Abstract
A recent study revealed that monoallelic missense or biallelic loss-of-function variants in the chloride voltage-gated channel 3 (CLCN3) cause neurodevelopmental disorders resulting in brain abnormalities. Functional studies suggested that some missense variants had varying gain-of-function effects on channel activity. Meanwhile, two patients with homozygous frameshift variants showed severe neuropsychiatric disorders and a range of brain structural abnormalities. Here we describe two patients with de novo CLCN3 variants affecting the same amino acid, Gly327 (p.(Gly327Ser) and p.(Gly327Asp)). They showed severe neurological phenotypes including global developmental delay, intellectual disability, hypotonia, failure to thrive, and various brain abnormalities. They also presented with characteristic brain and ophthalmological abnormalities, hippocampal and retinal degradation, which were observed in patients harboring homozygous loss-of-function variants. These findings were also observed in CLCN3-deficient mice, indicating that the monoallelic missense variant may also have a dominant negative effect. This study will expand the phenotypic spectrum of CLCN3-related disorders.
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Acknowledgements
We thank the patient’s family for participating in this work. We express our gratitude to the patient and his family for participating in this study. We would also like to thank M Tsujimura, K Shibasaki, and A. Kitamoto for their technical assistance.
This study was funded by the Japan Society for the Promotion of Science, a Grant-in-Aid for Scientific Research (B: JP20H03641), and (C: JP21K06819 and 20K08236), the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Takeda Science Foundation and HUSM Grant-in-Aid from Hamamatsu University School of Medicine.
URLs.
14KJPN (https://ijgvd.megabank.tohoku.ac.jp/)
gnomAD (https://gnomad.broadinstitute.org/)
SIFT (http://provean.jcvi.org/index.php)
Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/)
CADD (https://cadd.gs.washington.edu/)
GERP (http://mendel.stanford.edu/SidowLab/downloads/GERP/index.html)
PhastCons (http://compgen.cshl.edu/phast/)
PROTTER (https://wlab.ethz.ch/protter/start/)
HOPE (https://www3.cmbi.umcn.nl/hope/)
DECIPHER (https://www.deciphergenomics.org/).
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This study was approved by the Institutional Review Board Committee at Hamamatsu University School of Medicine and Showa University School of Medicine and was performed after obtaining written informed consent.
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Nakashima, M., Argilli, E., Nakano, S. et al. De novo CLCN3 variants affecting Gly327 cause severe neurodevelopmental syndrome with brain structural abnormalities. J Hum Genet 68, 291–298 (2023). https://doi.org/10.1038/s10038-022-01106-0
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DOI: https://doi.org/10.1038/s10038-022-01106-0
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