title: TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy.
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.
authors.affiliation: Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Toshio
authors.identifier: http://orcid.org/0000-0003-0055-9157
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Pediatrics, National Hospital Organization Miyazaki Hospital, Miyazaki, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nakahara
authors.affiliation: Department of Pediatrics, Aisenkai Nichinan Hospital, Miyazaki, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nagano
authors.affiliation: Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Utoyama
authors.affiliation: Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Obara
authors.affiliation: Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritake
authors.affiliation: Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
authors.forename: Tamayo
authors.initials: T
authors.lastname: Uechi
authors.affiliation: Department of Neurology, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.identifier: http://orcid.org/0000-0001-7425-4765
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Neurology, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.identifier: http://orcid.org/0000-0003-2975-7309
authors.initials: H
authors.lastname: Ishiura
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimura
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kenmochi
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ichizo
authors.identifier: http://orcid.org/0000-0001-9452-112X
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Department of Neurology, The University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nunoi
mesh_terms: D001927:Brain Diseases / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009046:Motor Neurons / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics* / Q000503:physiopathology
chemical_list: C575687:BAHCC1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; C418662:TBCD protein, human