Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40

AT Morgan; TS Scerri; AP Vogel; CA Reid; M Quach; VE Jackson; C McKenzie; EL Burrows; MF Bennett; SJ Turner; S Reilly; SE Horton; S Block; E Kefalianos; C Frigerio-Domingues; E Sainz; KA Rigbye; TJ Featherby; KL Richards; A Kueh; MJ Herold; MA Corbett; J Gecz; I Helbig; DGY Thompson-Lake; FJ Liégeois; RJ Morell; A Hung; D Drayna; IE Scheffer; DK Wright; M Bahlo; MS Hildebrand

Journal article

Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40

AT Morgan, TS Scerri, AP Vogel, CA Reid, M Quach, VE Jackson, C McKenzie, EL Burrows, MF Bennett, SJ Turner, S Reilly, SE Horton, S Block, E Kefalianos, C Frigerio-Domingues, E Sainz, KA Rigbye, TJ Featherby, KL Richards, A Kueh Show all

Brain | OXFORD UNIV PRESS | Published : 2023

DOI: 10.1093/brain/awad314

Abstract

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant..

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University of Melbourne Researchers

Angela Morgan Author

Adam Vogel Author

Christopher Reid Author

Vicki Jackson Author

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Funding Acknowledgements

We thank the families for their participation in this study. We thank the National Computational Infrastructure (NCI) and The Pawsey Supercomputing Centre in Australia, which are both supported by the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS). A.T.M., T.S.S., A.P.V., C.A.R., I.E.S., D.K.W., Me.B. and M.S.H., initiated and directed the project. M.S.H., C.F-D., Ed.S., K.A.R., M.A.C., J.G., R.J.M. and D.D. performed molecular genetics experiments. T.S.S., C.F.-D., Ed.S., V.E.J., M.F.B. and M.B. performed bioinformatics analyses. A.H. performed molecular dynamic simulations and docking calculations. S.J.T., S.R., S.B., E.K., O.V., D.J.A., I.H., D.G.Y.L., F.J.L., I.E.S., D.D. and A.T.M. conducted clinical phenotyping or imaging. A.P.V., M.Q., V.E.J., E.L.B., C.A.R., C.M., T.J.F., K.L.R., A.K., M.J.H. and D.K.W. generated or performed functional studies on the mouse model. A.T.M. and M.S.H. wrote the paper. All authors reviewed the manuscript.