failly et al 2008] to 9% of all PCD [Pennarun et al 1999, Guichard et al 2001, Zariwala et al 2001, Zariwala et al 2006].2. Often exons 1, 13, 16, 17, 18 [Failly et al 2008, Zariwala et al 2006]; however, selected exons may vary by laboratory.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Three mutant alleles of DNAAF3 have been described in persons with PCD of either Arab or Pakistani origin [Mitchison et al 2012].5. Biallelic mutations account for approximately 15% [Failly et al 2009] to 21% all PCD [Olbrich et al 2002, Hornef et al 2006]. Based on large studies, DNAH5 mutations have been found on at least one allele in 28% of individuals with PCD (21% of all patients with PCD tested had two mutations identified; an additional 7% had only one mutation identified despite full sequencing; thus combined, 28% of the patients had mutations identified at least on one allele) [Olbrich et al 2002, Hornef et al 2006]. 6. Often exons 34, 50, 63, 76, 77 [Hornef et al 2006]; however, selected exons may vary by laboratory.7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.8. Berg et al [2011]9. Duquesnoy et al [2009] identified biallelic DNAAF1 mutations in four of 23 unrelated individuals with outer+inner dynein arm defects. Loges et al [2009] identified biallelic DNAAF1 mutations in two of 58 unrelated individuals. Since outer+inner dynein arm defects account for ~30% of all PCD, mutations in DNAAF1 are estimated to account for 4%-5% of all PCD. 10. Duquesnoy et al [2009], Loges et al [2009]11. In 41 unrelated persons with PCD, one had a nonsense mutation and an intronic variant (allele frequency 1%) that alters splicing on the trans allele that appeared to be pathogenic in the presence of the nonsense mutation on the other allele [Duriez et al 2007] (see Molecular Genetics).12. In a family of German origin with PCD and normal ciliary dynein arms, five affected individuals had situs solitus and one had situs inversus totalis. All six had compound heterozygous DNAH11 mutations (p.Tyr4128X and p.Ala4518_Ala4523delinsGln) [Schwabe et al 2008]. Studying large cohort, Knowles et al [2012] identified DNAH11 mutations in 22% of person with PCD and normal ciliary ultrastructure that is estimated to be 6% of all PCD.13. In a large inbred Iranian Jewish kindred all affected individuals were homozygous for the splice site mutation c.1494+1G>C (IVS11+1G>C) [Loges et al 2008]. The same investigators, who evaluated 105 unrelated persons with PCD and identified two kindreds with DNAI2 mutations, concluded that DNAI2 accounts for 2% of all PCD mutations and 4% of PCD caused by outer dynein arm defects.14. Omran et al [2008] found DNAAF2 (C14orf104, KTU, PF13) mutations in 12% of persons with PCD caused by combined outer and inner dynein arm defects. Since outer+inner dynein arm defects account for ~30% of all PCD, mutations in DNAAF2 are estimated to account for <2% of all PCD.15. Castleman et al [2009] identified a homozygous nonsense mutation (p.Gln154X) in three inbred Pakistani families and one out-bred Pakistani family. They also identified compound heterozygous mutations p.Gln109X and p.Arg490X in a person of Northern European descent with PCD. 16. Castleman et al [2009] studied individuals with PCD and central microtubular pair abnormalities and found a homozygous mutation in-frame deletion (p.Lys268del) in two unrelated inbred Arab Bedouin families. 17. Biallelic mutations were identified in probands from 18 of 50 families [Merveille et al 2011] and 22 of 34 families [Blanchon et al 2012] with PCD with axonemal disorganization. Since axonemal disorganization accounts for 5%-15% of all PCD, mutations in CCDC39 are estimated to be present in 2%-10% of all PCD18. CCDC40 biallelic mutations were identified in 13 of 24 unrelated families [Becker-Heck et al 2011] and 8 of 34 families [Blanchon et al 2012] with PCD with axonemal disorganization. Since axonemal disorganization accounts for 5%-15% of all PCD, mutations in CCDC40 are estimated to be present in 1%-8% of all PCD.19. Sequence analysis of DNAL1 identified a homozygous missense mutation (p.Asn150Ser) in all individuals with PCD in two unrelated inbred families of Bedouin origin.20. Truncating, possible founder mutation (c.383_384insG) in CCDC103 has been reported in families of Pakistani origin [Panizzi et al 2012].21. Kott et al [2012] found LRRC6 mutations in 5 of 47 (~11%) of persons with PCD caused by combined outer and inner dynein arm defects. Since outer+inner dynein arm defects account for ~30% of all PCD, mutations in LRRC6 are estimated to account for ~3% of all PCD. Multiple mutant alleles have been reported.22. HYDIN comprising of 86-exons from chromosome 16q22.2 has duplicated gene HYDIN2 on chromosome 1q21.1 with identical intron-exon structure spanning exons 6-83. Thus, caution must be exercise in the interpretations of the sequencing results. Persons with PCD from Faroe Island carry nonsense founder mutation (p.Lys307*) [Olbrich et al 2012]. 23. Persons with PCD from Amish Mennonite community harbor missense founder mutation (p.Leu795Pro) in HEATR2 [Horani et al 2012]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyEstablishing the diagnosis in a proband. Diagnosis is based on the following: Clinical evaluation
AND Molecular genetic testing to identify biallelic mutations in one of the genes known to be associated with PCD: Sequential molecular genetic testing:Based on per cent of all PCD attributed to mutations in a given gene, molecular genetic testing is performed first on DNAH5. If only one mutation is identified in DNAH5, deletion/duplication analysis should be considered. If no mutations are identified, testing proceeds in the following order until at least one mutation is identified: DNAI1, DNAI2, DNAAF2, DNAAF1, LRRC6, DNAAF3, CCDC103, CCDC39, CCDC40, DNAH11, RSPH4A, RSPH9, NME8, DNAL1, and HYDIN. If no mutations are identified, deletion/duplication analysis for DNAH5 and DNAAF1 should be considered.
Full sequencing of DNAI1 (20 exons) and DNAH5 (80 exons) is estimated to detect at least one mutation in approximately 30%-38% of all individuals with PCD [Pennarun et al 1999, Guichard et al 2001, Zariwala et al 2001, Zariwala et al 2006]. Percentages are higher if the patients are selected for sequencing based on the presence of outer dynein arm defects. Additionally, if results of ciliary ultrastructural studies are available, molecular genetic testing can be focused on pertinent genes (see Table 2).
ORMulti-gene testing:Consider using a multi-gene PCD panel that includes DNAH5 as well as a number of other genes associated with PCD. Note: These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with the PCD phenotype also varies.
OR Ciliary ultrastructural analysis
Note: It is now clear that some individuals with PCD do not have ultrastructural abnormalities of the cilia, formerly the ‘gold standard’ for diagnosis. Table 2. Ciliary Ultrastructural Findings by Mutated Gene View in own windowGene Symbol / Locus Name Ciliary StructureDynein ArmsCentral PairAxonemal OrganizationOuterInnerDNAI1 / CILD1 Abnormal 1DNAAF3 / CILD2 Abnormal 2DNAH5 / CILD3 Abnormal 1, 3HYDIN / CILD5Normal 4NME8 (TXNDC3) / CILD6 66% abnormal 5DNAH11 / CILD7 Normal 6DNAI2 / CILD9 Abnormal 1DNAAF2 (C14orf104, KTU, PF13) / CILD10 Abnormal 7Abnormal 7RSPH4A / CILD11 Defective 8RSPH9 / CILD12 Normal 9Normal 9Defective 9DNAAF1 (LRRC50) / CILD13Abnormal 7Abnormal 7CCDC39 / CILD14 Abnormal 10CCDC40 / CILD15 Abnormal 11DNAL1 / CILD16 Abnormal 12CCDC103 / CILD17Abnormal 13HEATR2 / CILD18Abnormal 14LRRC6 / CILD19Abnormal 151. Pennarun et al [1999], Guichard et al [2001], Zariwala et al [2001], Hornef et al [2006], Zariwala et al [2006], Loges et al [2008] 2. Ciliary ultrastructure analysis shows ODA+IDA defects from person with biallelic mutations in DNAAF3 [Mitchison et al 2012].3. A mutation causing premature translation termination resulted in complete absence of outer dynein arms (ODA) a splice site mutation resulted in shortened outer dynein arms [Kispert et al 2003]. 4. Persons with biallelic mutations in HYDIN have defective C2b projections of central pair that is not detectable using routine ciliary ultrastructure analysis; thus, they exhibit normal cilia on cross-section analysis with a very rare occurrence of 9+0 or 8+1 central microtubular structure [Olbrich et al 2012].5. Only one patient with mutation identified who had heterogeneous ultrastructure including normal cilia and two thirds of cilia with defective ODA 6. Although DNAH11 encodes an outer dynein arm protein, individuals with biallelic mutations have normal dynein arms on ultrastructural examination [Bartoloni et al 2002, Schwabe et al 2008, Pifferi et al 2010, Knowles et al 2012]. 7. Cilial defects are outer plus inner dynein arms [Omran et al 2008, Duquesnoy et al 2009, Loges et al 2009].8. Ultrastructural analysis of cilia from affected individuals in the five families reported showed central pair transposition defects with the 9+0 or 8+1 microtubule configuration [Castleman et al 2009].9. RSPH9 mutations were associated with defective central pair (9+2 and 9+0 microtubular configuration) in one family; and normal ciliary ultrastructure another family [Castleman et al 2009]. 10. Axonemal disorganization includes eccentric central pair, abnormal radial spokes and nexin links, reduced number of inner dynein arms, and displacement of the outer doublet [Becker-Heck et al 2011, Merveille et al 2011]. Individuals with PCD with other cilial defects: isolated inner dynein arm defects (n=6); combined outer+inner dynein arm defects (n=18); or heterotaxy without any respiratory symptoms (n=216) did not have mutations in CCDC39.11. Axonemal disorganization includes eccentric central pair, abnormal radial spokes and nexin links, reduced number of inner dynein arms, and displacement of the outer doublet [Becker-Heck et al 2011].12. Mazor et al [2011]13. Ciliary ultrastructure analysis shows ODA+IDA defects from a person with biallelic mutations in CCDC103 [Panizzi et al 2012].14. Ciliary ultrastructure analysis shows ODA+IDA defects from a person with biallelic mutations in HEATR2 [Horani et al 2012].15. Ciliary ultrastructure analysis shows ODA+IDA defects from a person with biallelic mutations in LRRC6 [Kott et al 2012].The following adjunct tests can be used to support the diagnosis:Ciliary beat frequency and pattern, if available Nasal nitric oxide measurement, if available For adult males with unexplained infertility: semen analysis Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersTo date, mutations in the seventeen genes associated with PCD — DNAI1, DNAAF3, DNAH5, HYDIN, NME8 (previously TXNDC3), DNAH11, DNAI2, DNAAF2 (previously known as C14orf104, KTU, PF13), RSPH4A, RSPH9, DNAAF1 (previously known as LRRC50), CCDC39, CCDC40, DNAL1, CCDC103, HEATR2, and LRRC6 — are not known to be associated with other phenotypes.}

Natural HistoryPrimary ciliary dyskinesia (PCD) is associated with (1) abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract and lead to chronic oto-sino-pulmonary disease and (2) abnormal flagellar structure resulting in abnormal sperm motility. Pulmonary disease. The progression and severity of lung disease varies among individuals. More than 75% of full-term neonates with PCD have 'neonatal respiratory distress' requiring supplemental oxygen for days to weeks; however, few are diagnosed at this age [Coren et al 2002, Noone et al 2004, Ferkol & Leigh 2006]. Chronic airway infection is apparent in early childhood. Most children have chronic year-round cough; chronic sinusitis and nasal congestion (frequently with mucostasis and prominent nasal drainage) begin in the first months of life, often at birth. Sputum cultures typically yield oropharyngeal flora, Hemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus beginning in early childhood, after which Pseudomonas aeruginosa (first smooth and then mucoid) becomes more prevalent. Although rare in childhood, infection with non-tuberculous mycobacteria occurs in more than 10% of adults [Noone et al 2004]. Chronic airway infection results in bronchiectasis that may be apparent in some young children and is almost uniformly present in adulthood. A subset of adults with chronic airway infection have calcium deposition in the lung and expectorate small calcium stones (lithoptysis) [Kennedy et al 2006]. Some develop end-stage lung disease in mid-adulthood and several have undergone lung transplantation. The onset of airway disease in individuals with PCD occurs early in childhood; progression of lung disease can be slowed with appropriate therapy. Nasal congestion and sinus infections become apparent in early childhood and persist through adulthood [Noone et al 2004, Leigh 2006]. Chronic/recurrent ear infection, apparent in most young children with PCD, becomes less apparent by school age. In many infants and young children, chronic otitis media is associated with transient hearing loss that may affect speech development. If untreated, infections of the middle ear may result in irreversible hearing loss [Hadfield et al 1997, Majithia et al 2005]. Infertility. Males with PCD may be infertile secondary to impaired sperm motility because the flagella of the sperm and cilia often (but not always) have the same ultrastructural and functional defects. Some women with PCD have normal fertility; others have impaired fertility and an increased risk for ectopic pregnancy because of impaired ciliary function in the oviduct [Afzelius 2004].Situs abnormalities Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is observed in nearly 50% of individuals with PCD. Heterotaxy (also called "situs ambiguous") is present in at least 6% of individuals with PCD [Kennedy et al 2006]. Heterotaxy, discordance of right and left patterns of ordinarily asymmetric structures, is distinct from situs inversus and is often categorized clinically as asplenia (predominant bilateral right-sidedness, or right isomerism) or polysplenia (predominant bilateral left-sidedness, or left isomerism).
In those with heterotaxy, congenital cardiovascular malformations are common and complex, and often the cause of death. Specific cardiovascular defects associated with heterotaxy include atrial isomerism, transposition of the great vessels, double outlet right ventricle, anomalous venous return, interrupted inferior vena cava, and bilateral superior vena cavae [Zhu et al 2006].
Pulmonary isomerism, usually asymptomatic, can be right isomerism (a trilobed pulmonary anatomy bilaterally with bilateral eparterial bronchi) or left isomerism (both lungs have the lobar and hilar anatomy characteristic of a normal left lung).
The stomach may be displaced to the right; the liver may be midline, or the left and right lobes may be reversed.
Abnormal rotation of the intestinal loop can result in obstruction or volvulus (vascular obstruction).
CNS, skeletal, and genitourinary malformations may also be seen.Other. Hydrocephalus may occur in some individuals with PCD and may reflect dysfunctional ependymal cilia [Wessels et al 2003, Kosaki et al 2004].

Genotype-Phenotype CorrelationsGenotype-phenotype correlation for the majority of mutations is not available. (See Table 2 for information on correlations between mutated gene and ciliary defects observed.)

Differential DiagnosisChronic sinopulmonary disease and bronchiectasis. Appropriate studies to exclude the following disorders should be performed during the evaluation for primary ciliary dyskinesia (PCD): Cystic fibrosis Immunodeficiency, such as immunoglobulin G (IgG) subclass deficiency Allergies Gastroesophageal reflux disease Young syndrome: male infertility (obstruction of the epididymis by inspissated secretions) with chronic sinopulmonary infection [Handelsman et al 1984] Wegener's granulomatosis (upper- and lower-airway disease) Situs abnormalities. Failure to establish normal left-right asymmetry can result in a wide spectrum of congenital disorders including situs inversus totalis and heterotaxy syndrome (polysplenia and asplenia) that may be coincidentally associated with heart defects. More than 80 genes, including DNAH5 and DNAI1, are required for the development of visceral asymmetry. Approximately 25% of individuals with situs inversus totalis have PCD [Zhu et al 2006]. Prevalence of PCD within the heterotaxy subclass is unknown but at least 6% of individuals with PCD have heterotaxy [Kennedy et al 2006]. Other. PCD is usually inherited in an autosomal recessive manner, but in rare instances other modes of inheritance have been reported. Narayan et al [1994] described a mother and her five sons from three different fathers (who were not related to the mother), all of whom had PCD; one affected child also had dextrocardia. This finding suggests either X-linked or autosomal dominant inheritance. Occasionally, mutations in RPGR (involved in X-linked retinitis pigmentosa) have been identified in males with retinitis pigmentosa cosegregating with PCD (see Moore et al [2006] and references within).A mutation in OFD1 (involved in oral-facial-digital syndrome type 1) was found in a family in which X-linked intellectual disability cosegregated with PCD [Budny et al 2006].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with primary ciliary dyskinesia (PCD), the following evaluations are recommended:Pulmonary disease Respiratory cultures (typically sputum cultures) to define infecting organisms and to direct antimicrobial therapy. Specific cultures for non-tuberculous mycobacteria should be included for older children and adults. Chest radiographs and/or chest CT to define distribution and severity of airway disease and bronchiectasis Pulmonary function tests (spirometry) to define severity of obstructive impairment Pulse oximetry, with overnight saturation studies if borderline Nasal congestion and/or sinus symptoms. Sinus imaging (sinus x-rays or preferably sinus CT) Chronic/recurrent ear infections. Formal hearing evaluation (See Deafness and Hereditary Hearing Loss Overview for hearing evaluations available at different ages.) Treatment of ManifestationsAt present, no specific therapies can correct ciliary dysfunction. The therapies described in this section are empiric and aimed at treating consequences of dysfunctional cilia and sperm flagella. Little evidence supports use of specific therapeutic modalities in PCD. Pulmonary disease. Management of individuals with PCD should include aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial infections. Approaches to enhance mucus clearance are similar to those used in the management of cystic fibrosis, including chest percussion and postural drainage, oscillatory vest, and breathing maneuvers to facilitate clearance of distal airways. Because cough is an effective clearance mechanism, patients should be encouraged to cough and engage in activities that promote deep breathing and cough (e.g., vigorous exercise). Routine immunizations to protect against respiratory pathogens:Pertussis Haemophilus influenzae type b Pneumococcal vaccine Annual influenza virus vaccine Prompt institution of antibiotic therapy for bacterial infections of the airways (bronchitis, sinusitis, and otitis media) is essential for preventing irreversible damage. Sputum culture results may be used to direct appropriate choice of antimicrobial therapy. In those individuals in whom symptoms recur within days to weeks after completing a course of antibiotics, extended use of a broad-spectrum antibiotic or even prophylactic antibiotic coverage may be considered. (Consideration of chronic antibiotic therapy must include assessing the risk of selecting for multi-resistant organisms.)For individuals with localized bronchiectasis, lobectomy has been performed in an attempt to decrease infection of the remaining lung. This approach, however, is controversial; consultants with expertise in PCD should be involved in the decision-making process. Lung transplantation has been performed in persons with end-stage lung disease.Nasal congestion and sinus infections. In some persons with extensive sinus disease, sinus surgery can facilitate drainage and relieve symptoms. Chronic/recurrent ear infection. For chronic otitis media unresponsive to antibiotic therapy, PE tube placement may be helpful; however, some individuals with PCD have had offensive otorrhea following PE tube placement [Hadfield et al 1997]. Speech therapy and hearing aids may be necessary for children with hearing loss and delayed speech. Male infertility. A couple in which the male has PCD-related infertility has the option of in vitro fertilization using ICSI (intracytoplasmic sperm injection). In this procedure, spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with obstructive azoospermia) are injected into a harvested egg by in vitro fertilization [Cayan et al 2001, Westlander et al 2003, Peeraer et al 2004]. Other options are artificial insemination by donor sperm (AIDS). Situs abnormalities. Typically, situs abnormalities do not require intervention unless physiologic dysfunction (e.g., congenital heart disease) requiring surgical intervention is present. Prevention of Secondary ComplicationsMeasures to prevent respiratory illnesses include immunizations (annual influenza and pneumococcal vaccines and routine childhood immunization), as well as good hand hygiene and limitation of exposure to individuals with acute infections.SurveillanceAt follow-up visits with a pulmonologist, respiratory cultures, chest imaging studies, and spirometry are used to assess the extent and progression of the pulmonary disease. For young children with chronic otitis media, routine hearing evaluation is essential, and should be continued until the teenage years, by which time hearing is usually normal [Majithia et al 2005]. Typically, the ear disease improves in later childhood and hearing screening is not necessary.Agents/Circumstances to AvoidCough suppressants should not be used because cough is critical for clearing secretions. Exposure to respiratory pathogens, tobacco smoke, and other pollutants and irritants that may damage airway mucosa and stimulate mucus secretion should be avoided. Evaluation of Relatives at RiskRelatives with symptoms or findings suggestive of PCD including neonatal respiratory distress despite term gestation, chronic oto-sino-pulmonary disease, bronchiectasis, situs inversus totalis, other situs abnormalities, and male infertility should undergo diagnostic evaluation for PCD. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Primary Ciliary Dyskinesia: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCILD1DNAI19p13​.3Dynein intermediate chain 1, axonemalDNAI1 @ LOVDDNAI1CILD2DNAAF319q13​.42Dynein assembly factor 3, axonemal DNAAF3CILD3DNAH55p15​.2Dynein heavy chain 5, axonemalDNAH5 @ LOVDDNAH5CILD4Unknown15q13​.1-q15.1Unknown CILD5HYDIN16q22​.2Hydrocephalus-inducing protein homolog HYDINCILD6NME87p14​.1Thioredoxin domain-containing protein 3NME8 homepage - Mendelian genesNME8CILD7DNAH117p15​.3Dynein heavy chain 11, axonemalDNAH11 @ LOVDDNAH11CILD8Unknown15q24-q25Unknown CILD9DNAI217q25​.1Dynein intermediate chain 2, axonemalDNAI2 @ LOVDDNAI2CILD10DNAAF214q21​.3Protein kintounDNAAF2 homepage - Mendelian genesDNAAF2CILD11RSPH4A6q22​.1Radial spokehead-like protein 3RSPH4A homepage - Mendelian genesRSPH4ACILD12RSPH96p21​.1UPF0685 protein C6orf206RSPH9 homepage - Mendelian genesRSPH9CILD13DNAAF116q23​.3-q24.1Dynein assembly factor 1, axonemalDNAAF1 @ LOVDDNAAF1CILD14CCDC393q26​.33Coiled-coil domain-containing protein 39CCDC39 @ LOVDCCDC39CILD15CCDC4017q25​.3Coiled-coil domain-containing protein 40CCDC40 @ LOVDCCDC40CILD16DNAL114q24​.3Dynein light chain 1, axonemal DNAL1CILD17CCDC10317q21​.31Coiled-coil domain-containing protein 103 CCDC103CILD18HEATR2UnknownHEAT repeat-containing protein 2 HEATR2CILD19LRRC68q24​.22Protein TILB homolog LRRC6Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Primary Ciliary Dyskinesia (View All in OMIM) View in own window 244400CILIARY DYSKINESIA, PRIMARY, 1; CILD1 603335DYNEIN, AXONEMAL, HEAVY CHAIN 5; DNAH5 603339DYNEIN, AXONEMAL, HEAVY CHAIN 11; DNAH11 604366DYNEIN, AXONEMAL, INTERMEDIATE CHAIN 1; DNAI1 605483DYNEIN, AXONEMAL, INTERMEDIATE CHAIN 2; DNAI2 606763CILIARY DYSKINESIA, PRIMARY, 2; CILD2 607421THIOREDOXIN DOMAIN-CONTAINING PROTEIN 3; TXNDC3 608644CILIARY DYSKINESIA, PRIMARY, 3; CILD3 608646CILIARY DYSKINESIA, PRIMARY, 4; CILD4 608647CILIARY DYSKINESIA, PRIMARY, 5; CILD5 610062DYNEIN, AXONEMAL, LIGHT CHAIN 1; DNAL1 610812HYDROCEPHALUS-INDUCING, MOUSE, HOMOLOG OF; HYDIN 610852CILIARY DYSKINESIA, PRIMARY, 6; CILD6 611884CILIARY DYSKINESIA, PRIMARY, 7; CILD7 612274CILIARY DYSKINESIA, PRIMARY, 8; CILD8 612444CILIARY DYSKINESIA, PRIMARY, 9; CILD9 612517KINTOUN, MEDAKA, HOMOLOG OF; KTU 612518CILIARY DYSKINESIA, PRIMARY, 10; CILD10 612647RADIAL SPOKE HEAD 4, CHLAMYDOMONAS, HOMOLOG OF, A; RSPH4A 612648RADIAL SPOKE HEAD 9, CHLAMYDOMONAS, HOMOLOG OF; RSPH9 612649CILIARY DYSKINESIA, PRIMARY, 11; CILD11 612650CILIARY DYSKINESIA, PRIMARY, 12; CILD12 613190DYNEIN, AXONEMAL, ASSEMBLY FACTOR 1; DNAAF1 613193CILIARY DYSKINESIA, PRIMARY, 13; CILD13 613798COILED-COIL DOMAIN-CONTAINING PROTEIN 39; CCDC39 613799COILED-COIL DOMAIN-CONTAINING PROTEIN 40; CCDC40 613807CILIARY DYSKINESIA, PRIMARY, 14; CILD14 613808CILIARY DYSKINESIA, PRIMARY, 15; CILD15 614017CILIARY DYSKINESIA, PRIMARY, 16; CILD16 614566DYNEIN, AXONEMAL, ASSEMBLY FACTOR 3; DNAAF3 614677COILED-COIL DOMAIN-CONTAINING PROTEIN 103; CCDC103 614679CILIARY DYSKINESIA, PRIMARY, 17; CILD17 614864HEAT REPEAT-CONTAINING PROTEIN 2; HEATR2 614874CILIARY DYSKINESIA, PRIMARY, 18; CILD18 614930LEUCINE-RICH REPEAT-CONTAINING PROTEIN 6; LRRC6 614935CILIARY DYSKINESIA, PRIMARY, 19; CILD19Molecular Genetic PathogenesisCilia, organelles present on almost every cell, emanate from one of the basal bodies, a modified centriole. Different categories of cilia include: motile cilia, non-motile primary cilia, and motile primary cilia (e.g., nodal cilia). Cilia are complex, highly conserved structures. Motile cilia are made up of approximately 250 proteins; each cilium has a '9+2' arrangement with nine peripheral microtubule doublets surrounding the central microtubule pair, which is known as the axoneme (Figure 1). The outer and inner dynein arms are present on the peripheral microtubules and are visible on transmission electron microscopic images of the ciliary cross sections.The outer and inner dynein arms form a bridge between the doublet microtubules in the axoneme and are the force-generating proteins responsible for ciliary beating [Afzelius et al 2001, El Zein et al 2003, Afzelius 2004, Zariwala et al 2007]. The outer dynein arm comprises several heavy, intermediate, and light chains [Satir 1999]. The inner dynein arm is highly complex and varies along the entire length of the axoneme [Perrone et al 2000, DiBella & King 2001]. Defects in cilia have been associated with several human disorders including primary ciliary dyskinesia (PCD)/Kartagener syndrome, Bardet-Biedl syndrome (basal body of the cilia), autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease (defective renal monocilia), nephronophthisis, Joubert syndrome, retinitis pigmentosa (photoreceptor connecting cilia), hydrocephalus, and Alstrom syndrome [Afzelius 2004, Badano et al 2006, Zariwala et al 2007, Leigh et al 2009, Tobin & Beales 2009]. Most of these disorders are genetically heterogeneous, with many genes remaining to be identified [Badano et al 2006, Tobin & Beales 2009]. PCD is characterized by abnormalities in the structure and function of cilia of the respiratory tract and flagella of sperm. Absent (or shortened) dynein arms occur in approximately 90% of individuals who have defined ultrastructural defects; approximately 10% have defective central complex or radial spoke or nexin links [Chilvers et al 2003, Noone et al 2004, Carlen & Stenram 2005]. Some individuals with PCD have no apparent ciliary ultrastructural defects. Thus far, mutations causing autosomal recessive PCD have been clearly linked to seventeen genes (see Table A). DNAI1 and DNAH5 encode the outer dynein arm proteins. The presence of situs inversus totalis in 50% of individuals with PCD provides evidence of the role for cilia in directing left-right asymmetry in the embryo. Click here for information on model organisms.DNAI1 / CILD1Normal allelic variants. DNAI1 comprises 20 exons and encodes a 699-amino acid protein. Pathologic allelic variants. See Table 3. Approximately 18 different DNAI1 mutations have been identified. Approximately 29% of mutations are present in exons 13, 16, and 17, the conserved WD (Trp-Asp amino acid) repeat region of the gene. Based on a large study, 15% of mutations identified are missense; the remaining are insertions, deletions, and nonsense and splice site mutations [Zariwala et al 2006]. Mutations that appeared in two or more unrelated families include the mutations clustering in exons 13, 16, and 17 and c.48+2_3insT (also known as IVS1+2_3insT) in intron 1. The c.48+2_3insT mutation accounts for approximately 55% of mutant alleles; it abrogates the splice donor site in cDNA, leading to the addition of intron 1 sequences, predicted to lead to premature translation termination [Pennarun et al 1999]. Analysis of microsatellite markers in close proximity to DNAI1 revealed that c.48+2_3insT is a founder mutation [Zariwala et al 2006]. The splice site mutation c.1490G>A at the beginning of exon 16 causes the in-frame deletion of exons 15 and 16, comprising 56 amino acids. The mutation c.2001+1G>A (also known as IVS19+1G>A) leads to the in-frame deletion of exon 19 in cDNA [Zariwala et al 2006]. Table 3. Selected DNAI1 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change Reference Sequencesc.48+2_3insT
(IVS1+2_3insT)
(219+3insT)--NM_012144​.2
NP_036276​.1c.1490G>A --c.2001+1G>A
(IVS19+1G>A)--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions Normal gene product. Dynein axonemal intermediate chain 1 belongs to the large family of motor proteins [Pennarun et al 1999]. It contains five conserved WD repeat regions (containing tryptophane-aspartate) at the carboxy-terminal portion of the gene. In the human and mouse, DNAL1 is expressed only in tissues that contain motile cilia or flagella (including mouse embryonic node on E7.5 dpc). Abnormal gene product. Mutations in DNAI1 lead to defective (absent, or only shortened) outer dynein arms, as seen by ciliary ultrastructural analysis. DNAAF3 / CILD2Normal allelic variants. DNAAF3 comprises 12 exons and encodes a 588-amino acid protein.Pathologic allelic variants. See Table 4. Three DNAAF3 mutant alleles are described from three unrelated families. A family of Pakistani origin harbored a homozygous frameshift mutation; a family of Arab origin harbored a homozygous nonsense mutation; another Arab family harbored a homozygous missense mutation [Mitchison et al 2012].Table 4. Selected DNAAF3 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.323T>Cp.Leu108ProNM_178837​.4
NP_849159​.2c.406C>Tp.Arg136*c.762_763insTp.Val255Cysfs*12See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. DNAAF3 encodes dynein axonemal assembly factor 3, a protein of 588 amino acids. It does not have any characterized structural motifs or similarities to the known protein families and is predicted to function in axonemal dynein assembly [Mitchison et al 2012]. Abnormal gene product. Mutations in DNAAF3 lead to the defective outer+inner dynein arms as observed by ciliary ultrastructural analysis. In addition, immunofluorescent analysis using antibodies against DNAH5 (marker for outer dynein arms [ODA]) and DNALI1 (marker for inner dynein arms [IDA]) indicated that ODA and IDA are absent from the ciliary axoneme of individuals with biallelic DNAAF3 mutations, providing evidence that DNAAF3 is important for outer and inner raw dynein assembly [Mitchison et al 2012].DNAH5 / CILD3Normal allelic variants. DNAH5 comprises 79 exons with an alternative first exon. Pathologic allelic variants. See Table 5. A total of 42 mutant alleles are known, approximately 47% of which cluster in five exons (34, 50, 63, 76, and 77). Fifteen percent of mutations are missense and the remaining are nonsense and splice site mutations, insertions, and deletions [Hornef et al 2006].One mutation (c.10815delT) in exon 63 was present in seven unrelated families; this mutation is likely a founder mutation based on deduced haplotype analysis with a large number of intragenic single-nucleotide polymorphisms. In one individual, the splice mutation p.Arg577Thr led to the out-of-frame deletion of exon 13 predicted to cause premature translation termination signals [Hornef et al 2006]. Table 5. Selected DNAH5 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.10815delTp.Pro3606Hisfs*23NM_001369​.2
NP_001360​.1c.1730G>C p.Arg577ThrSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. DNAH5 encodes ciliary dynein axonemal heavy chain 5, a 4624-amino acid protein. The N-terminal domain forms the stem domain of the outer dynein arm complex and is involved in interaction with other heavy, intermediate, and light chains. The C-terminal region that makes the globular head contains six conserved 6 p-loop domains and a conserved microtubule binding (MTB) site. The first p-loop domain is known to bind and hydrolyze ATP [Olbrich et al 2002]. Abnormal gene product. Mutations in DNAH5 lead to defective outer dynein arms seen by ciliary ultrastructural analysis. Additionally, alteration in the distribution of the DNAH5 protein was observed by immunofluorescent analysis in individuals with mutations in DNAH5. HYDIN (CILD5)Normal allelic variants. HYDIN comprises 86 exons and encodes a 5121-amino acid protein at chromosomal locus 16q22.2. Intrachromosomal duplication during human evolution led to HYDIN2, a pseudogene at chromosomal locus 1q21.1 that has identical intron-exon structure consisting of exons 6-83 [Olbrich et al 2012].Pathologic allelic variants. See Table 6. Two truncating HYDIN mutant alleles are described: a nonsense mutation from the PCD affected kindred of Faroe Island and the splice acceptor-site mutation in a German family. Caution must be exercised in interpretation of variants analysis because of the presence of HYDIN2, an almost identical pseudogene [Olbrich et al 2012].Table 6. Selected HYDIN Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.922A>Tp.Lys307*NM_001270974​.1
NP_001257903​.1c.3985G>TTruncatingSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. HYDIN encodes hydrocephalus inducing protein of 5121 amino acids. Abnormal gene product. Expression analysis of splice mutations revealed insertion of 47 bp from the 3’end of intron 26 between exons 26 and 27 (r.3985-47_3985-1ins; 3985G>U). Mutations in HYDIN lead to defective C2b projection in the central pair that is undetectable by routine ciliary ultrastructure analysis; thus cross-sections appear normal with a very rare occurrence of 9+0 or 8+1 central microtubular structure. Consistent with these findings, cilia immunofluorescent analysis using antibodies directed against DNAH5 (marker for outer dynein arms [ODA]), DNALI1 (marker for inner dynein arms [IDA]), CCDC39, and GAS11 (markers for dynein regulatory complex), in a person with a HYDIN mutation showed a pattern similar to that seen in a healthy control [Olbrich et al 2012]. NME8 (previouslyTXNDC3) (CILD6)Normal allelic variants. NME8 (previously TXNDC3) has a full-length transcript NM_016616.4 of 2327 nucleotides and 18 exons.Pathologic allelic variants. See Table 7. One affected person with PCD and mutation in NME8 has been reported. Duriez et al [2007] identified a heterozygous nonsense mutation (p.Leu426X) in one individual who also had an intronic variant (c.271-27C>T, found in 1% of the general population) on the trans allele. The c.271-27C>T variant appeared to cause splicing defects affecting the ratio of the full-length transcript variant of NME8 and a shorter variant isoform with an in-frame deletion of exon 7, termed variant TXNDC3d7 [Duriez et al 2007]. Because of the abnormal gene product from the TXNDC3d7 allele (see Abnormal gene product), it is considered pathologic in the presence of the nonsense mutation on the other allele. Table 7. Selected NME8 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.1277T>Ap.Leu426XNM_016616​.4
NP_057700​.3c.271-27C>T--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. Thioredoxin domain-containing protein 3 is a member of the large family of thioedoxins, enzymatic proteins that function as disulfide reductases. The full-length transcript of NME8 encodes a protein of 588 amino acid residues. About 1% of NME8 alleles encode a shorter isoform resulting from the in-frame deletion of exon 7 in the transcript variant TXNDC3d7 [Duriez et al 2007].Orthologs of human thioredoxin domain-containing protein 3 are components of the sperm outer dynein arms of Chlamydomonas (light chain LC3 and LC5) and sea urchin (intermediate chain IC1).Abnormal gene product. The c.1277T>A is a nonsense mutation resulting in a nonfunctional thioredoxin domain-containing protein 3. The TXNDC3D7 isoform lacks part of the thioredoxin domain, rendering it nonfunctional. However, this isoform showed slightly higher binding to microtubules compared to the full-length isoform, suggesting functional significance. Comparison to orthologs and paralogs also suggested that the TXNDC3D7 isoform plays a role in binding to outer dynein arms. [Extracted from OMIM, May 29, 2012]. Ultrastructural analysis of respiratory cilia from the affected individual with the nonsense mutation and the c.271-27C>T intronic variant revealed a combination of normal dynein arms and defective outer dynein arms [Duriez et al 2007].DNAH11 (CILD7)Normal allelic variants. DNAH11 comprises 82 exons. Pathologic allelic variants. See Table 8. Three mutant alleles are described: a homozygous nonsense mutation (p.Arg2852X) that is predicted to disrupt the microtubule-binding domain; a nonsense mutation (p.Tyr4128X); and a frameshift mutation (A4518_A4523delinsQ) that affects the normal stop codon.One person with paternal uniparental isodisomy of chromosome 7 who had both PCD and situs inversus (i.e., Kartagener syndrome) and cystic fibrosis was doubly homozygous for the p.Arg2852X mutation in DNAH11 and the p.Phe508del mutation in CFTR [Bartoloni et al 2002]. Because it is difficult to distinguish between respiratory symptoms caused by cystic fibrosis and those caused by PCD, the authors concluded that mutations in DNAH11 may cause one form of PCD or one form of situs inversus. Ultrastructural analysis of respiratory cilia from this individual showed normal dynein arms. A recent large-scale study [Knowles et al 2012] describes various pathogenic mutations in persons with PCD and normal ciliary ultrastructure, providing further evidence that mutations in DNAH11 do not cause structural defects in cilia.Normal gene product. The ciliary dynein axonemal heavy chain 11 is a 4,523-amino acid protein that functions as a microtubule-dependent motor ATPase involved in ciliary motility. The C-terminal region that comprises the globular head contains six conserved 6 p-loop domains and a conserved microtubule-binding site [Bartoloni et al 2002]. In the mouse, the orthologous gene (lrd or Dnah11) is involved in left-right axis determination.Abnormal gene product. Ciliary dynein axonemal heavy chain 11 localizes to the outer dynein arms; however, the structure of respiratory ciliary dynein arms from individuals with PCD caused by DNAH11 mutations was normal. In addition, immunofluorescent analysis using antibodies against DNAH9 and DNAH5 (both heavy chain dyneins) of biopsies from individuals with PCD caused by mutation of DNAH11 shows a pattern similar to the control pattern, thereby indicating that mutations in DNAH11 do not lead to outer dynein arm defects [Schwabe et al 2008]. Multiple splice site mutations leading to aberrant expression have been described [Knowles et al 2012].Table 8. Selected DNAH11 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.12384C>Gp.Tyr4128XNM_003777​.3
NP_003768​.2c.13552_13608del57p.Ala4518_Ala4523delinsGlnc.8554C>Tp.Arg2852XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). DNAI2 (CILD9)Normal allelic variants. DNAI2 comprises 14 exons and encodes a 605-amino acid protein.Pathologic allelic variants. See Table 9. Three homozygous DNAI2 mutations are described in three unrelated families with PCD [Loges et al 2008]. Two are splice site mutations and one is a nonsense mutation.Table 9. Selected DNAI2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change
(Alias ¹)Reference Sequencesc.1494+1G>C
(IVS11+1G>C)(p.Ile116Glyfs*54)NM_023036​.3
NP_075462​.3c.346-3T>G
(IVS3-3T>G)--c.787C>Tp.Arg263XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. Dynein axonemal intermediate chain 2 is paralogous to DNAI1 and belongs to the large family of motor proteins [Pennarun et al 2000]. It contains five conserved WD (Trp-Asp) repeat regions at the carboxy-terminal portion of the gene. Abnormal gene product. The splice mutation c.1494+1G>C led to an in-frame skipping of exon 11 with predicted loss of 49 amino acid residues. Another splice mutation, c.346-3T>G, led to the skipping of exon 4 resulting in an out-of-frame fusion of exons 3 and 5 with a predicted mutant protein (p.Ile116Glyfs*54). Mutations in DNAI2 lead to the defective outer dynein arms seen by ciliary ultrastructural analysis. In addition, immunofluorescent analysis revealed absence of DNAI2 protein from the entire ciliary axoneme from individuals with biallelic DNAI2 mutations [Loges et al 2008]. DNAAF2 (C14orf104, KTU, PF13) (CILD10)Normal allelic variants. DNAAF2 (previously known as C14orf104, KTU, or PF13) comprises three exons. Pathologic allelic variants. See Table 10. Two homozygous truncating mutations have been described in persons with PCD: a nonsense mutation (p.Ser8X) and a frameshift mutation (p.Gly406Argfs*90).Table 10. Selected DNAAF2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change
(Alias ¹)Reference Sequencesc.1214_1215insACGATACCTGCGTGGCp.Gly406Argfs*90
(Gly406ArgFs*89) NM_018139​.2
NP_060609​.2c.23C>Ap.Ser8XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. Kintoun (previously known as ktu) is a 837-amino acid cytoplasmic protein thought to be involved in the pre-assembly of dynein arm complexes in the cytoplasm before they are transported to the ciliary compartment [Omran et al 2008]. Two alternatively spliced isoforms are described, one of full length and the other lacking in-frame exon 2.Abnormal gene product. Ultrastructural analysis of cilia from persons with PCD caused by mutation of DNAAF2 (C14orf104, KTU, PF13) showed absence of the outer and inner dynein arms. Ciliary immunofluorescent analysis supports these findings: antibodies to DNAH5 and DNAI2 (outer dynein arm proteins) showed no staining in the distal ciliary axoneme and DNALI1 antibodies (inner dynein arm protein) showed no staining throughout the entire ciliary axoneme [Omran et al 2008].RSPH4A (CILD11) Normal allelic variants. RSPH4A (RSHL3) comprises six exons. Pathologic allelic variants. See Table 11. Three RSPH4A mutant alleles are described; all are truncating mutations [Castleman et al 2009].Table 11. Selected RSPH4A Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.325C>Tp.Gln109XNM_001010892​.2
NP_001010892​.1c.460C>Tp.Gln154X c.1468C>Tp.Arg490XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. RSPH4A encodes radial spoke head 4 homolog A, a protein of 716 amino acids that regulates dynein-induced motility and governs axonemal waveform motion [Castleman et al 2009]. Abnormal gene product. Ultrastructural analysis showed ciliary transposition defects with either 9+0 or 8+1 microtubule configurations [Castleman et al 2009].RSPH9 (CILD12)Normal allelic variants. RSPH9 comprises five exons. Pathologic allelic variants. See Table 12. The one mutant allele described, p.Lys268del, caused an in-frame deletion of one amino acid in two unrelated Bedouin families with PCD [Castleman et al 2009].Table 12. Selected RSPH9 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.801_803delGAAp.Lys268delNM_152732​.3
NP_689945​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. RSPH9 encodes radial spoke head protein 9 homolog, a 276-amino acid protein that regulates dynein-induced motility and governs axonemal waveform motion [Castleman et al 2009]. Abnormal gene product. Ultrastructural analysis from one family with PCD revealed a mixture of 9+2 and 9+0 microtubular configuration, while the other family had normal dynein arm structure [Castleman et al 2009].DNAAF1 (CILD13)Normal allelic variants. DNAAF1 (LRRC50) comprises 12 exons and encodes a 725-amino acid protein.DNAAF1 emerged as a potential candidate gene for PCD based on the motility defects in the orthologous gene in Chlamydomonas (biflagellate unicellular algae) leading to outer and inner dynein arms defects. Independently, Loges et al [2009] considered DNAAF1 to be a candidate based on linkage analysis and a candidate gene approach. They subsequently identified a homozygous loss-of-function mutation in the family for which linkage had been established. Pathologic allelic variants. Duquesnoy et al [2009] identified seven mutant alleles in four affected individuals. Of these alleles, five were loss-of-function mutations; one was a large 5376-bp deletion involving portions of introns as well as an in-frame deletion of 76 amino acid residues (p.Glu42_Lys117del); and one was a missense mutation. Of note, the missense mutation (p.Leu175Arg), present in the homozygous state, is located in the LRR domain which is believed to be involved in protein-protein interaction. Functional analyses were performed using the Chlamymodonas motility defective null mutant known as oda7-1 that carries deletion of oda7 (ortholog of DNAAF1). Expression of wild type oda7 restored the wild type motility in the mutant oda7-1, whereas no phenotypic rescue occurred with expression of the Leu92Arg mutant oda7 (equivalent to Leu175Arg in DNAAF1), suggesting that Leu175Arg is likely a mutation. In another study, Loges et al [2009] observed five mutant DNAAF1 alleles from six individuals: one a homozygous frameshift mutation (p.Pro451Alafs*5); one a heterozygous nonsense (p.Arg271X) mutation; and three deletions (of 11 kb, 220 kb, and 640 kb) that involved multiple genes including DNAAF1. Normal gene product. DNAAF1 is 725-amino acid protein which encodes a member of the superfamily of leucine-rich-repeat (LRR) containing protein that is thought to play a role in cytoplasmic preassembly and/or targeting of dynein-arm complexes [Loges et al 2009]. In Chlamydomonas, oda7 (ortholog of DNAAF1) resides primarily in cytoplasm with very low levels present in the axoneme [Duquesnoy et al 2009].Abnormal gene product. Mutations in DNAAF1 lead to the combined defects of outer+inner dynein arms that are seen by ciliary ultrastructural analysis. Immunofluorescent analysis revealed absence of the proteins DNAH5, DNAH9, DNAI2 (outer dynein arms), and DNALI1 (inner dynein arms) [Loges et al 2009].CCDC39 (CILD14)Normal allelic variants. CCDC39 comprises 20 exons and encodes a 941-amino acid protein. In bobtail dogs mutations in CCDC39 causes PCD with ultrastructural defects including eccentric central pair, abnormal radial spokes and nexin links, reduced number of inner dynein arms, and displacement of the outer doublet consistent with axonemal disorganization; thus, the human ortholog, CCDC39, was considered a potential candidate.Pathologic allelic variants. Mutations in CCDC39 were found in 19 of 50 unrelated families with axonemal disorganization: 18 had biallelic mutations that were either loss-of-function or splice-site mutations. A total of 15 different mutations were observed: seven frameshift, four nonsense, and four splice site; of these 15, 11 were private and four were observed in unrelated individuals. Microsatellite marker testing flanking CCDC39 showed that three of the four shared mutations (p.Thr358Glnfs*3, p.Ser786Ilefs*33, and c.357+1G>C) also had a shared haplotype, suggesting a founder effect. One mutation (p.Glu731Asnfs*31) had a shared haplotype in three families, but a distinct haplotype in one family suggested a recurrent mutational event [Merveille et al 2011]. Normal gene product. CCDC39 encodes the axonemal protein CCDC39 which contains coiled-coil domains. Immunofluorescent analysis of respiratory epithelial cells from a healthy individual localized CCDC39 along the entire length of the axoneme as well as in the apical cytoplasm.Abnormal gene product. In individuals who harbor mutations in CCDC39, ciliary ultrastructural analysis shows a variety of defects including abnormal radial spokes and nexin links, reduced number of inner dynein arms, and the displacement of outer doublets, consistent with axonemal disorganization; immunofluorescent analysis reveals that CCDC39 protein is absent from the ciliary axoneme and markedly reduced in the apical cytoplasm. Immunofluorescent analysis using antibodies specific for outer dynein arms (DNAH5, DNAI2 and DNAH9), inner dynein arms (DNALI1), and dynein regulatory complex (GAS11) revealed that localization to the outer dynein arms was unchanged, whereas inner dynein arms protein was absent and GAS11 was absent from the entire length of axoneme but was present in the cytoplasm. These results were consistent with the ultrastructural findings [Merveille et al 2011].CCDC40 (CILD15)Normal allelic variants. CCDC40 comprises 20 exons and encodes a 1142-amino acid protein.Based on the similarity of human PCD phenotype with mouse and zebra fish phenotype, the human ortholog CCDC40 was considered as a candidate gene.Pathologic allelic variants. Mutations in CCDC40 were found in 14 of 24 unrelated families with axonemal disorganization. Of these 14 families, 13 had biallelic mutations. There were 14 unique alleles, including insertions/deletions (6), nonsense (6) and splice site (1) mutations, and a large deletion (1). Of these 14 unique mutations, 12 were private and two occurred in unrelated individuals. Whether the shared mutations reflected a founder effect was not clear: one mutation (p.Ala83Valfs*82) was present on at least one allele in seven unrelated persons; the other mutation (p.Arg942MetinsTrp) was observed in two unrelated persons [Becker-Heck et al 2011]. Normal gene product. CCDC40 encodes the axonemal protein CCDC40 which contains coiled-coil domains. Immunofluorescent analysis from healthy mice using Ccdc40 polyclonal antibody showed that the protein is localized to the 9+2 respiratory axonemal structure from multiciliated tracheal cells and is not readily detected in the 9+0 nodal cilium. Abnormal gene product. Similar to CCDC39, ciliary ultrastructural analysis from individuals who harbor mutations in CCDC40 showed a variety of defects including abnormal radial spokes and nexin links, reduced number of inner dynein arms, and displacement of outer doublets, consistent with axonemal disorganization. Immunofluorescent analysis using antibodies specific for outer dynein arms (DNAH5, DNAI2, and DNAH9), inner dynein arms (DNALI1), and dynein regulatory complex (GAS11) revealed findings similar to those for CCDC39 mutant cilia, i.e. localization to the outer dynein arms was unchanged, whereas inner dynein arms protein was absent and GAS11 was absent from the axoneme. These results were consistent with the ultrastructural findings. In addition, CCDC39 was also absent in all persons with CCDC40 mutations suggesting that CCDC40 may be required for axonemal recruitment of CCDC39 [Becker-Heck et al 2011]. Immunofluorescent analysis from mice with a Ccdc40 homozygous mutation showed loss of Ccdc40 localization in the tracheal cells. DNAL1 (CILD16)Normal allelic variants. DNAL1 comprises eight exons and encodes a 190-amino acid protein.In homozygosity mapping studies in two unrelated inbred families with PCD of Bedouin origin, Mazor et al [2011] identified a linked locus on chromosome 14 that included DNAL1, which encodes the axonemal dynein light chain of outer dynein arms.Pathologic allelic variants. The missense mutation p.Asn150Ser was identified in two unrelated Bedouin families. The parents of the probands were carriers. The allele frequency in control chromosome from Bedouins was 0.004 (1 of 248 chromosomes analyzed). Asn150 is an evolutionarily conserved residue in the leucine-rich-repeat (LRR) consensus domain [Mazor et al 2011]. Normal gene product. DNAL1 encodes the dynein axonemal light chain 1 protein of outer dynein arms. It is a member of leucine-rich-repeat (LRR) subclass defined by SDS22+ (which contains 22 residue repeats). Co-immunoprecipitation assay showed that DNAL1 interacts with DNAH5 [Horvath et al 2005]. Abnormal gene product. Ciliary ultrastructural analysis of those with the missense mutation p.Asn150Ser revealed outer dynein arm defects. In silico analysis using the SWISS-MODEL tool predicted that alteration of the conserved Asn150 disturbs the sixth LRR consensus domain. Immunoblotting showed instability and reduced levels of the mutant DNAL1 protein [Mazor et al 2011].CCDC103 (CILD17)Normal allelic variants. CCDC103 comprises four exons and encodes a 242-amino acid protein.Pathologic allelic variants. See Table 13. Two mutant alleles have been described. One truncating mutation that is probably a founder mutation is described in three unrelated consanguineous families of Pakistani origin and a missense mutation is described in two unrelated families of Pakistani origin as well in a German family [Panizzi et al 2012].Table 13. Selected CCDC103 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.383_384insGp.Gly128fs25*NM_213607​.2
NP_998772​.1c.461A>Cp.His154ProSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. CCDC103 encodes coiled-coil domain-containing protein 103, a protein of 242 amino acids with N-terminal coiled-coil domain. It is expressed in the cytoplasm of the respiratory epithelial cells [Panizzi et al 2012]. Abnormal gene product. Mutations in CCDC103 lead to the defective outer+inner dynein arms as observed by ciliary ultrastructural analysis. In addition, immunofluorescent analysis showed that DNAH5, DNAI2, and DNAH9 (markers for ODA) were absent from the distal part of cilia from an individual with biallelic CCDC103 mutations, consistent with the abnormal assembly of ODA [Panizzi et al 2012].HEATR2 (CILD18)Normal allelic variants. HEATR2 comprises 13 exons and encodes a 855-amino acid protein.Pathologic allelic variants. See Table 14. One missense mutant allele in HEATR2 is described in an Amish Mennonite kindred [Horani et al 2012].Table 14. Selected HEATR2 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.2384T>Cp.Leu795ProNM_017802​.3
NP_060272​.3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. HEATR2 encodes heat repeat-containing 2, a protein of 855 amino acids that belongs to a family of ten uncharacterized proteins. The HEAT repeat is related to the armadillo/beta-catenin-like repeats, found in many eukaryotes and prokaryotes. In addition, immunofluorescent analysis from a healthy person showed that HEATR2 is present in the cytoplasm of the ciliated cells [Kott et al 2012].Abnormal gene product. Mutations in HEATR2 lead to the defective outer+inner dynein arms as observed by ciliary ultrastructural analysis in a person with biallelic mutations. In addition, immunofluorescent analysis revealed absence of HEATR2 proteins in the cytoplasm of the ciliated cells from individuals with biallelic HEATR2 mutations [Kott et al 2012].LRRC6 (CILD19)Normal allelic variants. LRRC6 comprises 12 exons and encodes a 466-amino acid protein.Pathologic allelic variants. See Table 15. Five LRRC6 mutant alleles are described; all are truncating mutations [Kott et al 2012].Table 15. Selected LRRC6 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.598_599delAAp.Lys200Glufs*3NM_012472​.3
NP_036604​.2c.574C>Tp.Gln192*c.576dupAp.Glu193Argfs*4c.220G>Cp.Ala74Proc.436G>Cp.Asp146HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. LRRC6 encodes leucine-rich repeat-containing protein 6 (also referred to as protein TILB homolog), a protein of 466 amino acids with five N-terminal LRR motifs containing the consensus sequence which defines the SDS22-like subfamily of LRR-containing proteins. LRRC6 also contains LRR cap, a coiled-coil domain, a polylysine motif, and a C-terminal alpha-crystallin-p23-like domain. In addition, immunofluorescent analysis from a healthy person showed LRRC6 to be localized to the cytoplasm of the cell and the cilia [Kott et al 2012]. Abnormal gene product. Mutations in LRRC6 lead to the defective outer+inner dynein arms as observed by ciliary ultrastructural analysis. In addition, immunofluorescent analysis revealed absence of LRRC6 protein from the cell cytoplasm as well as ciliary axoneme from individuals with biallelic LRRC6 mutations [Kott et al 2012].