2. Academic Validation
  3. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

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

  • Am J Hum Genet. 2019 Mar 7;104(3):422-438. doi: 10.1016/j.ajhg.2019.01.007.
Lindsay C Burrage 1,  John J Reynolds 2,  Nissan Vida Baratang 3,  Jennifer B Phillips 4,  Jeremy Wegner 4,  Ashley McFarquhar 3,  Martin R Higgs 2,  Audrey E Christiansen 5,  Denise G Lanza 6,  John R Seavitt 6,  Mahim Jain 7,  Xiaohui Li 6,  David A Parry 8,  Vandana Raman 9,  David Chitayat 10,  Ivan K Chinn 11,  Alison A Bertuch 6,  Lefkothea Karaviti 12,  Alan E Schlesinger 13,  Dawn Earl 14,  Michael Bamshad 15,  Ravi Savarirayan 16,  Harsha Doddapaneni 17,  Donna Muzny 17,  Shalini N Jhangiani 17,  Christine M Eng 18,  Richard A Gibbs 19,  Weimin Bi 18,  Lisa Emrick 20,  Jill A Rosenfeld 6,  John Postlethwait 4,  Monte Westerfield 4,  Mary E Dickinson 21,  Arthur L Beaudet 6,  Emmanuelle Ranza 22,  Celine Huber 23,  Valérie Cormier-Daire 23,  Wei Shen 24,  Rong Mao 24,  Jason D Heaney 6,  Jordan S Orange 25,  University of Washington Center for Mendelian Genomics,  Undiagnosed Diseases Network,  Débora Bertola 26,  Guilherme L Yamamoto 26,  Wagner A R Baratela 27,  Merlin G Butler 28,  Asim Ali 29,  Mehdi Adeli 30,  Daniel H Cohn 31,  Deborah Krakow 32,  Andrew P Jackson 33,  Melissa Lees 34,  Amaka C Offiah 35,  Colleen M Carlston 24,  John C Carey 36,  Grant S Stewart 2,  Carlos A Bacino 1,  Philippe M Campeau 3,  Brendan Lee 37
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 2 Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 3 Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T1J4, Canada.
  • 4 Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
  • 5 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7 Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • 8 Medical Research Council Institute of Genetics & Molecular Medicine, the University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
  • 9 Division of Pediatric Endocrinology and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.
  • 10 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1Z5, Canada; Department of Pediatrics, Division of Clinical and Metabolic Genetics, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 11 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Pediatric Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, TX 77030, USA.
  • 12 Division of Diabetes and Endocrinology, Texas Children's Hospital, Houston, TX 77030, USA.
  • 13 Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 14 Seattle Children's Hospital, Seattle, WA 98195, USA.
  • 15 Seattle Children's Hospital, Seattle, WA 98195, USA; Departments of Pediatrics and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 16 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Parkville, VIC 3052, Australia.
  • 17 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 18 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77030, USA.
  • 19 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 20 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 21 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 22 Service of Genetic Medicine, University of Geneva Medical School, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • 23 Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, Paris 75015, France.
  • 24 Associated Regional and University Pathologists Laboratories, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
  • 25 Division of Pediatric Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, TX 77030, USA; Current affiliation: Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian, New York, NY 10032, USA.
  • 26 Clinical Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil; Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, SP 05508-0900, Brazil.
  • 27 Clinical Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil.
  • 28 Departments of Psychiatry and Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, KS 66160, USA.
  • 29 Department of Ophthalmology and Vision Sciences, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 30 Department of Allergy and Immunology, Sidra Medicine, Hamad Medical Corporation, Weill Cornell Medicine, Qatar, Doha, Qatar.
  • 31 Department of Molecular, Cell, and Developmental Biology and Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 32 Department of Orthopaedic Surgery, Department of Human Genetics and Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 33 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 34 North East Thames Regional Genetics Service, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • 35 Department of Oncology and Metabolism, Academic Unit of Child Health, University of Sheffield, Sheffield S10 2TH, UK.
  • 36 Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84112, USA.
  • 37 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.
PMID: 30773277 DOI: 10.1016/j.ajhg.2019.01.007
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.

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