Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.
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Acknowledgements
We thank the individuals with atypical SMA and their family for their participation in this study. We also thank Drs K Kanako and S Yuko (Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry) for their helpful comments on the sural nerve biopsy, and Dr K Shiomi (Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki) for help with the nerve conduction study. This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI) for Scientific Research on Innovative Areas (Exploring Molecular Basis for Brain Diseases Based on Personal Genomics), Priority Areas (Applied Genomics), Integrated Database Project and Scientific Research (A) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a Clinical Research Grant from Miyazaki University Hospital.
Author contributions
TI confirmed the diagnosis in each participating patient, conceived the study, participated in the sequence alignment, designed and performed the experiments, analyzed the data, contributed reagents/materials/analysis tools and drafted the manuscript. AN confirmed the diagnosis for the participating patient designated as case 2, conceived the study, participated in the sequence alignment, designed and performed the experiments, analyzed the data and helped to draft the manuscript. RN confirmed the diagnosis for the participating patient designated as case 1. MU performed the experiments. MO designed and performed the experiments and analyzed the data. HM conceived the study and helped to draft the manuscript. TU conceived and designed the experiments. JM, HI, JY, KD and SM performed the experiments and contributed reagents/materials/analysis tools. NK and NI conceived and designed the experiments. ST conceived and designed the experiments and contributed reagents/materials/analysis tools and drafted manuscript. HN conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
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Ikeda, T., Nakahara, A., Nagano, R. et al. TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy. J Hum Genet 62, 473–480 (2017). https://doi.org/10.1038/jhg.2016.149
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DOI: https://doi.org/10.1038/jhg.2016.149
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