Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Lindsay Burrage, John Reynolds, Nissan Baratang, Jennifer Phillips, Jeremy Wegner, Ashley McFarquhar, Martin Higgs, Audrey Christiansen, Denise Lanza, John Seavitt, Mahim Jain, Xiaohui Li, David Parry, Vandana Raman, David Chitayat, Ivan Chinn, Alison Bertuch, Lefkothea Karaviti, Alan Schlesinger, Dawn EarlMichael Bamshad, Ravi Savarirayan, Harsha Doddapaneni, Donna Muzny, Shalini Jhangiani, Christine Eng, Richard Gibbs, Weimin Bi, Lisa Emrick, Jill Rosenfeld, John Postlethwait, Monte Westerfield, Mary Dickinson,, Arthur Beaudet, Emmanuelle Ranza, Celine Huber, Valérie Cormier-Daire, Wei Shen, Rong Mao, Jason Heaney, Jordan Orange, Undiagnosed Diseases Network, Débora Bertola, Guilherme Yamamoto, Wagner Baratela, Merlin Butler, Asim Ali, Mehdi Adeli, Daniel Cohn, Deborah Krakow, Andrew Jackson, Melissa Lees, Amaka Offiah, Colleen Carlston, John Carey, Grant Stewart, Carlos Bacino, Philippe Campeau, Brendan Lee

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6 Citations (Scopus)
180 Downloads (Pure)


SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl −/− murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl −/− zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Original languageEnglish
Pages (from-to)422-438
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number3
Early online date14 Feb 2019
Publication statusPublished - 7 Mar 2019

Bibliographical note

Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


  • DNA repair
  • DNA replication
  • SPONASTRIME dysplasia
  • exome sequencing
  • skeletal dysplasia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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  • Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

    Chang, H. R., Cho, S. Y., Lee, J. H., Lee, E., Soo, J., Lee, H. R., Cavalcanti, D. P., Mäkitie, O., Valta, H., Girisha, K. M., Lee, C., Neethukrishna, K., Bhavani, G. S., Shukla, A., Nampoothiri, S., Phadke, S. R., Park, M. J., Ikegawa, S., Wang, Z., Higgs, M., & 15 othersStewart, G., Jung, E., Lee, M-S., Park, J. H., Lee, E. A., Kim, H., Myung, K., Jeon, W., Lee, K., Kim, D., Kim, O-H., Choi, M., Lee, H-W., Kim, Y. & Cho, T-J., 7 Mar 2019, In: American Journal of Human Genetics. 104, 3, p. 439-453

    Research output: Contribution to journalArticlepeer-review

    Open Access
    7 Citations (Scopus)
    147 Downloads (Pure)

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