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

Journal of Human Genetics volume 65, pages 175–180 (2020)Cite this article

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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.

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Acknowledgements

The authors would like to thank the PCD subjects and family members for their participation, Michele Manion (founder of US PCD Foundation), and the US PCD Foundation, and the investigators and the coordinators of the Genetic Disorders of Mucociliary Clearance Consortium, part of the Rare Disease Clinical Research Network. We thank Dr Tony Perdue for assistance with confocal imaging; and Dr S. H. Randell and the UNC Cell culture core for providing human airway cells. The UNC Cell Core Facility is supported by BOUCHE15R0 and P30DK065988 grants. We thank Whitney Wolf, Weining Yin, and Kimberly Burns from UNC for technical assistance and Dr Hong Dang from UNC for bioinformatics assistance. We thank Drs Shrikanth Mane and Francesc Loez-Giraldez and Ms Weilai Dong from Yale Center for Mendelian Genomics for providing whole-exome sequencing and bioinformatics support.

Funding

Funding support for this research was provided to MRK, MWL and MAZ by US NIH/ORDR/NHLBI grant 5U54HL096458; to MRK, LEO, and MAZ by NIH-NHLBI grant R01HL071798; to LEO, MAZ, and MRK by NIH/NHLBI R01HL117836 and to UNC-CH by NIH/NCATS grant UL1 TR000083; to DFC by NIH/NICHD R01HD078641 and NIH/NIMH R01MH101810. WLC is supported by NIH/NIMH T32-MH014677. Whole-exome sequencing was carried out at Yale Center for Mendelian Genomics (UM1HG006504); funded by the NHGRI and the GSP Coordinating Center (U24 HG008956) that contributes to cross-program scientific initiatives logistical and general study coordination. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. These authors contributed equally: Lawrence E. Ostrowski, Maimoona A. Zariwala

  2. These authors contributed equally: Ximena M. Bustamante-Marin, Adam Shapiro

Authors and Affiliations

  1. Department of Medicine, Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA

    Ximena M. Bustamante-Marin, Patrick R. Sears, Michael R. Knowles & Lawrence E. Ostrowski

  2. Department of Pediatrics, Division of Pediatric Respiratory Medicine, McGill University Health Centre Research Institute, Montreal, QC, Canada

    Adam Shapiro

  3. Department of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Wu-Lin Charng & Donald F. Conrad

  4. Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Donald F. Conrad

  5. Department of Pediatrics, Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA

    Margaret W. Leigh

  6. Department of Pathology and Laboratory Medicine, Marsico Lung Institute University of North Carolina, Chapel Hill, NC, 27599, USA

    Maimoona A. Zariwala

Authors
  1. Ximena M. Bustamante-Marin
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  2. Adam Shapiro
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  3. Patrick R. Sears
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  6. Margaret W. Leigh
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  8. Lawrence E. Ostrowski
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  9. Maimoona A. Zariwala
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Contributions

XBM and LEO wrote the paper and MRK and MAZ contributed to the paper. XBM, MRK, MAZ, and LEO conceived the experiments, and designed strategies. XBM cultured the HNE cells, and performed experiments, and MAZ performed genotyping and segregation analysis. XBM, LEO, PRS, and MAZ analyzed and interpreted data. AS, MWL, MAZ, and MRK, identified the patient and performed exome sequencing. DFC and WLC performed the whole-exome sequencing analysis, AS performed nasal scrape, and PRS, performed waveform analysis. All authors reviewed the paper.

Corresponding authors

Correspondence to Lawrence E. Ostrowski or Maimoona A. Zariwala.

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Bustamante-Marin, X.M., Shapiro, A., Sears, P.R. et al. Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia. J Hum Genet 65, 175–180 (2020). https://doi.org/10.1038/s10038-019-0686-1

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