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A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor


ANO3 encodes Anoctamin-3, also known as TMEM16C, a calcium-activated chloride channel. Heterozygous variants of ANO3 can cause dystonia 24, an adult-onset focal dystonia. Some pediatric cases have been reported, but most patients were intellectually normal with some exceptions. Here, we report a two-year-old girl who showed mild to moderate developmental delay, tremor, and ataxic gait, but no obvious dystonia. Trio exome sequencing identified a heterozygous de novo missense variant NM_031418.4:c.1809T>G, p.(Asn603Lys) in the ANO3 gene. Three cases with ANO3 variants and intellectual disability have been reported, including the present case. These variants were predicted to face in the same direction on the same alpha-helix (the transmembrane 4 domain), suggesting an association between these variants and childhood-onset movement disorder with intellectual disability. In pediatric cases with developmental delay and movement disorders such as tremor and ataxia, specific variants in the transmembrane 4 domain of ANO3 may be a cause, even in the absence of dystonia.

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Fig. 1: Variants in ANO3 in our case and previously reported pediatric cases.


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The authors would like to thank the patient and her family for their participation in this study. We thank Yoko Chiba and Kumi Ito for the technical assistance. We also acknowledge the support obtained from the Biomedical Research Core of the Tohoku University Graduate School of Medicine and the Biomedical Research Unit of Tohoku University Hospital. This research was supported by the Japanese Agency for Medical Research and Development (AMED) to SK (No. JP17ek0109151).

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Authors and Affiliations



YuA, MS and AK performed data analyses and wrote the manuscript, YuA and YK performed case examination and evaluation, TN, MS, RF, KN, and YoA performed exome sequencing and data collection, and SK designed and supervised the study.

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Correspondence to Atsuo Kikuchi.

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The authors declare no competing interests.

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This study was approved by the ethics committee of Tohoku University School of Medicine. Written informed consent was obtained from the parents of the patient for the publication of this case report.

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Aihara, Y., Shirota, M., Kikuchi, A. et al. A novel variant in the transmembrane 4 domain of ANO3 identified in a two-year-old girl with developmental delay and tremor. J Hum Genet (2022).

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