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

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

In: American Journal of Human Genetics, Vol. 104, No. 3, 07.03.2019, p. 422-438.

Research output: Contribution to journalArticle

Harvard

Burrage, L, Reynolds, J, Baratang, N, Phillips, J, Wegner, J, McFarquhar, A, Higgs, M, Christiansen, A, Lanza, D, Seavitt, J, Jain, M, Li, X, Parry, D, Raman, V, Chitayat, D, Chinn, I, Bertuch, A, Karaviti, L, Schlesinger, A, Earl, D, Bamshad, M, Savarirayan, R, Doddapaneni, H, Muzny, D, Jhangiani, S, Eng, C, Gibbs, R, Bi, W, Emrick, L, Rosenfeld, J, Postlethwait, J, Westerfield, M, Dickinson, M, Beaudet, A, Ranza, E, Huber, C, Cormier-Daire, V, Shen, W, Mao, R, Heaney, J, Orange, J, Undiagnosed Diseases Network, Bertola, D, Yamamoto, G, Baratela, W, Butler, M, Ali, A, Adeli, M, Cohn, D, Krakow, D, Jackson, A, Lees, M, Offiah, A, Carlston, C, Carey, J, Stewart, G, Bacino, C, Campeau, P & Lee, B 2019, 'Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes', American Journal of Human Genetics, vol. 104, no. 3, pp. 422-438. https://doi.org/10.1016/j.ajhg.2019.01.007

APA

Burrage, L., Reynolds, J., Baratang, N., Phillips, J., Wegner, J., McFarquhar, A., Higgs, M., Christiansen, A., Lanza, D., Seavitt, J., Jain, M., Li, X., Parry, D., Raman, V., Chitayat, D., Chinn, I., Bertuch, A., Karaviti, L., Schlesinger, A., ... Lee, B. (2019). Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. American Journal of Human Genetics, 104(3), 422-438. https://doi.org/10.1016/j.ajhg.2019.01.007

Vancouver

Author

Burrage, Lindsay ; Reynolds, John ; Baratang, Nissan ; Phillips, Jennifer ; Wegner, Jeremy ; McFarquhar, Ashley ; Higgs, Martin ; Christiansen, Audrey ; Lanza, Denise ; Seavitt, John ; Jain, Mahim ; Li, Xiaohui ; Parry, David ; Raman, Vandana ; Chitayat, David ; Chinn, Ivan ; Bertuch, Alison ; Karaviti, Lefkothea ; Schlesinger, Alan ; Earl, Dawn ; Bamshad, Michael ; Savarirayan, Ravi ; Doddapaneni, Harsha ; Muzny, Donna ; Jhangiani, Shalini ; Eng, Christine ; Gibbs, Richard ; Bi, Weimin ; Emrick, Lisa ; Rosenfeld, Jill ; Postlethwait, John ; Westerfield, Monte ; Dickinson, Mary ; Beaudet, Arthur ; Ranza, Emmanuelle ; Huber, Celine ; Cormier-Daire, Valérie ; Shen, Wei ; Mao, Rong ; Heaney, Jason ; Orange, Jordan ; Undiagnosed Diseases Network ; Bertola, Débora ; Yamamoto, Guilherme ; Baratela, Wagner ; Butler, Merlin ; Ali, Asim ; Adeli, Mehdi ; Cohn, Daniel ; Krakow, Deborah ; Jackson, Andrew ; Lees, Melissa ; Offiah, Amaka ; Carlston, Colleen ; Carey, John ; Stewart, Grant ; Bacino, Carlos ; Campeau, Philippe ; Lee, Brendan . / Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 3. pp. 422-438.

Bibtex

@article{62964312be074cb7ae8842e94cf1574c,
title = "Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes",
abstract = "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. ",
keywords = "DNA repair, DNA replication, SPONASTRIME dysplasia, TONSL, exome sequencing, skeletal dysplasia",
author = "Lindsay Burrage and John Reynolds and Nissan Baratang and Jennifer Phillips and Jeremy Wegner and Ashley McFarquhar and Martin Higgs and Audrey Christiansen and Denise Lanza and John Seavitt and Mahim Jain and Xiaohui Li and David Parry and Vandana Raman and David Chitayat and Ivan Chinn and Alison Bertuch and Lefkothea Karaviti and Alan Schlesinger and Dawn Earl and Michael Bamshad and Ravi Savarirayan and Harsha Doddapaneni and Donna Muzny and Shalini Jhangiani and Christine Eng and Richard Gibbs and Weimin Bi and Lisa Emrick and Jill Rosenfeld and John Postlethwait and Monte Westerfield and Mary Dickinson, and Arthur Beaudet and Emmanuelle Ranza and Celine Huber and Val{\'e}rie Cormier-Daire and Wei Shen and Rong Mao and Jason Heaney and Jordan Orange and {Undiagnosed Diseases Network} and D{\'e}bora Bertola and Guilherme Yamamoto and Wagner Baratela and Merlin Butler and Asim Ali and Mehdi Adeli and Daniel Cohn and Deborah Krakow and Andrew Jackson and Melissa Lees and Amaka Offiah and Colleen Carlston and John Carey and Grant Stewart and Carlos Bacino and Philippe Campeau and Brendan Lee",
note = "Copyright {\textcopyright} 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = mar
day = "7",
doi = "10.1016/j.ajhg.2019.01.007",
language = "English",
volume = "104",
pages = "422--438",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Elsevier",
number = "3",

}

RIS

TY - JOUR

T1 - Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

AU - Burrage, Lindsay

AU - Reynolds, John

AU - Baratang, Nissan

AU - Phillips, Jennifer

AU - Wegner, Jeremy

AU - McFarquhar, Ashley

AU - Higgs, Martin

AU - Christiansen, Audrey

AU - Lanza, Denise

AU - Seavitt, John

AU - Jain, Mahim

AU - Li, Xiaohui

AU - Parry, David

AU - Raman, Vandana

AU - Chitayat, David

AU - Chinn, Ivan

AU - Bertuch, Alison

AU - Karaviti, Lefkothea

AU - Schlesinger, Alan

AU - Earl, Dawn

AU - Bamshad, Michael

AU - Savarirayan, Ravi

AU - Doddapaneni, Harsha

AU - Muzny, Donna

AU - Jhangiani, Shalini

AU - Eng, Christine

AU - Gibbs, Richard

AU - Bi, Weimin

AU - Emrick, Lisa

AU - Rosenfeld, Jill

AU - Postlethwait, John

AU - Westerfield, Monte

AU - Dickinson,, Mary

AU - Beaudet, Arthur

AU - Ranza, Emmanuelle

AU - Huber, Celine

AU - Cormier-Daire, Valérie

AU - Shen, Wei

AU - Mao, Rong

AU - Heaney, Jason

AU - Orange, Jordan

AU - Undiagnosed Diseases Network, null

AU - Bertola, Débora

AU - Yamamoto, Guilherme

AU - Baratela, Wagner

AU - Butler, Merlin

AU - Ali, Asim

AU - Adeli, Mehdi

AU - Cohn, Daniel

AU - Krakow, Deborah

AU - Jackson, Andrew

AU - Lees, Melissa

AU - Offiah, Amaka

AU - Carlston, Colleen

AU - Carey, John

AU - Stewart, Grant

AU - Bacino, Carlos

AU - Campeau, Philippe

AU - Lee, Brendan

N1 - Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

KW - DNA repair

KW - DNA replication

KW - SPONASTRIME dysplasia

KW - TONSL

KW - exome sequencing

KW - skeletal dysplasia

UR - http://www.scopus.com/inward/record.url?scp=85062417308&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2019.01.007

DO - 10.1016/j.ajhg.2019.01.007

M3 - Article

C2 - 30773277

VL - 104

SP - 422

EP - 438

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -