Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Author(s):Show less -

Burrage, Lindsay C. ^{[1, 2]} ; Reynolds, John J. ^[3] ; Baratang, Nissan Vida ^[4] ; Phillips, Jennifer B. ^[5] ; Wegner, Jeremy ^[5] ; McFarquhar, Ashley ^[4] ; Higgs, Martin R. ^[3] ; Christiansen, Audrey E. ^[6] ; Lanza, Denise G. ^[2] ; Seavitt, John R. ^[2] ; Jain, Mahim ^[7] ; Li, Xiaohui ^[2] ; Parry, David A. ^[8] ; Raman, Vandana ^[9] ; Chitayat, David ^{[10, 11]} ; Chinn, Ivan K. ^{[12, 13]} ; Bertuch, Alison A. ^[2] ; Karaviti, Lefkothea ^[14] ; Schlesinger, Alan E. ^{[15, 16]} ; Earl, Dawn ^[17] ; Bamshad, Michael ^{[18, 19, 17]} ; Savarirayan, Ravi ^[20] ; Doddapaneni, Harsha ^[21] ; Muzny, Donna ^[21] ; Jhangiani, Shalini N. ^[21] ; Eng, Christine M. ^{[2, 22]} ; Gibbs, Richard A. ^{[21, 2]} ; Bi, Weimin ^{[2, 22]} ; Emrick, Lisa ^{[2, 12, 23]} ; Rosenfeld, Jill A. ^[2] ; Postlethwait, John ^[5] ; Westerfield, Monte ^[5] ; Dickinson, Mary E. ^{[2, 6]} ; Beaudet, Arthur L. ^[2] ; Ranza, Emmanuelle ^[24] ; Huber, Celine ^[25] ; Cormier-Daire, Valerie ^[25] ; Shen, Wei ^{[26, 27]} ; Mao, Rong ^{[26, 27]} ; Heaney, Jason D. ^[2] ; Orange, I. Jordan S. ^{[13, 28]} ; Bertola, Debora ^{[29, 30]} ; Yamamoto, Guilherme L. ^{[29, 30]} ; Baratela, Wagner Ar ^[29] ; Butler, Merlin G. ^{[31, 32, 33]} ; Ali, Asim ^[34] ; Adeli, Mehdi ^[35] ; Cohn, Daniel H. ^{[36, 37]} ; Krakow, Deborah ^{[38, 39]} ; Jackson, Andrew P. ^[40] ; Lees, Melissa ^[41] ; Offiah, Amaka C. ^[42] ; Carlston, Colleen M. ^{[26, 27]} ; Carey, John C. ^[43] ; Stewart, Grant S. ^[3] ; Bacino, Carlos A. ^{[1, 2]} ; Campeau, Philippe M. ^[4] ; Lee, Brendan ^{[1, 2]} ; Mendelian, Univ Washington Ctr ; Network, Undiagnosed Dis

Affiliation:Show less -

^[1] Texas Childrens Hosp, Houston, TX 77030 - USA

^[2] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 - USA

^[3] Univ Birmingham, Inst Canc & Genom Sci, Birmingham B15 2TT, W Midlands - England

^[4] Univ Montreal, Ctr Hosp Univ St Justine Res Ctr, Montreal, PQ H3T 1J4 - Canada

^[5] Univ Oregon, Inst Neurosci, Eugene, OR 97403 - USA

^[6] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 - USA

^[7] Kennedy Krieger Inst, Dept Bone & Osteogenesis Imperfecta, Baltimore, MD 21205 - USA

^[8] Univ Edinburgh, Western Gen Hosp, Med Res Council Inst Genet & Mol Med, Crewe Rd, Edinburgh EH4 2XU, Midlothian - Scotland

^[9] Univ Utah, Div Pediat Endocrinol & Diabet, Salt Lake City, UT 84112 - USA

^[10] Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1Z5 - Canada

^[11] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8 - Canada

^[12] Baylor Coll Med, Dept Pediat, Houston, TX 77030 - USA

^[13] Texas Childrens Hosp, Div Pediat Immunol Allergy & Rheumatol, Houston, TX 77030 - USA

^[14] Texas Childrens Hosp, Div Diabet & Endocrinol, Houston, TX 77030 - USA

^[15] Baylor Coll Med, Dept Radiol, Houston, TX 77030 - USA

^[16] Texas Childrens Hosp, Dept Pediat Radiol, Houston, TX 77030 - USA

^[17] Seattle Childrens Hosp, Seattle, WA 98195 - USA

^[18] Univ Washington, Dept Genome Sci, Seattle, WA 98195 - USA

^[19] Univ Washington, Dept Pediat, Seattle, WA 98195 - USA

^[20] Univ Melbourne, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Parkville, Vic 3052 - Australia

^[21] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 - USA

^[22] Baylor Genet, Houston, TX 77030 - USA

^[23] Baylor Coll Med, Div Neurol & Dev Neurosci, Houston, TX 77030 - USA

^[24] Univ Geneva, Geneva Univ Hosp, Serv Genet Med, Med Sch, CH-1205 Geneva - Switzerland

^[25] Univ Paris 05, Hop Necker Enfants Malades, AP HP, Dept Genet, INSEAM UMR1163, Sorbonne Paris Cite, Ins, F-75015 Paris - France

^[26] Associated Reg & Univ Pathologists Labs, Salt Lake City, UT 84108 - USA

^[27] Univ Utah, Dept Pathol, Salt Lake City, UT 84112 - USA

^[28] Columbia Univ, Dept Pediat, Vagelos Coll Phys & Surg, New York Presbyterian, New York, NY 10032 - USA

^[29] Univ Sao Paulo, Inst Crianca, Clin Genet Unit, Hosp Clin, Fac Med, BR-05403000 Sao Paulo, SP - Brazil

^[30] Univ Sao Paulo, Ctr Pesquisa Genoma Humano & Celulas Tronco, Inst Biociencias, BR-05508090 Sao Paulo, SP - Brazil

^[31] Kansas Univ, Med Ctr, Dept Psychiat, Kansas City, KS 66160 - USA

^[32] Kansas Univ, Med Ctr, Dept Behav Sci, Kansas City, KS 66160 - USA

^[33] Kansas Univ, Med Ctr, Dept Pediat, Kansas City, KS 66160 - USA

^[34] Univ Toronto, Hosp Sick Children, Dept Ophthalmol & Vis Sci, Toronto, ON M5G 1X8 - Canada

^[35] Hamad Med Corp, Weill Cornell Med, Dept Allergy & Immunol Sidra Med, Doha - Qatar

^[36] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 - USA

^[37] Univ Calif Los Angeles, Dept Orthopaed Surg, Los Angeles, CA 90095 - USA

^[38] Univ Calif Los Angeles, David Geffen Sch Med, Dept Orthopaed Surg, Dept Human Genet, Los Angeles, CA 90095 - USA

^[39] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 - USA

^[40] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian - Scotland

^[41] Great Ormond St Hosp Sick Children, North East Thames Reg Genet Serv, London WC1N 3JH - England

^[42] Univ Sheffield, Acad Unit Child Hlth, Dept Oncol & Metab, Sheffield S10 2TH, S Yorkshire - England

^[43] Univ Utah, Dept Pediat, Div Med Genet, Salt Lake City, UT 84112 - USA

• Document type: Journal article
• Source: American Journal of Human Genetics; v. 104, n. 3, p. 422-438, MAR 7 2019.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/21783-9 - Analysis of genetic variants in rare osteochondrodysplasias using whole exome sequencing
• Grantee: Débora Romeo Bertola
• Support Opportunities: Regular Research Grants