PCD 61™
Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome (ICS), is a genetically heterogeneous, usually autosomal recessive disorder with impaired ciliary function leading to progressive sinopulmonary disease.
PrintPrimary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome (ICS), is a genetically heterogeneous, usually autosomal recessive disorder with impaired ciliary function leading to progressive sinopulmonary disease.
Upper and lower respiratory tract manifestations are key features of PCD and are often present at birth. Upper respiratory tract features include chronic nasal drainage, sinusitis, and otitis media. Lower respiratory features include neonatal respiratory distress, chronic productive cough, chronic bronchitis, recurrent pneumonia, and bronchiectasis. Approximately half of PCD patients have situs inversus, and the triad of sinusitis, bronchiectasis and situs inversus is also known as Kartagener’s syndrome.
Approximately ~6% of individuals with PCD have situs ambiguous (heterotaxy), which is attributed to dysmobility of embryological nodal cilia. The prevalence of congenital heart disease is 200 fold higher in PCD that in the general population. In adults with PCD, male infertility and female sub-fertility are also common. Prompt diagnosis of PCD is critical for the prevention of secondary respiratory complications. Defective dynein arms occur in ~90% of individuals who have defined ultrastructural defects; and ~10% have defective central pair or radial spoke or nexin links. The involvement of multiple genes in PCD reflects the complexity of cilia.
The genes in which disease-causing mutations have been identified include eleven genes coding for outer dynein arm (ODA) proteins (DNAI1, DNAI2, DNAH5, DNAH11, TXNDC3), radial spoke (RS) proteins (RSPH4A, RSPH9), cytoplasmic proteins involved in dynein arm (DA) assembly (c14orf104/KTU, LRRC50) and in RPGR and OFD1. The three additional genes that were more recently implicated in PCD are CCDC39 (OMIM *613798)1 on 3q26.33 (PCD 14), CCDC40 (OMIM *613799)2 on 17q25.3 (PCD 15), and DNAL1 (OMIM *610062)3 on 14q24.3 (PCD16).
The two genes that are most commonly associated with PCD are DNAI1 and DNAH5. Mutations in DNAI1 or DNAH5 have been detected on at least one chromosome in 38% of all PCD patients. Affected patients with single mutations have been described. The Ambry Panel PCD 61™ detects 61 known disease-causing mutations in these two genes. Novel variants at or immediately adjacent to the site of the known mutations may be detected and will be reported.
Ambry also offers the PCD Next-Gen Sequencing Panel, which analyzes eleven PCD genes as well as CFTR, and is estimated to detect mutations in approximately 56-56.9% of patients with PCD and PCD-related disorders. For more information about this option, please refer to the Test entry for the PCD Next-Gen Sequencing Panel.
Primary ciliary dyskinesia (PCD) is a disorder of the structure and function of cilia that causes respiratory disease, random left-right orientation of internal organs, male infertility, chronic ear infections, and other symptoms related to defective cilia action in embryonic and postnatal life. PCD is also called Immotile Cilia Syndrome and when present with situs inversus is called Kartagener Syndrome. Approximately 1 in 16,000 individuals are affected1 and most cases are autosomal recessive.
The involvement of multiple genes in PCD reflects the complexity of cilia. Respiratory cilia, for example, include approximately 250 structural and functional proteins. Research studies that correlate specific ultrastructural ciliary defects with mutations in corresponding structural genes are defining the genetic spectrum of PCD.
Two genes directly implicated in autosomal recessive PCD are DNAI1 and DNAH5, which encode components of cilias’ outer dynein arm complex. Mutations in DNAI1 or DNAH5 have been detected in 38%4-6 of PCD patients. The Ambry Panel: PCD 61 detects all of the known disease-causing mutations in these two genes published through September 2007.
Genetic testing complements and may allow bypass of more invasive diagnostic procedures. Positive results allow patient and family counseling.
DNA testing is appropriate for the following indications:
- known or suspected primary ciliary dyskinesia
- chronic sinusitis or bronchiectasis not due to cystic fibrosis
- suspected PCD with heterotaxy, situs ambiguus, or situs inversus (Kartagener Syndrome)
- congenital heart defect associated with recurrent respiratory disease or heterotaxy
- chronic otitis media with effusion
- male infertility with other signs of PCD
- idiopathic respiratory distress in full-term neonates
- carrier status determination for relatives of patients with known mutations
The Ambry Panel: PCD 61 analyzes for the 61 published mutations in DNAH5 and DNAI1 causing PCD. All 43 known disease-causing mutations on DNAH5 and 18 mutations on DNAI1 published through September 2007 are analyzed (listed below). Novel variants at or immediately adjacent to the site of the known mutations may be detected and will be reported. Detection of sequence variation(s) at the sites of the 61 mutations is performed by PCR amplification of all analyzed regions of the two genes followed by single-stranded pyrosequencing.
DNAH5 mutations analyzed: R78X, c.1730G>C, R1454X, Q1828X, E2347K, Q2723X, F2971SfsX12 (previously reported in the literature as 2970XfsX7), G4205V, R4476X, Y84X, Q610X, R1454Q, I1855NfsX6, R2501P, R2772X, W3409S, IVS74-1G>C, N4487fsX1, A278RfsX27, IVS17+2T>C, R1711TfsX37 (previously reported in literature as R1711TfsX36), L1867PfsX35, R2639X, Q2802X, G3519R, IVS75-2A>T, R4496X, F476SfsX26, L1302RfsX19, R1716L, R2013X, R2639TfsX19, E2814fsX1, P3606HfsX23 (previously reported in literature as P3606HfsX20), D4398EfsX16, Q543X, IVS27+1G>A, R1761X, S2264N, R2677X, F2843S, S3843L, IVS76+5G>A.
DNAI1 mutations analyzed: IVS1+2_3insT,T155LfsX18, Q292X, Y404X, W436X, G515S, W548X, W568S, I643PfsX48, G95NfsX24, IVS7-2A>G, IVS10-4_7delGTTT, V408M, c.1490G>A, A538T,T553_F556del, W568X, IVS19+1G>A.
Specific mutation analysis for individual DNAH5 or DNAI1 mutations known to be in the family is also available.
Mutations tested have been detected on at least one chromosome in approximately 38% of all PCD patients. Affected patients with single gene mutations have been described.4,5
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Minimum of one complete spot approximately 0.5 inch in diameter on S&S 903 collection paper or similar. Store in a clean plastic bag at room temperature. Ship at room temperature.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 8120 | PCD 61 (DNAH5 and DNAI1 Mutation Panel) | 83891x1, 83894x1, 83898x20, 83904x20, 83909x20, 83912x1 |
| Technique | Days |
|---|---|
| PCD 61 (DNAH5 and DNAI1 Mutation Panel) | 7-21 |
1. Merveille et al., Nature Genet. 43: 72-78, 2011.
2. Becker-Heck et al., Nature Genet. 43: 79-84, 2011.
3. Mazor et al., Am. J. Hum. Genet. 88: 599-607, 2011.
4. Zariwala M et al. Am J Respir Crit Care Med. 2006;174:858-866.
5. Hornef N et al. Am J Respir Crit Care Med. 2006;174:120-126.
6. Zariwala M et al. Annu Rev Physiol. 2007;69:423-450.