Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in approximately 50% of PCD patients (Kartagener's syndrome in PCD), and there are a few reports of PCD with heterotaxy (situs ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association. METHODS AND RESULTS: The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal situs) and situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with situs solitus, those with situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm genes (DNAI1 and DNAH5; P=0.022). Seven of 12 patients with heterotaxy who were genotyped had mutations in DNAI1 or DNAH5. Twelve patients with heterotaxy had cardiac and/or vascular abnormalities, and most (8 of 12 patients) had complex congenital heart disease. CONCLUSIONS: At least 6.3% of patients with PCD have heterotaxy, and most of those have cardiovascular abnormalities. The prevalence of congenital heart disease with heterotaxy is 200-fold higher in PCD than in the general population (1:50 versus 1:10 000); thus, patients with PCD should have cardiac evaluation. Conversely, mutations in genes that adversely affect both respiratory and embryological nodal cilia are a significant cause of heterotaxy and congenital heart disease, and screening for PCD is indicated in those patients.

Genetic causes of bronchiectasis: primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder reflecting abnormalities in the structure and function of motile cilia and flagella, causing impairment of mucociliary clearance, left-right body asymmetry, and sperm motility. Clinical manifestations include respiratory distress in term neonates, recurrent otosinopulmonary infections, bronchiectasis, situs inversus and/or heterotaxy, and male infertility. Genetic discoveries are emerging from family-based linkage studies and from testing candidate genes. Mutations in 2 genes, DNAI1 and DNAH5, frequently cause PCD as an autosomal recessive disorder. A clinical genetic test has been recently established for DNAI1 and DNAH5, which involves sequencing 9 exons that harbor the most common mutations. This approach will identify at least one mutation in these 2 genes in approximately 25% of PCD patients. If biallelic mutations are identified, the test is diagnostic. If only one mutation is identified, the full gene may be sequenced to search for a trans-allelic mutation. As more disease-causing gene mutations are identified, broader genetic screening panels will further identify patients with PCD. Ongoing investigations are beginning to identify genetic mutations in novel clinical phenotypes for PCD, such as congenital heart disease and male infertility, and new associations are being established between 'ciliary' genetic mutations and clinical phenotypes.