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De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.

De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.

Authors :
Manivannan, Sathiya N
Roovers, Jolien
Smal, Noor
Myers, Candace T
Turkdogan, Dilsad
Roelens, Filip
Kanca, Oguz
Chung, Hyung-Lok
Scholz, Tasja
Hermann, Katharina
Bierhals, Tatjana
Caglayan, Hande S
Stamberger, Hannah
Consortium, MAE Working Group of EuroEPINOMICS RES
Mefford, Heather
Jonghe, Peter de
Yamamoto, Shinya
Weckhuysen, Sarah
Bellen, Hugo J
MAE Working Group of EuroEPINOMICS RES Consortium
Source :
Brain: A Journal of Neurology; May2022, Vol. 145 Issue 5, p1684-1697, 14p
Publication Year :
2022

Abstract

FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00068950
Volume :
145
Issue :
5
Database :
Complementary Index
Journal :
Brain: A Journal of Neurology
Publication Type :
Academic Journal
Accession number :
157886118
Full Text :
https://doi.org/10.1093/brain/awab409