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J Hum Genet. 2019 Oct 21. doi: 10.1038/s10038-019-0686-1. [Epub ahead of print]

Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia.

Author information

1
Department of Medicine, Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA.
2
Department of Pediatrics, Division of Pediatric Respiratory Medicine, McGill University Health Centre Research Institute, Montreal, QC, Canada.
3
Department of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
4
Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, 97006, USA.
5
Department of Pediatrics, Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA.
6
Department of Medicine, Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA. ostro@med.unc.edu.
7
Department of Pathology and Laboratory Medicine, Marsico Lung Institute University of North Carolina, Chapel Hill, NC, 27599, USA. maimoona_zariwala@med.unc.edu.

Abstract

Primary ciliary dyskinesia (PCD) is a rare disorder that affects the biogenesis or function of motile cilia resulting in chronic airway disease. PCD is genetically and phenotypically heterogeneous, with causative mutations identified in over 40 genes; however, the genetic basis of many cases is unknown. Using whole-exome sequencing, we identified three affected siblings with clinical symptoms of PCD but normal ciliary structure, carrying compound heterozygous loss-of-function variants in CFAP221. Computational analysis suggests that these variants are the most damaging alleles shared by all three siblings. Nasal epithelial cells from one of the subjects demonstrated slightly reduced beat frequency (16.5 Hz vs 17.7 Hz, p = 0.16); however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. These results show that genetic variants in CFAP221 cause PCD and that CFAP221 should be considered a candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.

PMID:
31636325
DOI:
10.1038/s10038-019-0686-1

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