Abstract
Biallelic SHQ1 variant-related neurodevelopmental disorder is extremely rare. To date, only six affected individuals, from four families, have been reported. Here, we report eight individuals, from seven unrelated families, who exhibited neurodevelopmental disorder and/or dystonia, received whole-genome sequencing, and had inherited biallelic SHQ1 variants. The median age at disease onset was 3.5 months old. All eight individuals exhibited normal eye contact, profound hypotonia, paroxysmal dystonia, and brisk deep tendon reflexes at the first visit. Varying degrees of autonomic dysfunction were observed. One individual had cerebellar atrophy at the initial neuroimaging study, however, three individuals showed cerebellar atrophy at follow-up. Seven individuals who underwent cerebral spinal fluid analysis all had a low level of homovanillic acid in neurotransmitter metabolites. Four individuals who received 99mTc-TRODAT-1 scan had moderate to severe decreased uptake of dopamine in the striatum. Four novel SHQ1 variants in 16 alleles were identified: 9 alleles (56%) were c.997C > G (p.L333V); 4 (25%) were c.195T > A (p.Y65X); 2 (13%) were c.812T > A (p.V271E); and 1 (6%) was c.146T > C (p.L49S). The four novel SHQ1 variants transfected into human SH-SY5Y neuronal cells resulted in a retardation in neuronal migration, suggestive of SHQ1 variant correlated with neurodevelopmental disorders. During the follow-up period, five individuals still exhibited hypotonia and paroxysmal dystonia; two showed dystonia; and one had hypotonia only. The complex interactions among movement disorders, dopaminergic pathways, and the neuroanatomic circuit needs further study to clarify the roles of the SHQ1 gene and protein in neurodevelopment.
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Acknowledgements
The authors gratefully thank Professor Huei-Jane Lee who works at Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, for her generous contribution with interpretation of experimental data.
Funding
This work was supported by TCVGH-1096502B and TCVGH-1106504B for the molecular research and in vitro study.
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All authors contributed to the study conception and design. C-SC participated in recruitment of patients, acquisition, analysis, and interpretation of data. C-RT participated in the sequence alignment and carried out the molecular genetic studies and the in vitro functional study. H-FL made great contributions to recruitment of patients and interpretation of data, revised the manuscript critically for important intellectual content, and gave final approval of the version. The first draft of the manuscript was written by C-SC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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The authors have non-financial interests to disclose. The founders had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Taichung Veterans General Hospital (Date April 20th 2022/ No TCVGH IRB CE22134B).
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Chi, CS., Tsai, CR. & Lee, HF. Biallelic SHQ1 variants in early infantile hypotonia and paroxysmal dystonia as the leading manifestation. Hum. Genet. 142, 1029–1041 (2023). https://doi.org/10.1007/s00439-023-02533-5
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DOI: https://doi.org/10.1007/s00439-023-02533-5