Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.,American Journal of Human Genetics

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Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2019-02-14 , 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 , , , 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 ₁

Affiliation

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T1J4, Canada.
Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Medical Research Council Institute of Genetics & Molecular Medicine, the University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Division of Pediatric Endocrinology and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.
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.
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.
Division of Diabetes and Endocrinology, Texas Children's Hospital, Houston, TX 77030, USA.
Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
Seattle Children's Hospital, Seattle, WA 98195, USA.
Seattle Children's Hospital, Seattle, WA 98195, USA; Departments of Pediatrics and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Parkville, VIC 3052, Australia.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77030, USA.
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.
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.
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.
Service of Genetic Medicine, University of Geneva Medical School, Geneva University Hospitals, 1205 Geneva, Switzerland.
Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, Paris 75015, France.
Associated Regional and University Pathologists Laboratories, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
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.
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.
Clinical Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil.
Departments of Psychiatry and Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, KS 66160, USA.
Department of Ophthalmology and Vision Sciences, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
Department of Allergy and Immunology, Sidra Medicine, Hamad Medical Corporation, Weill Cornell Medicine, Qatar, Doha, Qatar.
Department of Molecular, Cell, and Developmental Biology and Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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.
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
North East Thames Regional Genetics Service, Great Ormond Street Hospital, London WC1N 3JH, UK.
Department of Oncology and Metabolism, Academic Unit of Child Health, University of Sheffield, Sheffield S10 2TH, UK.
Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84112, USA.

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.

中文翻译：

TONSL 中的双等位基因变异导致 SPONASTRIME 发育不良和一系列骨骼发育不良表型。

SPONASTRIME 发育不良是一种常染色体隐性脊柱干骺端发育不良，其特征是脊柱（脊椎）异常、面中部发育不全伴鼻梁凹陷、干骺端条纹和不成比例的身材矮小。脊柱侧弯、髋关节内翻、儿童白内障、短牙根和低丙种球蛋白血症也有报道出现在这种疾病中。尽管已假设常染色体隐性遗传模式，但尚未在患有 SPONASTRIME 发育不良的个体中发现特定基因的致病变异。在这里，我们在 9 个患有 SPONASTRIME 发育不良的受试者（来自 8 个家庭）中鉴定了 TONSL 中的双等位基因变异，该变异编码 Tonsoku 样 DNA 修复蛋白，和四名受试者（来自三个家庭）具有不同严重程度的身材矮小和脊椎干骺端发育不良，有或没有免疫学和血液学异常，但在诊断时没有明确的干骺端条纹。在 Tonsl-/- 小鼠模型中发现早期胚胎致死率，以及在 Tonsl-/- 斑马鱼模型中发现长度减少、脊柱异常、中性粒细胞数量减少和早期致死率都支持已识别的 TONSL 变体的亚形性. 此外，功能研究显示自发复制叉停滞和染色体畸变的数量增加，以及更少的喜树碱 (CPT) 诱导的受试者来源细胞系中的 RAD51 病灶。重要的是，这些细胞缺陷在重新表达野生型 (WT) TONSL 后得以挽救；这种拯救与亚形 TONSL 变异是致病性的假设一致。总体而言，我们在人类、小鼠、斑马鱼和受试者来源的细胞系中的研究证实，TONSL 中的致病变异会损害 DNA 复制和同源重组依赖性修复过程，并导致一系列骨骼发育不良表型和许多骨骼外表现.

更新日期：2019-02-14

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