Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45

Abstract

Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences. (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)Hum Mol Genet. 1992 Nov;1(8):662. (PMID: 1301186); Nat Genet. 2013 Apr;45(4):445-9, 449e1. (PMID: 23435086); Epilepsia. 2015 Mar;56(3):431-8. (PMID: 25785782); J Hum Genet. 2016 Jul;61(7):653-61. (PMID: 27030146); Neuropediatrics. 2016 Apr;47(2):123-7. (PMID: 26859818); J Hum Genet. 2014 May;59(5):292-5. (PMID: 24621584); Am J Hum Genet. 2012 Dec 7;91(6):1144-9. (PMID: 23176820); Lancet Neurol. 2016 Mar;15(3):304-16. (PMID: 26597089); Brain. 2013 Jun;136(Pt 6):1708-17. (PMID: 23687123); Eur J Hum Genet. 2016 Apr;24(4):615-8. (PMID: 26173968); Curr Neurol Neurosci Rep. 2013 Dec;13(12):413. (PMID: 24142851); Am J Hum Genet. 1992 Dec;51(6):1229-39. (PMID: 1281384); Mol Cell Probes. 2016 Feb;30(1):44-9. (PMID: 26790960); Nat Genet. 2013 Jul;45(7):825-30. (PMID: 23708187). Linking ISSN: 00139580. Subset: MEDLINE; Grant Information: K99 NS089858 United States NS NINDS NIH HHS; R01 NS069605 United States NS NINDS NIH HHS; U54 HD083091 United States HD NICHD NIH HHS Date of Electronic Publication: 2017 Nov 24. Current Imprints: Publication: Malden, MA : Blackwell Science; Original Imprints: Publication: Copenhagen : Munskgaard <br />