The role of molecular genetic analysis in the diagnosis of primary ciliary dyskinesia.
BACKGROUND
Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disorder of motile cilia. The diagnosis of PCD has previously relied on ciliary analysis with transmission electron microscopy or video microscopy. However, patients with PCD may have normal ultrastructural appearance, and ciliary analysis has limited accessibility. Alternatively, PCD can be diagnosed by demonstrating biallelic mutations in known PCD genes. Genetic testing is emerging as a diagnostic tool to complement ciliary analysis where interpretation and access may delay diagnosis.


OBJECTIVE
To determine the diagnostic yield of genetic testing of patients with a confirmed or suspected diagnosis of PCD in a multiethnic urban center.


METHODS
Twenty-eight individuals with confirmed PCD on transmission electron microscopy of ciliary ultrastructure and 24 individuals with a probable diagnosis of PCD based on a classical PCD phenotype and low nasal nitric oxide had molecular analysis of 12 genes associated with PCD.


RESULTS
Of 49 subjects who underwent ciliary biopsy, 28 (57%) were diagnosed with PCD through an ultrastructural defect. Of the 52 individuals who underwent molecular genetic analysis, 22 (42%) individuals had two mutations in known PCD genes. Twenty-four previously unreported mutations in known PCD genes were observed. Combining both diagnostic modalities of biopsy and molecular genetics, the diagnostic yield increased to 69% compared with 57% based on biopsy alone.


CONCLUSIONS
The diagnosis of PCD is challenging and has traditionally relied on ciliary biopsy, which is unreliable as the sole criterion for a definitive diagnosis. Molecular genetic analysis can be used as a complementary test to increase the diagnostic yield.
1 Division of Clinical and Metabolic Genetics.
Raymond H
RH
Kim
David
D
A Hall
Ernest
E
Cutz
Michael R
MR
Knowles
Kathleen A
KA
Nelligan
Keith
K
Nykamp
Maimoona A
MA
Zariwala
Sharon D
SD
Dell
D000293:Adolescent; D000328:Adult; D056444:Axonemal Dyneins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007619:Kartagener Syndrome / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation / Q000235:genetics; D015203:Reproducibility of Results; D012189:Retrospective Studies; D055815:Young Adult
D056444:Axonemal Dyneins; C497507:DNAH5 protein, human