Advertisement

A Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysis

  • Nihan Hande Akçakaya
  • Barış Salman
  • Zeliha Görmez
  • Yelda Tarkan Argüden
  • Ayşe Çırakoğlu
  • Raif Çakmur
  • Berril Dönmez Çolakoğlu
  • Seniha Hacıhanefioğlu
  • Uğur Özbek
  • Zuhal Yapıcı
  • Sibel Aylin Uğur İşeri
Original Paper

Abstract

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients remain crucial for deciphering BPAN and other X-linked dominant diseases. We performed whole exome sequencing (WES) followed by segregation analysis and identified a novel nonsense and mosaic variant in WDR45, namely NM_007075.3:c.873C>G; p.(Tyr291*) in an affected male at the age of 34. His biphasic medical history was compatible with BPAN, which was characterized by delayed psychomotor development, intellectual disability, and progression into dystonia parkinsonism in his twenties. The variant had an apparently mosaic pattern both in whole exome and Sanger sequencing findings. In order to figure out if mosaicism was restricted to this variant or related to a chromosomal level mosaicism, we used our in-house WES data from 129 unrelated individuals to calculate the threshold values of male and female X chromosome heterozygosity (XcHet) in WES data for our pipeline. A background level of heterozygous variants on X chromosome excluding the pseudoautosomal loci is an observed phenomenon in WES analysis and this level has been used as a quality measure. Herein, we suggest utilization of this measure for detection of digital anomalies of the X chromosome in males by potentially observing a higher XcHet value than the threshold value. This approach has revealed a variant level mosaicism in the affected male, which was further supported with cytogenetic analyses.

Keywords

WDR45 Mosaicism Whole exome sequencing X chromosome heterozygosity BPAN 

Notes

Acknowledgements

The authors wish to thank the patient and his family for participating in this study. This work was supported by grant from the Scientific Research Projects Coordination Unit of Istanbul University, Project Number TDK-2017-26646.

Funding

This study was funded by the Scientific Research Projects Coordination Unit of Istanbul University, Project Number TDK-2017-26646.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This study was approved by the Ethics Committee of Istanbul Faculty of Medicine, Istanbul University (protocol number 2017/113). Written consent was received from patients family authorizing us to use his medical data in this publication.

Informed Consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Supplementary material

12017_2018_8522_MOESM1_ESM.pdf (408 kb)
Supplementary material 1 (PDF 408 KB)

References

  1. Abidi, A., Mignon-Ravix, C., Cacciagli, P., Girard, N., Milh, M., & Villard, L. (2016). Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient. European Journal of Human Genetics, 24(4), 615–618.CrossRefGoogle Scholar
  2. Civelli, O., & Zhou, Q. (2007). Dopamine receptors: Molecular pharmacology. Encyclopedia of life sciences. Hoboken: Wiley.Google Scholar
  3. Coban-Akdemir, Z., White, J. J., Song, X., Jhangiani, S. N., Fatih, J. M., Gambin, T., Bayram, Y., Chinn, I. K., Karaca, E., Punetha, J., et al. (2018). Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles. American Journal of Human Genetics, 103, 1–17.CrossRefGoogle Scholar
  4. Danecek, P., Auton, A., Abecasis, G., Albers, C. A., Banks, E., DePristo, M. A., Handsaker, R. E., Gerton, L., Marth, G. T., Sherry, S. T., et al. (2011). The variant call Format and VCFtools. Bioinformatics., 1(15), 2156–2158. 27).CrossRefGoogle Scholar
  5. Ebrahimi-Fakhari, D., Saffari, A., Wahlster, L., Lu, J., Byrne, S., Hoffmann, G. F., Jungbluth, H., & Sahin, M. (2016). Congenital disorders of autophagy: An emerging novel class of inborn errors of neuro-meabolism. Brain, 139, 317–337.CrossRefGoogle Scholar
  6. Haack, T. B., Hogarth, P., Kruer, M. C., Gregory, A., Wieland, T., Schwarzmayr, T., Graf, E., Sanford, L., Meyer, E., Kara, E., et al. (2012). Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. American Journal of Human Genetics, 91, 1144.CrossRefGoogle Scholar
  7. Hor, C. H. H., & Tang, B. L. (2018). Beta-propeller protein-associated neurodegeneration (BPAN) as agenetically simple model of multifaceted neuropathology resulting from defects in autophagy. Reviews in the Neurosciences.  https://doi.org/10.1515/revneuro-2018-0045 Google Scholar
  8. Kruer, M. C., Boddaert, N., Schneider, S. A., Houlden, H., Bhatia, K. P., Gregory, A., Anderson, J. C., Rooney, W. D., Hogarth, P., & Hayflick, S. J. (2012). Neuroimaging features of neurodegeneration with brain iron accumulation. American Journal of Neuroradiology. 33, 407iol.c.CrossRefGoogle Scholar
  9. Li, H., & Durbin, R. (2009). Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics, 15(14), 1754–1760. 25(.CrossRefGoogle Scholar
  10. McKinney, W. (2011). pandas: A Foundational Python Library for Data Analysis and Statistics, PyHPC2011.Google Scholar
  11. McLaren, W., Gil, L., Hunt, S. E., Riat, H. S., Ritchie, G. R., Thormann, A., Flicek, P., & Cunningham, F. (2016). The Ensembl variant effect predictor. Genome Biology, 17(1), 122.CrossRefGoogle Scholar
  12. Nakashima, M., Takano, K., Tsuyusaki, Y., Yoshitomi, S., Shimono, M., Aoki, Y., Kato, M., Aida, N., Mizuguchi, T., Miyatake, S., et al. (2016). WDR45 mutations in three male patients with West syndrome. Journal of Human Genetics, 61(7), 653–661.CrossRefGoogle Scholar
  13. Redon, S., Benech, C., Schutz, S., Despres, A., Gueguen, P., Le Berre, P., Le Marechal, C., Peudenier, S., Meriot, P., Parent, P., et al. (2017). Intragenic deletion of the WDR45 gene in a male with encephalopathy, severe psychomotor disability, and epilepsy. American Journal of Medical Genetics Part A, 9999, 1–3.Google Scholar
  14. Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011). Integrative genomics viewer. Nature Biotechnology, 29(1), ;24–6.CrossRefGoogle Scholar
  15. Spiegel, R., Shalev, S., Bercovich, D., Khayat, M., Shaag, A., & Elpeleg, O. (2016). Severe infantile male encephalopathy is a result of early post-zygotic WDR45 somatic mutation. Clinical Genetics, 90(6), 560–562.CrossRefGoogle Scholar
  16. Takano, K., Goto, K., Motobayashi, M., Wakui, K., Kawamura, R., Yamaguchi, T., Fukushima, Y., & Kosho, T. (2017). Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. European Journal of Medical Genetics, 60(10), 521–526.CrossRefGoogle Scholar
  17. Taudien, S., Lausser, L., Giamarellos-Bourboulis, E.J., Sponholz C., Schöneweck, F., Felder, M., Schirra, L.R., Schmid F., Gogos C., Groth, S. et al. (2016). Genetic factors of the disease course after sepsis: Rare deleterious variants are predictive. EBioMedicine 12, 227–238.CrossRefGoogle Scholar
  18. Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy-Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013). From FastQ data to high-confidence variant calls: The genome analysis toolkit best practices pipeline. Current Protocols in Bioinformatics., 43, 11.Google Scholar
  19. Zarate, Y. A., Jones, J. R., Jones, A. M., Millan, F., Juusola, J., Vertino-Bell, A., Schaefer, G. B., & Kruer, M. C. (2016). Lessons from a pair of siblings with BPAN. European Journal of Human Genetics, 24(7), 1095.CrossRefGoogle Scholar

Web Resources

  1. BrainSpan, Retrieved from http://www.brainspan.org/.
  2. Variant Effect Predictor-Ensembl. Retrieved from https://www.ensembl.org/info/docs/tools/vep/index.html/.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Nihan Hande Akçakaya
    • 1
  • Barış Salman
    • 1
  • Zeliha Görmez
    • 2
  • Yelda Tarkan Argüden
    • 3
  • Ayşe Çırakoğlu
    • 3
  • Raif Çakmur
    • 4
  • Berril Dönmez Çolakoğlu
    • 4
  • Seniha Hacıhanefioğlu
    • 3
  • Uğur Özbek
    • 5
  • Zuhal Yapıcı
    • 6
  • Sibel Aylin Uğur İşeri
    • 1
  1. 1.Department of Genetics, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityÇapa/istanbulTurkey
  2. 2.Department of Software Engineering, Faculty of EngineeringIstinye UniversityIstanbulTurkey
  3. 3.Department of Medical Biology, Cerrahpasa Faculty of MedicineIstanbul UniversityIstanbulTurkey
  4. 4.Department of NeurologyDokuz Eylul Faculty of MedicineİzmirTurkey
  5. 5.Department of Medical Genetics, Acibadem Faculty of MedicineAcibadem UniversityIstanbulTurkey
  6. 6.Department of Neurology, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey

Personalised recommendations