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Primary Ciliary Dyskinesia

Synonym: Immotile Cilia Syndrome

, PhD, FACMG, , MD, and , MD.

Author Information
, PhD, FACMG
Department of Pathology and Laboratory Medicine
Marsico Lung Institute
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
, MD
Department of Medicine
Pulmonary and Critical Care Medicine
Marsico Lung Institute
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
, MD
Department of Pediatrics
Marsico Lung Institute
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

Initial Posting: ; Last Update: September 3, 2015.

Summary

Clinical characteristics.

Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have ‘neonatal respiratory distress’ requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.

Diagnosis/testing.

The diagnosis of PCD can be established by clinical phenotype and by ciliary ultrastructural analysis or molecular genetic testing. About two thirds of probands can be diagnosed by the presence of biallelic pathogenic variants in one of the 32 genes known to be associated with PCD.

Management.

Treatment of manifestations: Aggressive measures to enhance clearance of mucus (chest percussion and postural drainage, oscillatory vest, breathing maneuvers to facilitate clearance of distal airways) and prompt antibiotic therapy for bacterial infections of the airways (bronchitis, sinusitis, and otitis media); consideration of lobectomy for localized bronchiectasis; lung transplantation for end-stage lung disease; sinus surgery for extensive sinus infections; consideration of PE tube placement for chronic otitis media; speech therapy and hearing aids as needed. Surgical intervention as needed for congenital heart disease. ICSI (intracytoplasmic sperm injection) or artificial insemination by donor sperm (AIDS) for male infertility.

Prevention of secondary complications: Routine immunizations (including influenza vaccine and pneumococcal vaccine) to prevent respiratory infections; education about infection control including attention to hand washing, avoidance of sick contacts, and proper cleaning/disinfecting of respiratory devices; early use of antibiotics for respiratory illnesses (directed by prior respiratory cultures).

Surveillance: Follow up by a pulmonologist to monitor lung function and pathogens in sputum cultures as well as to assess pulmonary disease extent/progression; for those with chronic otitis media, routine hearing evaluation until the teenage years.

Agents/circumstances to avoid: Cough suppressants; exposure to respiratory pathogens, tobacco smoke, and other air pollutants and respiratory irritants.

Genetic counseling.

PCD is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and therefore carry one allele with a pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Primary ciliary dyskinesia (PCD) is suggested by clinical findings that may include (but are not limited to) the following:

  • Chronic otosinopulmonary disease
    • Chronic wet 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
    • Chest CT scan showing bronchiectasis
    • Sinus radiograph with chronic pansinusitis
    • Chronic otitis media, most prominent in pre-school age
    • Neonatal respiratory distress, despite term gestation
    • Chronic nasal congestion dating from the newborn period
  • Situs abnormalities that can be any one of the following:
    • Laterality defects (mirror-image reversal of all visceral organs with no apparent physiologic consequences)
    • Situs ambiguous
    • 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 typically associated with bronchiectasis
  • Male infertility

Establishing the Diagnosis

The diagnosis of primary ciliary dyskinesia in a proband can be based on clinical findings and the presence of biallelic pathogenic variants in one of the 32 genes known to be associated with PCD (see Table 1A, Table 1B). If the diagnosis cannot be established with molecular genetic testing, ciliary analysis can be performed; however, it should be noted that an estimated 30% of individuals with PCD do not have ultrastructural abnormalities of the cilia, formerly the ‘gold standard’ for diagnosis. In many instances a panel of diagnostic tests may be required [Lucas & Leigh 2014].

When requesting molecular genetic testing for the diagnosis of PCD, clinicians need to bear in mind that the majority of pathogenic variants will be identified in genes included in Table 1A, that pathogenic variants are rarely seen in genes included in Table 1B, and that more than one third of individuals with well-characterized PCD do not have identifiable pathogenic variants in any of 32 known genes.

Molecular Genetic Testing

Molecular testing approaches can include serial single-gene testing, targeted analysis for pathogenic variants, use of a multi-gene panel, and genomic testing.

Serial single-gene testing is performed in the order in which pathogenic variants most commonly occur (Table 1A) (i.e., DNAH5, DNAH11, CCDC39, DNAI1, CCDC40, CCDC103, SPAG1, ZMYND10, ARMC4, CCDC151, DNAI2, RSPH1, CCDC114, RSPH4A, DNAAF1, DNAAF2, and LRRC6). Often testing of a gene begins with sequence analysis, followed by gene-targeted deletion/duplication analysis of that gene if only one pathogenic variant is identified.

Targeted analysis for pathogenic variants in a specific gene can be performed first in individuals of the following ethnicity/ancestry if appropriate:

    • p.Trp453Ter in DNAI2
    • p.Tyr245Ter in C21orf59
    • c.876_877delAT in CCDC65
  • Bedouin
    • p.Asn150Ser in DNAL1
    • p.Lys268del in RSPH9
  • Amish or Mennonite
    • p.Leu795Pro in DNAAF5 (formerly HEATR2)
    • c.10815delT in DNAH5
    • p.Gln1450Ter in DNAH5
    • c.48+2dupT in DNAI1
  • Faroe Islands. p.Lys308Ter in HYDIN
  • Irish Traveller
    • c.258_262dupGGCCC in CCNO
    • c.166dupC in RSPH4A
    • 3549-bp large deletion in DYX1C1
  • Northern Holland (Volendam). c.742G>A in CCDC114
  • UK-Pakistani
    • c.630delG in LRRC6
    • p.Gln154Ter in RSPH4A
    • c.383dupG in CCDC103
    • p.His154Pro in CCDC103
  • Hispanic from Puerto Rico. c.921+3_6delAAGT in RSPH4A

A multi-gene panel that includes some or all of the 32 genes known to be associated with PCD (see Table 1A, Table 1B) as well as other genes of interest (see Differential Diagnosis) may be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Genomic testing (when available) including whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq) may be considered if serial single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of PCD. For issues to consider in interpretation of genomic test results, click here.

Table 1A.

Molecular Genetics of Primary Ciliary Dyskinesia: Most Common Genetic Causes

Gene 1, 2Locus NameProportion of All PCD Attributed to This Gene
Observed (Identification of Biallelic Pathogenic Variants in Unrelated Affected Persons) 3, 4, 5Estimate of All PCD 6
DNAH5CILD3 15%-29%
DNAH11CILD7 6%-9%
CCDC39CILD14
  • 22/34 (65%) persons with inner dynein arm defects + axonemal disorganization [Blanchon et al 2012]
4%-9% 9
DNAI1CILD1 2%-10%
CCDC40CILD15 3%-4% 9
CCDC103CILD17 <4% 10
SPAG1CILD28 <4% 10
ZMYND10CILD22 <2%-4% 10
ARMC4CILD23 <3% 10, 12
CCDC151CILD30 <3% 10
DNAI2CILD9 2% 12
RSPH1CILD24 2% 14
CCDC114CILD20 <2% 10, 12
RSPH4ACILD11 1%-2% 14
DNAAF1 (LRRC50)CILD13 1%-2% 15
DNAAF2 (KTU)CILD10
  • 1/47 (2%) unrelated persons w/outer+inner dynein arm defects [Kott et al 2012]
<1%-2% 15
LRRC6CILD19 1% 15

Pathogenic variants of any one of the genes included in this table account for ≥1% of PCD.

1.

Genes are listed from most frequent to least frequent genetic cause of PCD.

2.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in the genes listed.

3.

Refers to all persons with PCD regardless of their underlying ciliary defects unless otherwise specified.

4.

The majority of pathogenic variants are detectable by sequence analysis. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

The following genes have had intragenic deletions or duplications reported: DNAH5, CCDC40, SPAG1, ZMYND10, ARMC4, and DNAAF1. Gene-targeted deletion/duplication analysis methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Some estimates are extrapolations based on defects in ciliary structure (see Ciliary Ultrastructural Analysis).

7.

24 of 65 (37%) with outer dynein arm defects [Hornef et al 2006]

8.

13 of 58 (22%) with normal ciliary ultrastructure [Knowles et al 2012]

9.

Axonemal disorganization with inner dynein arm defects accounts for ~14% of all PCD.

10.

Gene was screened in a large cohort in a single study. Percentage may be an overestimate if the study cohort was selected on the basis of prior molecular genetic testing results (i.e., individuals with biallelic pathogenic variants in previously known genes were excluded).

11.

10 of 63 (~<15%) with outer+inner dynein arm defect [Knowles et al 2013c]

12.

Outer dynein arm defects account for 38.5% of all PCD.

13.

2 of 47 (4%) with outer dynein arm defects [Loges et al 2008]

14.

Central complex defects account for 7% of all PCD.

15.

Outer+inner dynein arm defects account for ~10.5% of PCD.

Table 1B.

Molecular Genetics of Primary Ciliary Dyskinesia: Less Common Genetic Causes

Gene 1, 2, 3Locus NameComment
C21orf59CILD264 (<1%) of 295 4 unrelated persons with PCD 5 had biallelic pathogenic variants [Austin-Tse et al 2013].
CCDC65
(DRC2)
CILD272 (<1%) of 295 4 unrelated persons with PCD 5 had biallelic pathogenic variants [Austin-Tse et al 2013].
CCNOCILD2910 (~19%) of 54 4 unrelated persons with ciliary aplasia/oligoplasia had biallelic pathogenic variants [Wallmeier et al 2014]. This corresponds to <1% of all PCD 6.
DNAAF3CILD23/3 Arab or Pakistani families previously mapped to the region had homozygous pathogenic variants; no pathogenic variants were detected in 111 other families [Mitchison et al 2012].
DNAH12 sibs from Saudi Arabia (whose parents were consanguineous) were homozygous for the missense variant p.Lys1154Gln [Imtiaz et al 2015].
DNAH81 individual with PCD was homozygous for a pathogenic variant [Watson et al 2014].
DNAL1CILD16Individuals with PCD from 2 unrelated consanguineous families of Bedouin origin were homozygous for the pathogenic missense variant (p.Asn150Ser) [Mazor et al 2011].
DRC1
(CCDC164)
CILD213 families with nexin-link defects 7 had biallelic pathogenic variants [Wirschell et al 2013].
DYX1C1CILD2510 (<9%) of 106 4 unrelated persons with outer+inner dynein arm defects had biallelic pathogenic variants [Tarkar et al 2013]. This corresponds to <1% of all PCD 8.
DNAAF5 (HEATR2)CILD18
  • The missense founder pathogenic variant, p.Leu795Pro, was identified in individuals of Amish Mennonite ancestry [Horani et al 2012].
  • 2 Pakistani families with outer+inner dynein arm defects harbored biallelic pathogenic variants.
  • No pathogenic variants were detected in an additional 23 unrelated persons with PCD 5 tested [Diggle et al 2014].
HYDINCILD5
  • The nonsense founder variant (table 6) was identified in individuals with ancestry in the Faroe Islands.
  • An additional family with PCD had biallelic pathogenic variants [Olbrich et al 2012].
MCIDAS4 (<7%) of 60 4 unrelated persons with ciliary aplasia/oligoplasia had biallelic pathogenic variants [Boon et al 2014]. This corresponds to <1% of all PCD 6.
NME8
(TXNDC3)
CILD61/41 unrelated persons with PCD had a pathogenic nonsense variant in trans configuration with an intronic variant that was demonstrated to alter splicing [Duriez et al 2007].
RSPH35 (10%) of 48 unrelated persons with central apparatus9 and radial spoke defects had pathogenic variants [Jeanson et al 2015].
RSPH9CILD124/48 unrelated persons with central apparatus defects9 had pathogenic variants [Kott et al 2013]; none of 184 unrelated persons with PCD 5 [Ziętkiewicz et al 2012]. This corresponds to <1% of all PCD 9.

Pathogenic variants of any one of the genes listed in this table is reported in only a few families (i.e., <1% of PCD).

1.

Genes are listed in alphabetical order.

2.
3.

Click here (pdf) for information on allelic variants detected in the genes listed.

4.

Gene was screened in a large cohort in a single study. Percentage may be an overestimate if the study cohort was selected on the basis of prior molecular genetic testing results (i.e., individuals with biallelic pathogenic variants in previously known genes were excluded).

5.

Refers to all persons with PCD regardless of their underlying ciliary defect

6.

Ciliary aplasia/oligoplasia is a rare finding in all PCD.

7.

Nexin links (which are present between the outer microtubular doublets) are part of the dynein regulatory complex that is critical for axonemal bending.

8.

Outer+inner dynein arm defects account for ~10.5% of all PCD.

9.

Central apparatus defects account for 7% of all PCD.

Ciliary Ultrastructural Analysis

Transmission electron microscopy to identify ciliary ultrastructural defects 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]. Approximately 30% of individuals with a clinical phenotype strongly suggestive of PCD and low levels of nasal nitric oxide have normal ciliary ultrastructure (in many of whom the diagnosis has been confirmed by identification of biallelic pathogenic variants in one of the genes listed in Table 1A or Table 1B) [Knowles et al 2013a].

The dynein arm defects are often specific for the mutated gene. See Table 2 (pdf). The most prevalent of the defined ultrastructural defects in primary ciliary dyskinesia are the following (Figure 1) [Knowles et al 2013a, Davis et al 2015]:

Figure 1. . Cross section of the cilia 
A.

Figure 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 (more...)

  • Shortening and/or absence of outer dynein arms alone (~55% with defined ultrastructural defects, or 38.5% of all PCD)
  • Shortening or absence of both outer and inner dynein arms (~15% with defined ultrastructural defects, or 10.5% of all PCD)
  • Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (5%-20% of defined ultrastructural defects, or ~14% of all PCD)
  • Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (~10% of defined ultrastructural defects, or 7% of all PCD)
  • Shortening and/or absence of inner dynein arms alone (rare)
  • Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare).

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 pathogenic variants in DNAH11 (locus name CILD7).

For information on ciliary ultrastructural findings by mutated gene, see Table 2 (pdf).

For information on other tests under evaluation as screening or supportive tests for PCD, click here (pdf).

Clinical Characteristics

Clinical Description

Primary ciliary dyskinesia (PCD) is associated with: (1) abnormal ciliary structure, function, and biogenesis defects that result in retention of mucus and bacteria in the respiratory tract and lead to chronic otosinopulmonary disease; and (2) abnormal flagellar structure resulting in abnormal sperm motility.

Pulmonary disease. The progression and severity of lung disease varies among individuals [Marthin et al 2010]. Some of this variability reflects genotype (see Genotype-Phenotype Correlations).

More than 75% of full-term neonates with PCD have ‘neonatal respiratory distress’ requiring supplemental oxygen for days to weeks; however, few are diagnosed with PCD at this age [Noone et al 2004, Ferkol & Leigh 2006, Mullowney et al 2014].

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, Davis et al 2015].

Chronic airway infection results in bronchiectasis that may be apparent in some young children and is almost uniformly present in adulthood [Noone et al 2004, Brown et al 2008, Davis et al 2015].

A subset of adults with chronic airway infection have calcium deposition in the lung and, as a result, 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 et al 2009].

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. Virtually all males with PCD are infertile as a result of abnormal sperm motility.

Some women with PCD have normal fertility; others have impaired fertility and are at 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 40%-50% of individuals with PCD.
  • Heterotaxy (also called "situs ambiguous") is present in approximately 12% of individuals with PCD [Kennedy et al 2006, Shapiro et al 2014a]. 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 on rare occasion in individuals with PCD and may reflect dysfunctional ependymal cilia [Wessels et al 2003, Kosaki et al 2004].

Genotype-Phenotype Correlations

Genotype-phenotype correlation for the majority of pathogenic variants is not available. See Table 2 (pdf) for information on correlations between mutated gene and ciliary defects observed. For example:

  • Children with biallelic pathogenic variants in CCDC39 or CCDC40 (associated with microtubular disorganization plus inner dynein arm defects) have worse lung function, more bronchiectasis of chest CT, and worse weight gain than children with biallelic pathogenic variants in genes associated with outer dynein arm defects alone or both outer+inner dynein arm defects [Davis et al 2015].
  • Individuals with biallelic pathogenic variants in RSPH1 have milder lung disease than age-matched individuals with biallelic pathogenic variants in genes associated with outer dynein arm defects [Knowles et al 2014].
  • Individuals with PCD harboring biallelic pathogenic variants in CCDC65, DRC1, HYDIN, RSPH1, RSPH4A, and RSPH9 may not have ultrastructural findings that are discrete/clear enough to distinguish from normal.
  • Individuals harboring pathogenic variants in the genes that encode the components of central apparatus or radial spokes (e.g., RSPH1, RSPH3, RSPH4A, RSPH9, and HYDIN) do not have situs abnormalities.

Nomenclature

Terms used in the past to describe the condition currently known as primary ciliary dyskinesia (PCD) include dyskinetic cilia syndrome and acilia syndrome.

PCD associated with situs inversus totalis is known as Kartagener syndrome.

Prevalence

The incidence of PCD, estimated at 1:16,000 individuals in Norway and Japan, was extrapolated from radiographic surveys associating dextrocardia with clinical evidence of bronchiectasis [Torgersen 1950, Katsuhara et al 1972]. Based on these figures, the total number of individuals with PCD in the United States is estimated at 12,000 to 17,000.

The incidence may be higher in population isolates with a high rate of consanguinity. For example:

  • PCD incidence is 1:400 in a Volendam population residing in a fishing village of North Holland [Onoufriadis et al 2013].
  • Using ciliary beat frequency measurements, PCD prevalence was found to be 1:2265 in a South Asian (mainly Pakistani) population in the UK [O’Callaghan et al 2010].
  • High prevalence of PCD has been seen in Amish and Mennonite communities in the US [Ferkol et al 2013].

Differential Diagnosis

Chronic sinopulmonary disease and bronchiectasis. Appropriate studies to exclude the following disorders should be performed during the evaluation for primary ciliary dyskinesia (PCD):

  • Immunodeficiency, such as immunoglobulin G (IgG) subclass deficiency
  • Allergies
  • Gastroesophageal reflux disease
  • 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 genes associated with PCD, 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 12% of individuals with PCD have heterotaxy [Kennedy et al 2006, Shapiro et al 2014a].

Occasionally, pathogenic variants in RPGR (involved in X-linked retinitis pigmentosa) have been identified in males with retinitis pigmentosa cosegregating with PCD [Bukowy-Bieryłło et al 2013]; see also Moore et al [2006] and references within.

A pathogenic variant 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].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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.)
  • Clinical genetics consultation

Treatment of Manifestations

At 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 [Sha et al 2014].

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 Complications

Appropriate preventive measures:

  • Routine immunizations (including influenza vaccine and pneumococcal vaccine) to prevent respiratory infections
  • Education about infection control including attention to hand washing, avoidance of sick contacts, proper cleaning/disinfecting respiratory devices, and early use of antibiotics for respiratory illnesses (directed by prior respiratory cultures)

Surveillance

Follow up by a pulmonologist to monitor lung function and pathogens in sputum cultures as well as to assess pulmonary disease extent/progression is indicated.

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 Avoid

Cough 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 Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known, a rigorous clinical history and physical examination accompanied by chest imaging and nasal nitric oxide measurements can be used to clarify the disease status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For a female with PCD, any pulmonary infections and pulmonary functional status should be rigorously evaluated by an expert in PCD (or cystic fibrosis) to define the risk associated with child bearing.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Primary ciliary dyskinesia (PCD) is inherited in an autosomal recessive manner.

Note: Although other modes of inheritance have been suggested in rare reports [Narayan et al 1994, Badano et al 2006, Moore et al 2006, Bukowy-Bieryłło et al 2013], autosomal dominant inheritance has not been reported in any subsequent publications or observed in the authors’ experience with more than 500 patients participating in the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC).

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PCD-related pathogenic variant).
  • Heterozygotes are asymptomatic and are not at risk of developing PCD.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (carrier), and a 25% chance of being unaffected and not a heterozygote.
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with PCD are obligate heterozygotes (carriers of a PCD-related pathogenic variant).

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier of a PCD-related pathogenic variant.

Heterozygote (Carrier) Detection

Carrier testing for at-risk relatives requires prior identification of the PCD-related pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PCD-related pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for PCD are possible options.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
    Cystic Fibrosis / Pulmonary Research & Treatment Center
    Marsico Lung Institute
    7215 Marsico Hall
    CB #7248
    Chapel Hill NC 27599-7248
    Fax: 919-966-7524; 919-843-5309
    Email: godwine@med.unc.edu; kelli_sullivan@med.unc.edu
  • Kartagener's Syndrome and Primary Ciliary Dyskinesia Foundation
    Lärchenweg 14
    Ettlingen 76275
    Germany
    Phone: 07243 39338
    Email: info@kartagener-syndrome.de; rerafra@web.de
  • PCD (Primary Ciliary Dyskinesia) Foundation
    10137 Portland Avenue South
    Minneapolis MN 55420
    Phone: 952-303-3155; 612-386-1261
    Fax: 952-303-3178
    Email: info@pcdfoundation.org
  • Primary Ciliary Dyskinesia Family Support Group
    15 Shuttleworth Grove
    Wavendon Gate Milton Keynes MK7 7RX
    United Kingdom
    Phone: 01908 281635
    Email: chair@pcdsupport.org.uk
  • American Lung Association
    1301 Pennsylvania Avenue Northwest
    Washington DC 20004
    Phone: 800-548-8252 (Toll-free HelpLine); 800-586-4872 (toll-free); 202-785-3355
    Fax: 202-452-1805
    Email: info@lungusa.org
  • Ciliopathy Alliance
    United Kingdom
    Phone: 44 20 7387 0543

Molecular Genetics

Information 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 Databases

Locus NameGeneChromosome LocusProteinLocus SpecificHGMD
CILD1DNAI19p13​.3Dynein intermediate chain 1, axonemalDNAI1 @ LOVDDNAI1
CILD2DNAAF319q13​.42Dynein assembly factor 3, axonemal DNAAF3
CILD3DNAH55p15​.2Dynein heavy chain 5, axonemalDNAH5 @ LOVDDNAH5
CILD4Unknown15q13​.1-q15.1Unknown
CILD5HYDIN16q22​.2Hydrocephalus-inducing protein homolog HYDIN
CILD6NME87p14​.1Thioredoxin domain-containing protein 3NME8 databaseNME8
CILD7DNAH117p15​.3Dynein heavy chain 11, axonemalDNAH11 @ LOVDDNAH11
CILD8Unknown15q24-q25Unknown
CILD9DNAI217q25​.1Dynein intermediate chain 2, axonemalDNAI2 @ LOVDDNAI2
CILD10DNAAF214q21​.3Protein kintounDNAAF2 databaseDNAAF2
CILD11RSPH4A6q22​.1Radial spokehead-like protein 3RSPH4A databaseRSPH4A
CILD12RSPH96p21​.1UPF0685 protein C6orf206RSPH9 databaseRSPH9
CILD13DNAAF116q24​.1Dynein assembly factor 1, axonemalDNAAF1 @ LOVDDNAAF1
CILD14CCDC393q26​.33Coiled-coil domain-containing protein 39CCDC39 @ LOVDCCDC39
CILD15CCDC4017q25​.3Coiled-coil domain-containing protein 40CCDC40 @ LOVDCCDC40
CILD16DNAL114q24​.3Dynein light chain 1, axonemal DNAL1
CILD17CCDC10317q21​.31Coiled-coil domain-containing protein 103 CCDC103
CILD18DNAAF57p22​.3Dynein assembly factor 5, axonemal DNAAF5
CILD19LRRC68q24​.22Protein TILB homolog LRRC6
CILD20CCDC11419q13​.33Coiled-coil domain-containing protein 114 CCDC114
CILD21DRC12p23​.3Dynein regulatory complex protein 1 DRC1
CILD22ZMYND103p21​.31Zinc finger MYND domain-containing protein 10 ZMYND10
CILD23ARMC410p12​.1Armadillo repeat-containing protein 4 ARMC4
CILD24RSPH121q22​.3Radial spoke head 1 homolog RSPH1
CILD25DYX1C115q21​.3Dyslexia susceptibility 1 candidate gene 1 proteinDYX1C1 databaseDYX1C1
CILD26C21orf5921q22​.11UPF0769 protein C21orf59 C21orf59
CILD27CCDC6512q13​.12Coiled-coil domain-containing protein 65 CCDC65
CILD28SPAG18q22​.2Sperm-associated antigen 1 SPAG1
CILD29CCNO5q11​.2Cyclin-O CCNO
CILD30CCDC15119p13​.2Coiled-coil domain-containing protein 151 CCDC151
DNAH13p21​.1Dynein heavy chain 1, axonemal DNAH1
DNAH86p21​.2Dynein heavy chain 8, axonemal DNAH8
MCIDAS5q11​.2Multicilin MCIDAS
RSPH36q25​.3Radial spoke head protein 3 homolog RSPH3

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

244400CILIARY DYSKINESIA, PRIMARY, 1; CILD1
603332DYNEIN, AXONEMAL, HEAVY CHAIN 1; DNAH1
603335DYNEIN, AXONEMAL, HEAVY CHAIN 5; DNAH5
603337DYNEIN, AXONEMAL, HEAVY CHAIN 8; DNAH8
603339DYNEIN, AXONEMAL, HEAVY CHAIN 11; DNAH11
603395SPERM-ASSOCIATED ANTIGEN 1; SPAG1
604366DYNEIN, AXONEMAL, INTERMEDIATE CHAIN 1; DNAI1
605483DYNEIN, AXONEMAL, INTERMEDIATE CHAIN 2; DNAI2
606763CILIARY DYSKINESIA, PRIMARY, 2; CILD2
607070ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 10; ZMYND10
607421THIOREDOXIN DOMAIN-CONTAINING PROTEIN 3; TXNDC3
607752CYCLIN O; CCNO
608644CILIARY DYSKINESIA, PRIMARY, 3; CILD3
608646CILIARY DYSKINESIA, PRIMARY, 4; CILD4
608647CILIARY DYSKINESIA, PRIMARY, 5; CILD5
608706DYX1C1 GENE; DYX1C1
609314RADIAL SPOKE HEAD 1, CHLAMYDOMONAS, HOMOLOG OF; RSPH1
610062DYNEIN, AXONEMAL, LIGHT CHAIN 1; DNAL1
610812HYDROCEPHALUS-INDUCING, MOUSE, HOMOLOG OF; HYDIN
610852CILIARY DYSKINESIA, PRIMARY, 6; CILD6
611088COILED-COIL DOMAIN-CONTAINING PROTEIN 65; CCDC65
611884CILIARY DYSKINESIA, PRIMARY, 7; CILD7
612274CILIARY DYSKINESIA, PRIMARY, 8; CILD8
612444CILIARY DYSKINESIA, PRIMARY, 9; CILD9
612517DYNEIN, AXONEMAL, ASSEMBLY FACTOR 2; DNAAF2
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
614086MULTICILIATE DIFFERENTIATION AND DNA SYNTHESIS-ASSOCIATED CELL CYCLE PROTEIN; MCIDAS
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; CILD19
615038COILED-COIL DOMAIN-CONTAINING PROTEIN 114: CCDC114
615067CILIARY DYSKINESIA, PRIMARY, 20; CILD20
615288DYNEIN REGULATORY COMPLEX, SUBUNIT 1, CHLAMYDOMONAS, HOMOLOG OF; DRC1
615294CILIARY DYSKINESIA, PRIMARY, 21; CILD21
615408ARMADILLO REPEAT-CONTAINING PROTEIN 4; ARMC4
615444CILIARY DYSKINESIA, PRIMARY, 22; CILD22
615451CILIARY DYSKINESIA, PRIMARY, 23; CILD23
615481CILIARY DYSKINESIA, PRIMARY, 24; CILD24
615482CILIARY DYSKINESIA, PRIMARY, 25; CILD25
615494CHROMOSOME 21 OPEN READING FRAME 59; C21ORF59
615500CILIARY DYSKINESIA, PRIMARY, 26; CILD26
615504CILIARY DYSKINESIA, PRIMARY, 27; CILD27
615505CILIARY DYSKINESIA, PRIMARY, 28; CILD28
615872CILIARY DYSKINESIA, PRIMARY, 29; CILD29
615876RADIAL SPOKE HEAD 3, CHLAMYDOMONAS, HOMOLOG OF; RSPH3
615956COILED-COIL DOMAIN-CONTAINING PROTEIN 151; CCDC151
616037CILIARY DYSKINESIA, PRIMARY, 30; CILD30

Molecular Genetic Pathogenesis

Cilia, 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, 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 motile cilia have been associated with primary ciliary dyskinesia (PCD)/Kartagener syndrome, and defects in “primary” (sensory) cilia have been associated with several human disorders including 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, function, and biogenesis of cilia of the respiratory tract and flagella of sperm. Absent (or shortened) dynein arms occur in approximately 55% of individuals who have defined ultrastructural defects; approximately 10% have defective central complex or radial spoke or nexin links (which are present between the outer microtubular doublets and are part of the dynein regulatory complex that is critical for axonemal bending). Some individuals with PCD (~30%) have no apparent ciliary ultrastructural defects [Knowles et al 2013a, Davis et al 2015].

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.

Thus far, pathogenic variants in 32 genes causing autosomal recessive PCD have been identified (see Table A). Many genes have had few pathogenic variants reported. Characterization of an affected individual’s cilia by transmission electron microscopic analysis (see Table 2), immunofluorescent analysis, and/or high-speed videomicroscopic analysis may help to further interpret the clinical significance of allelic variants otherwise classified as variants of uncertain significance.

Note: Details on the commonly mutated genes (i.e., those that account for >1% of PCD; see Table 1A) are provided below, ordered by locus name.

Click here (pdf) for details on the less commonly mutated genes (i.e., those that account for <1% of PCD; see Table 1B).

For a detailed summary of gene and protein information for the genes below, see Table A, Gene.

DNAI1 / CILD1

Gene structure. DNAI1 comprises 20 exons.

Pathogenic variants. See Table 3. Based on a large study, 15% of pathogenic variants identified are missense; the remaining are insertions, deletions, and nonsense and splice site variants [Zariwala et al 2006]. Approximately one third of pathogenic variants occur in exons 13, 16, and 17, the conserved WD (Trp-Asp amino acid) repeat region of the gene.

Pathogenic variants that appeared in two or more unrelated families include the pathogenic variants 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 pathogenic variant accounts for approximately 55% of mutant alleles; mRNA studies showed that 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]. Microsatellite analysis indicates that c.48+2_3insT had a single origin [Zariwala et al 2006]. This variant has been observed in individuals from the Amish community [Ferkol et al 2013].

The splice site pathogenic variant c.1490G>A at the beginning of exon 16 causes the in-frame deletion of exons 15 and 16.

The pathogenic variant 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.

DNAI1 Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias) 1
Predicted Protein ChangeReference Sequences
c.48+2dupT
(c.48+2_3insT)
(IVS1+2_3insT)
(219+3insT)
p.Ser17ValfsTer12NM_012144​.2
NP_036276​.1
c.1490G>A
r.1402_1569del
p.Arg468_Lys523del
c.2001+1G>A
(IVS19+1G>A)
r.1819_2001del
p.Ala607_Lys667del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. DNAI1 encodes 699-amino acid protein ciliary dynein axonemal intermediate chain 1, which 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, DNAI1 is expressed only in tissues that contain motile cilia or flagella (including mouse embryonic node on E7.5 dpc).

Abnormal gene product. Pathogenic variants in DNAI1 lead to defective (absent, or only shortened) outer dynein arms, as seen by ciliary ultrastructural analysis.

DNAH5 / CILD3

Gene structure. DNAH5 comprises 79 exons with an alternative first exon.

Pathogenic variants. See Table 4. Of the total of 42 pathogenic variant alleles, approximately 47% clustered in five exons (34, 50, 63, 76, and 77) [Hornef et al 2006]. Fifteen percent of pathogenic variants are missense and the remaining are nonsense and splice site variants, insertions, and deletions [Hornef et al 2006].

One pathogenic variant (c.10815delT) in exon 63 has been found in Europeans and likely has a common origin based on haplotype analysis [Hornef et al 2006].

The variant p.Gln1450Ter was observed in individuals with PCD from the Amish and Mennonite communities [Ferkol et al 2013].

Two individuals with cri du chat syndrome and PCD had deletion of DNAH5 due to the chromosome 5p deletion and a DNAH5 pathogenic variant on the remaining allele [Shapiro et al 2014b].

In one individual, the pathogenic splice site variant p.Arg577Thr led to the out-of-frame deletion of exon 13 predicted to cause premature translation termination signals [Hornef et al 2006].

Table 4.

DNAH5 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.10815delTp.Pro3606HisfsTer23NM_001369​.2
NP_001360​.1
c.4348C>Tp.Gln1450Ter
c.1730G>Cp.Arg577Thr

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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. Pathogenic variants in DNAH5 lead to defective outer dynein arms.

DNAH11 (CILD7)

Gene structure. DNAH11 comprises 82 exons.

Pathogenic variants. See Table 5. Nonsense, frameshift, splice site, and missense pathogenic variants have been described [Knowles et al 2012].

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.Arg2852Ter pathogenic variant in DNAH11 and the p.Phe508del pathogenic variant in CFTR [Bartoloni et al 2002].

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 pathogenic variants (p.Tyr4128Ter and p.Ala4518_Ala4523delinsGln) [Schwabe et al 2008].

Table 5.

DNAH11 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.12384C>Gp.Tyr4128TerNM_001277115​.1
NP_001264044​.1
c.13552_13608del57p.Ala4518_Ala4523delinsGln
c.8554C>Tp.Arg2852Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The ciliary dynein axonemal heavy chain 11 is a 4,516-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 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 pathogenic variants is normal [Schwabe et al 2008].

DNAI2 (CILD9)

Gene structure. DNAI2 comprises 14 exons.

Pathogenic variants. See Table 6. Homozygous splice site and nonsense DNAI2 pathogenic variants have been described in unrelated families with PCD [Loges et al 2008, Knowles et al 2013b, Kim et al 2014].

In a large inbred Iranian Jewish kindred all affected individuals were homozygous for the splice site pathogenic variant c.1494+1G>C (IVS11+1G>C) which led to an in-frame skipping of exon 11 with predicted loss of 49 amino acid residues. [Loges et al 2008]. Another splice site pathogenic variant, 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 abnormal protein (p.Ile116GlyfsTer54).

The pathogenic variant p.Trp453Ter was identified in Ashkenazi Jewish individuals [Knowles et al 2013b].

Table 6.

Selected DNAI2 Variants

DNA Nucleotide Change
(Alias) 1
Predicted Protein ChangeReference Sequences
c.346-3T>G
(IVS3-3T>G)
r.346_467del
p.Ile116GlyfsTer54NM_023036​.4
NP_075462​.3
c.787C>Tp.Arg263Ter
c.1494+1G>C
(IVS11+1G>C)
r.1348_1494del
p.Val450_Ser498del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The ciliary dynein axonemal intermediate chain 2 (DNAI2) is a 605-amino acid protein paralogous to DNAI1 and belongs to the large family of motor proteins. It contains five conserved WD (Trp-Asp) repeat regions at the carboxy-terminal portion of the gene.

Abnormal gene product. Pathogenic variants in DNAI2 lead to defective outer dynein arms [Loges et al 2008].

DNAAF2 (C14orf104, KTU, PF13) (CILD10)

Gene structure. DNAAF2 (previously known as C14orf104, KTU, or PF13) comprises three exons.

Pathogenic variants. See Table 7. Three homozygous truncating pathogenic variants have been described in persons with PCD: p.Ser8Ter, c.31delG, and c.1199_1216dup16 (p.Gly406ArgfsTer90) [Omran et al 2008, Kim et al 2014].

Table 7.

DNAAF2 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.23C>Ap.Ser8TerNM_018139​.2
NP_060609​.2
c.31delGp.Glu11ArgfsTer5
c.1199_1214dup16p.Gly406ArgfsTer90

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal 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 have been described, one of full length and the other lacking in-frame exon 2.

Abnormal gene product. Pathogenic variants in DNAAF2 lead to absence of the outer and inner dynein arms [Omran et al 2008].

RSPH4A (CILD11)

Gene structure. RSPH4A (RSHL3) comprises six exons.

Pathogenic variants. See Table 8. Approximately 20 RSPH4A pathogenic variants, the majority of which are nonsense and frameshift variants, have been described. A common pathogenic variant (p.Gln154Ter) has been described in affected individuals of Pakistani origin from the UK [Castleman et al 2009]. A large study identified biallelic pathogenic variants in four of 184 (~2%) families of Eastern European descent [Ziętkiewicz et al 2012]. A truncating (c.166dupC) variant was identified in a sib-pair of Irish Travellers ancestry [Casey et al 2015].

Additionally, a common splice site variant (c.921+3_6delAAGT) has been identified in individuals of Hispanic ancestry from Puerto Rico [Daniels et al 2013]. Transcript analysis of this splice-site variant revealed out-of-frame deletion of exon 2 leading to premature translation of the termination signal (p.Tyr230GlnfsTer8).

Table 8.

RSPH4A Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.166dupCp.Arg56ProfsTer11NM_001010892​.2
NP_001010892​.1
c.460C>Tp.Gln154Ter
c.921+3_+6delAAGT
r.687_921del
p.Tyr230GlnfsTer8

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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. Pathogenic variants in RSPH4A lead to ciliary transposition defects with either 9+0 or 8+1 microtubule configurations [Castleman et al 2009].

DNAAF1 (CILD13)

Gene structure. DNAAF1 (LRRC50) comprises 12 exons.

Pathogenic variants. See Table 9. Loss-of-function pathogenic variants in DNAAFI cause disease [Loges et al 2009]. Duquesnoy et al [2009] identified seven pathogenic variant alleles in four affected individuals including five nonsense or frameshift variants; one large deletion of exons 2 and 3 (p.Glu42_Lys117del) and one missense pathogenic variant.

The missense pathogenic variant, 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 support p.Leu175Arg being a likely pathogenic variant [Duquesnoy et al 2009].

Loges et al [2009] observed five pathogenic DNAAF1 alleles from six individuals: one a homozygous frameshift pathogenic variant, c.1349dupC (p.Pro451AlafsTer5); one a heterozygous nonsense, p.Arg271Ter, pathogenic variant; and three large deletions that involved multiple genes including DNAAF1.

Table 9.

Selected DNAAF1 Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.524T>Gp.Leu175ArgNM_178452​.4
NP_848547​.4
c.811C>Tp.Arg271Ter
c.1349dupCp.Pro451AlafsTer5

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

Abnormal gene product. Pathogenic variants 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)

Gene structure. CCDC39 comprises 20 exons.

Pathogenic variants. See Table 10. Nonsense, frameshift, splice site, and missense pathogenic variants have been described. Three pathogenic variants (p.Thr358GlnfsTer3, p.Ser786IlefsTer33, and c.357+1G>C) each have a shared haplotype, suggesting a common origin for each. One pathogenic variant (p.Glu731AsnfsTer31) had a shared haplotype in three families, but a distinct haplotype in one family suggested a recurrent mutational event [Merveille et al 2011].

Table 10.

CCDC39 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.357+1G>C--NM_181426​.1
NP_852091​.1
c.1072delAp.Thr358GlnfsTer3
c.2190delAp.Glu731AsnfsTer31
c.2357_2359delinsTp.Ser786IlefsTer33

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CCDC39 encodes the 941-amino acid 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. Pathogenic variants in CCDC39 cause inner dynein arm defects with axonemal disorganization (including abnormal radial spokes and nexin links, reduced number of inner dynein arms, and the displacement of outer doublets) (see Table 2) [Merveille et al 2011].

CCDC40 (CILD15)

Gene structure. CCDC40 comprises 20 exons.

Pathogenic variants. See Table 11. Pathogenic variants in CCDC40 were found in 14 of 24 unrelated families with axonemal disorganization. Of these 14 families, 13 had biallelic pathogenic variants. There were 14 unique alleles, including insertions/deletions, nonsense and splice site pathogenic variants, and a large deletion. One pathogenic variant (p.Ala83ValfsTer82) was present on at least one allele in seven unrelated persons; the other pathogenic variant (p.Arg942MetinsTrp) was observed in two unrelated persons [Becker-Heck et al 2011].

Table 11.

CCDC40 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.248delCp.Ala83ValfsTer82NM_017950​.3
NP​_060420
c.2824_2825insTGTp.Arg942MetinsTrp

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CCDC40 encodes the 1142-amino acid axonemal protein which contains coiled-coil domains. In mice, the protein is localized to the 9+2 respiratory axonemal structure from multi-ciliated tracheal cells and is not readily detected in the 9+0 nodal cilium.

Abnormal gene product. Similar to CCDC39, pathogenic variants in CCDC40 cause inner dynein arm defects with axonemal disorganization (including abnormal radial spokes and nexin links, reduced number of inner dynein arms, and the displacement of outer doublets) (see Table 2) [Merveille et al 2011].

In addition, CCDC39 was also absent in all persons with CCDC40 pathogenic variants suggesting that CCDC40 may be required for axonemal recruitment of CCDC39 [Becker-Heck et al 2011].

CCDC103 (CILD17)

Gene structure. CCDC103 comprises four exons and encodes a 242-amino acid protein.

Pathogenic variants. See Table 12. Two pathogenic variant alleles have been described. One truncating pathogenic variant has been described in three unrelated consanguineous families of Pakistani origin and a missense pathogenic variant is described in two unrelated families of Pakistani origin as well in a German family [Panizzi et al 2012].

Table 12.

CCDC103 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.383dupGp.Gly128fsTer25NM_213607​.2
NP_998772​.1
c.461A>Cp.His154Pro

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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. Pathogenic variants 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 pathogenic variants, consistent with the abnormal assembly of ODA [Panizzi et al 2012].

LRRC6 (CILD19)

Gene structure. LRRC6 comprises 12 exons.

Pathogenic variants. Table 13. More than ten LRRC6 pathogenic variants, many predicted to be truncating variants, have been described [Kott et al 2012, Zariwala et al 2013]. In particular, the variant c.630delG has been seen in affected individuals of Pakistani ancestry [Zariwala et al 2013, Watson et al 2014].

Table 13.

LRRC6 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.598_599delAAp.Lys200GlufsTer3NM_012472​.3
NP_036604​.2
c.574C>Tp.Gln192Ter
c.576dupAp.Glu193ArgfsTer4
c.220G>Cp.Ala74Pro
c.436G>Cp.Asp146His
c.630delGp.Trp210CysfsTer12

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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. Pathogenic variants in LRRC6 lead to the defective outer+inner dynein arms as observed by ciliary ultrastructural analysis [Kott et al 2012].

CCDC114 (CILD20)

Gene structure. CCDC114 comprises 14 exons.

Pathogenic variants. See Table 14. Pathogenic variants in CCDC114 include frameshift and splice site variants [Knowles et al 2013b]. All four of the splice-site pathogenic alleles were shown to cause abnormal transcripts [Knowles et al 2013b, Onoufriadis et al 2013].

A common ancestral pathogenic variant, c.742G>A, was identified in eight families from the genetically isolated Volendam fishing village of Northern Holland [Onoufriadis et al 2013]. The c.742G>A splice-site allele shared a haplotype in multiple affected families suggesting a possible founder effect [Knowles et al 2013b]; indeed the same allele was seen in all affected individuals from the Volendam village cohort, explaining the carrier frequency of 1:10 in that population [Onoufriadis et al 2013].

Table 14.

CCDC114 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.742G>Ap.Ala248SerfsTer52NM_144577​.3
NP_653178​.3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CCDC114 encodes the 670-amino acid axonemal protein containing coiled-coil domains. It is a component of the outer dynein arm docking complex in ciliated cells. Studies of human airway epithelial cell cultures show that the full length CCDC114 transcript is induced at the time of ciliated cell differentiation [Knowles et al 2013b]. CCDC114 was found to be present in the cilia from human airway epithelial cells [Hjeij et al 2013, Onoufriadis et al 2013].

Abnormal gene product. Pathogenic variants in CCDC114 lead to defective outer dynein arms and abnormal cilia motility [Knowles et al 2013b, Onoufriadis et al 2013].

ZMYND10 (CILD22)

Gene structure. ZMYND10 comprises 12 exons.

Pathogenic variants. See Table 15. Thirteen different pathogenic alleles in ZMYND10 including truncating variants, missense variants, and one large deletion have been reported. Individuals with biallelic missense variants c.47T>G (p.Val16Gly) showed partial retention of dynein arms along with partial retention of motility (but stiff beating pattern and abnormal beat amplitude) suggesting that this is a hypomorphic allele [Moore et al 2013].

Table 15.

ZMYND10 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.47T>Gp.Val16GlyNM_015896​.2
NP_056980​.2
c.797T>Cp.Leu66Pro

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. ZMYND10 encodes the 440-amino acid cytoplasmic protein which contains the C-terminal MYND zinc-finger domain. ZMYND10 interacts with LRRC6, another cytoplasmic protein associated with primary ciliary dyskinesia.

Abnormal gene product. Pathogenic variants in ZMYND10 lead to outer+inner dynein arm defects and static cilia [Moore et al 2013, Zariwala et al 2013].

ARMC4 (CILD23)

Gene structure. ARMC4 comprises 20 exons.

Pathogenic variants. See Table 16. Eight independent pathogenic alleles in ARMC4 have been identified including one large deletion and nonsense, splice-site, frameshift, and missense variants [Hjeij et al 2013].

One nonsense variant, p.Glu557Ter, has been observed in multiple unrelated families. Functional studies suggest the missense variant p.Leu927Trp is hypomorphic [Hjeij et al 2013].

Table 16.

ARMC4 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1669G>Tp.Glu557TerNM_018076​.2
NP_060546​.2
c.2780T>Gp.Leu927Trp

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. ARMC4 encodes the 1044-amino acid axonemal protein with ten armadillo repeat motifs (ARMs) and one HEAT repeat and involved in variety of cellular functions. ARMC4 is present in the ciliary axoneme [Hjeij et al 2013].

Abnormal gene product. Pathogenic variants in ARMC4 lead to defective outer dynein arms and reduced ciliary beat frequency and immotile cilia [Hjeij et al 2013]. ARMC4 does not appear to be a structural component of the outer dynein arms [Hjeij et al 2013].

RSPH1 (CILD24)

Gene structure. RSPH1 comprises nine exons.

Pathogenic variants. See Table 17. Pathogenic variants in RSPH1 include truncating and splice-site variants and a missense variant [Kott et al 2013, Knowles et al 2014]. Of the eight reported pathogenic variants, three (p.Glu29Ter, c.407_410delAGTA, and c.275-2A>C) had a shared haplotype in two or more unrelated families [Knowles et al 2014].

Analysis of four splice-site variants (c.275-2A>C, c.727+5G>A, c.366-3C>A, and c.366G>A) revealed aberrant transcripts with premature translation termination signals.

Table 17.

RSPH1 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.85G>Tp.Glu29TerNM_080860​.2
NP_543136​.1
c.275-2A>Cp.Gly92AlafsTer10
c.366G>Ap.Arg122SerfsTer22
c.366-3C>ANot determined.
c.407_410delAGTAp.Lys136MetfsTer6
c.727+5G>Ap.Ala244ValfsTer22

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RSPH1 encodes the 309-amino acid axonemal protein with five N-terminal MORN (membrane occupation and recognition nexus) repeats followed by a linker and a sixth MORN repeat. RSPH1 is expressed at the time of ciliated cell differentiation of human airway epithelial cells. RSPH1 is present in the ciliary axoneme of human nasal epithelial cells [Kott et al 2013, Knowles et al 2014].

Abnormal gene product. Pathogenic variants in RSPH1 lead to defective central microtubule doublets in most, but not all, cases as well as abnormal beat patterns [Kott et al 2013, Knowles et al 2014]. Absence of RSPH1 from the entire length of the cilia results in absence of RSPH4A, another radial spokehead protein, from the distal tip of the cilia [Kott et al 2013].

SPAG1 (CILD28)

Gene structure. SPAG1 comprises 19 exons.

Pathogenic variants. See Table 18. A total of eight independent pathogenic alleles have been identified including truncating alleles, an allele abrogating the start codon and one large deletion (11,971-bp) that includes the 5’ end of SPAG1. Of the eight independent pathogenic variants, three alleles (p.Gln672Ter, c.902_906delAAGTA, and 11,971-bp del) had a shared haplotype suggesting a common origin of each [Knowles et al 2013c].

Table 18.

SPAG1 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.2014C>Tp.Gln672TerNM_172218​.2
NP_757367​.1
c.902_906delAAGTAp.Lys301ThrfsTer4
11,971 bp del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SPAG1 encodes the 926-amino acid cytoplasmic protein that contains a nine tetratricopeptide repeat (TPR) motif involved in protein-protein interactions. Studies of human airway epithelial cell cultures show that full length SPAG1 transcript is induced at the time of ciliated cell differentiation. SPAG1 was found to be present in the cultured human airway epithelial cell lysates.

Abnormal gene product. Pathogenic variants in SPAG1 lead to outer+inner dynein arm defects. Additionally, videomicroscopic analysis depicted near complete immotility [Knowles et al 2013c].

CCDC151 (CILD30)

Gene structure. CCDC151 comprises 13 exons.

Pathogenic variants. See Table 19. The p.Glu309Ter pathogenic variant was identified in three families of Arab descent and p.Ser419Ter was found in an individual of Pakistani descent. Situs abnormalities were seen in four of the five affected individuals, demonstrating that CCDC151 is important for left-right axis determination [Alsaadi et al 2014, Hjeij et al 2014].

Table 19.

CCDC151 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.925G>Tp.Glu309TerNM_145045​.4
NP_659482​.3
c.1256C>Ap.Ser419Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CCDC151 encodes the 595-amino acid axonemal protein with three highly conserved coiled-coil domains. CCDC151 is shown to be localized to the respiratory cilia by immunofluorescent analysis. Co-immunoprecipitation studies showed CCDC151 with CCDC114 but not with the other outer dynein arm proteins DNAI1, DNAI2, and DNAL1 [Hjeij et al 2014].

Abnormal gene product. Pathogenic variants in CCDC151 lead to defective outer dynein arms and immotile cilia. CCDC114 and ARMC4 (outer dynein arm proteins) are undetectable in respiratory cells of individuals with pathogenic variants in CCDC151, suggesting their localization is dependent on each other [Hjeij et al 2014].

Click here (pdf) for details on some of the less commonly mutated genes from Table 1B.

References

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Suggested Reading

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Chapter Notes

Acknowledgments

We are grateful to the patients and their families for their participation. We also thank the US PCD foundation. We would like to thank Dr. Johnny Carson for the assistance with the figure.

Funding research support

  • NIH/ORD/NCRR U54 HL096458
  • NIH/NHLBI 1 R01 HL071798
  • NHLBI/NIH 5 R01 HL117836

The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.

Revision History

  • 3 September 2015 (me) Comprehensive update posted live
  • 28 February 2013 (cd) Revision: DNAAF3, CCDC103, and LRRC6 mutation testing clinically available; mutations in HYDIN and HEATR2 associated with PCD
  • 7 June 2012 (cd) Revision: nomenclature change: TXNDC3NME8; clarifications to Molecular Genetics
  • 8 March 2012 (cd) Revision: deletion of part or all of DNAAF1 and an exon deletion in DNAH5 reported
  • 12 January 2012 (cd) Revision: multi-gene panels for primary ciliary dyskinesia now listed in the GeneTests™ Laboratory Directory
  • 10 November 2011 (cd) Revision: sequence analysis and prenatal testing available clinically for DNAL1
  • 15 September 2011 (me) Comprehensive update posted live
  • 6 October 2009 (me) Comprehensive update posted live
  • 1 February 2008 (cd) Revision: targeted mutation analysis (mutation panel includes 61 mutations in DNAH5 and DNAI1) and prenatal diagnosis available clinically
  • 13 June 2007 (cd) Revision: sequence analysis of select exons of DNAI1 and DNAH5 available clinically
  • 24 January 2007 (me) Review posted to live Web site
  • 19 July 2006 (mbz) Original submission
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