West syndrome is an early-onset epileptic encephalopathy characterized by clustered spasms with hypsarrhythmia seen on electroencephalogram (EEG). West syndrome is genetically heterogeneous, and its genetic causes have not been fully elucidated. WD Repeat Domain 45 (WDR45) resides on Xp11.23, and encodes a member of the WD repeat protein interacting with phosphoinositides (WIPI) family, which is crucial in the macroautophagy pathway. De novo mutations in WDR45 cause beta-propeller protein-associated neurodegeneration characterized by iron accumulation in the basal ganglia. In this study, we performed whole exome sequencing of individuals with West syndrome and identified three WDR45 mutations in three independent males (patients 1, 2 and 3). Two novel mutations occurred de novo (patients 1 and 2) and the remaining mutation detected in a male patient (patient 3) and his affected sister was inherited from the mother, harboring the somatic mutation. The three male patients showed early-onset intractable seizures, profound intellectual disability and developmental delay. Their brain magnetic resonance imaging scans showed cerebral atrophy. We found no evidence of somatic mosaicism in the three male patients. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Saemundsen, E., Ludvigsson, P. & Rafnsson, V. Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life. Epilepsia 49, 1865–1870 (2008).
Cowan, L. D. & Hudson, L. S. The epidemiology and natural history of infantile spasms. J. Child Neurol. 6, 355–364 (1991).
Osborne, J. P., Lux, A. L., Edwards, S. W., Hancock, E., Johnson, A. L., Kennedy, C. R. et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia 51, 2168–2174 (2010).
Pavone, P., Striano, P., Falsaperla, R., Pavone, L. & Ruggieri, M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev. 36, 739–751 (2014).
Epi, K. C. Epilepsy Phenome/Genome P. Allen, A. S., Berkovic, S. F., Cossette, P., Delanty, N. et al. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).
Dimassi, S., Labalme, A., Ville, D., Calender, A., Mignot, C., Boutry-Kryza, N. et al. Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome. Clin. Genet. 89, 198–204 (2016).
Paciorkowski, A. R., Thio, L. L. & Dobyns, W. B. Genetic and biologic classification of infantile spasms. Pediatr. Neurol. 45, 355–367 (2011).
Grimmel, M., Backhaus, C. & Proikas-Cezanne, T. WIPI-mediated autophagy and longevity. Cells 4, 202–217 (2015).
Proikas-Cezanne, T., Takacs, Z., Donnes, P. & Kohlbacher, O. WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome. J. Cell Sci. 128, 207–217 (2015).
Bakula, D., Takacs, Z. & Proikas-Cezanne, T. WIPI beta-propellers in autophagy-related diseases and longevity. Biochem. Soc. Trans. 41, 962–967 (2013).
Jiang, P. & Mizushima, N. Autophagy and human diseases. Cell Res. 24, 69–79 (2014).
Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467 (2009).
Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
Verhoeven, W. M., Egger, J. I., Koolen, D. A., Yntema, H., Olgiati, S., Breedveld, G. J. et al. Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients. Parkinsonism Relat. Disord. 20, 332–336 (2014).
Tschentscher, A., Dekomien, G., Ross, S., Cremer, K., Kukuk, G. M., Epplen, J. T. et al. Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation. J. Neurol. Sci. 349, 105–109 (2015).
Takano, K., Shiba, N., Wakui, K., Yamaguchi, T., Aida, N., Inaba, Y. et al. Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: Additional case report and review of the literature. Am. J. Med. Genet. A 170, 322–328 (2015).
Ohba, C., Nabatame, S., Iijima, Y., Nishiyama, K., Tsurusaki, Y., Nakashima, M. et al. De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain. J. Hum. Genet. 59, 292–295 (2014).
Nishioka, K., Oyama, G., Yoshino, H., Li, Y., Matsushima, T., Takeuchi, C. et al. High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. Neurobiol. Aging 36, 2004.e9–2004.e15 (2015).
Long, M., Abdeen, N., Geraghty, M. T., Hogarth, P., Hayflick, S. & Venkateswaran, S. Novel WDR45 mutation and pathognomonic BPAN imaging in a young female with mild cognitive delay. Pediatrics 136, e714–e717 (2015).
Rathore, G. S., Schaaf, C. P. & Stocco, A. J. Novel mutation of the WDR45 gene causing beta-propeller protein-associated neurodegeneration. Mov. Disord. 29, 574–575 (2014).
Okamoto, N., Ikeda, T., Hasegawa, T., Yamamoto, Y., Kawato, K., Komoto, T. et al. Early manifestations of BPAN in a pediatric patient. Am. J. Med. Genet. A 164A, 3095–3099 (2014).
Khalifa, M. & Naffaa, L. Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings. Eur. J. Med. Genet. 58, 381–386 (2015).
Haack, T. B., Hogarth, P., Kruer, M. C., Gregory, A., Wieland, T., Schwarzmayr, T. et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J. Hum. Genet. 91, 1144–1149 (2012).
Saitsu, H., Nishimura, T., Muramatsu, K., Kodera, H., Kumada, S., Sugai, K. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45, 445–449 449e441 (2013).
Ryu, S. W., Kim, J. S. & Lee, S. H. Beta-propeller-protein-associated neurodegeneration: a case of mutation in WDR45. J. Clin. Neurol. 11, 289–291 (2015).
Aminkeng, F. WDR45 mutations define a novel disease entity—static encephalopathy of childhood with neurodegeneration in adulthood. Clin. Genet. 84, 209 (2013).
Abidi, A., Mignon-Ravix, C., Cacciagli, P., Girard, N., Milh, M. & Villard, L. Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient. Eur. J. Hum. Genet. 24, 615–618 (2016).
Zarate, Y. A., Jones, J. R., Jones, M. A., Millan, F., Juusola, J., Vertino-Bell, A. et al. Lessons from a pair of siblings with BPAN. Eur. J. Hum. Genet. 24, 1080–1083 (2016).
Ozawa, T., Koide, R., Nakata, Y., Saitsu, H., Matsumoto, N., Takahashi, K. et al. A novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). Am. J. Med. Genet. A 164A, 2388–2390 (2014).
Hamdan, F. F., Srour, M., Capo-Chichi, J. M., Daoud, H., Nassif, C., Patry, L. et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10, e1004772 (2014).
Hayflick, S. J., Kruer, M. C., Gregory, A., Haack, T. B., Kurian, M. A., Houlden, H. H. et al. Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 136, 1708–1717 (2013).
Kruer, M. C., Boddaert, N., Schneider, S. A., Houlden, H., Bhatia, K. P., Gregory, A. et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am. J. Neuroradiol. 33, 407–414 (2012).
Gregory, A., Polster, B. J. & Hayflick, S. J. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J. Med. Genet. 46, 73–80 (2009).
Schneider, S. A. & Bhatia, K. P. Syndromes of neurodegeneration with brain iron accumulation. Semin. Pediatr. Neurol. 19, 57–66 (2012).
Gregory, A. & Hayflick, S. J. Genetics of neurodegeneration with brain iron accumulation. Curr. Neurol. Neurosci. Rep. 11, 254–261 (2011).
Ichinose, Y., Miwa, M., Onohara, A., Obi, K., Shindo, K., Saitsu, H. et al. Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN). Neurol. Clin. Pract. 4, 175–177 (2014).
Nakashima, M., Miyajima, M., Sugano, H., Iimura, Y., Kato, M., Tsurusaki, Y. et al. The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome. J. Hum. Genet. 59, 691–693 (2014).
Robinson, J. T., Thorvaldsdottir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
Thorvaldsdottir, H., Robinson, J. T. & Mesirov, J. P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 14, 178–192 (2013).
Acuna-Hidalgo, R., Bo, T., Kwint, M. P., van de Vorst, M., Pinelli, M., Veltman, J. A. et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am J. Hum. Genet. 97, 67–74 (2015).
Campbell, I. M., Yuan, B., Robberecht, C., Pfundt, R., Szafranski, P., McEntagart, M. E. et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J. Hum. Genet. 95, 173–182 (2014).
Campbell, I. M., Stewart, J. R., James, R. A., Lupski, J. R., Stankiewicz, P., Olofsson, P. et al. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J. Hum. Genet. 95, 345–359 (2014).
We express our heartfelt gratitude to all the patients and their families for participating in this study. We would like to thank Ms N Watanabe, M Sato and K Takabe for their excellent technical assistance. We also thank Mr D Yamaguchi for his assistance with the bioinformatics analysis. This work was supported in part by a grant for Research on Measures for Intractable Diseases, a grant for Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science (SRPBS) and a grant for Initiative on Rare and Undiagnosed Diseases in Pediatrics (IRUD-P) from Japan Agency for Medical Research and Development (AMED); a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); Grants-in-Aid for Scientific Research (A, B and C), and challenging Exploratory Research from the Japan Society for the Promotion of Science (JSPS); the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency (JST); the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists.
The authors declare no conflict of interest.
About this article
Clinical Genetics (2019)
Journal of Inherited Metabolic Disease (2019)
Beta-propeller protein-associated neurodegeneration (BPAN) as a genetically simple model of multifaceted neuropathology resulting from defects in autophagy
Reviews in the Neurosciences (2019)
Current Opinion in Cell Biology (2019)
European Journal of Medical Genetics (2019)