Very Rare X Chromosome Abnormalities in SLE and SjöGren’s May Localize X Gene Dose Effect

Rohan Sharma¹, Valerie M Harris², Joshua Cavett³, Biji T Kurien³, Ke Liu⁴, Kristi A. Koelsch⁵, Lida Radfar⁶, David M. Lewis⁷, Donald U. Stone⁸, C. Erick Kaufman⁹, Shibo Li¹⁰, Barbara M. Segal¹¹, Daniel J Wallace¹², Michael Weisman¹³, Jennifer A. Kelly¹⁴, Bernado Pons-Estel¹⁵, Roland Jonsson¹⁶, Jacques-Eric Gottenberg¹⁷, Juan-Manuel Anaya¹⁸, Deborah S. Cunninghame-Graham¹⁹, Vivian P. Bykerk²⁰, Gideon Hirschfield²¹, Gang Xie²², Wan-Fai Ng²³, Gunnel Nordmark²⁴, Per Eriksson²⁵, Roald Omdal²⁶, Nelson L. Rhodus²⁷, Maureen Rischmueller²⁸, Michael D. Rohrer²⁹, Marie Wahren-Herlenius³⁰, Torsten Witte³¹, Xavier Mariette³², Christopher J. Lessard³³, John B. Harley³⁴, Kathy L. Sivils³³, Astrid Rasmussen³⁵, R. Hal Scofield³³, Swamy Venturopalli³⁶, Xianglan Lu¹⁰, Pamela Hughes³⁷, Andrew J.W. Huang³⁸ and Corinnine Miceli-Richard³⁹, ¹Medical Service, US Department of Veterans Affaris Medical Center, Oklahoma City, OK, ²Oklahoma Medical Research Foundation, Oklahoma City, OK, ³Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁴3333 Burnet Ave., University of Cincinnati & Cincinnati Childre, Cincinnati, OH, ⁵U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK, ⁶Oral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, OK, ⁷Department of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, OK, ⁸King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, ⁹Medicine, University of Oklahoam Health Sciences Center, Oklahoma City, OK, ¹⁰Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ¹¹Division of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, ¹²Cedars-Sinai Medical Center, West Hollywood, CA, ¹³Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, ¹⁴Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁵Sanatorio Parque, Rosario, Argentina, ¹⁶Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway, ¹⁷Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France, ¹⁸Center for Autoimmune Diseases Research (CREA). School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia., Bogotá, Colombia, ¹⁹Department of Medical and Molecular Genetics, King's College London, London, United Kingdom, ²⁰Divison of Rheumatology, Hospital for Special Surgery, New York, NY, ²¹Centre for Liver Research, Institute of Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom, ²²Mount Sinai Hospital, Toronto, ON, Canada, ²³Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom, ²⁴Rheumatology, Department of Medical Sciences, Uppsala University, Sweden, Uppsala, Sweden, ²⁵University Hospital, Rheumatology clinic, Linköping, Sweden, ²⁶Department of internal medicine, Clinical Immunology unit, Stavanger, Norway, ²⁷Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, ²⁸Rheumatology, Queen Elizabeth Hospital, Adelaide, Australia, ²⁹Hard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, MN, ³⁰Department of Medicine, Experimental Rheumatology Unit, Solna, Sweden, ³¹Hannover Medical School, Hanover, Germany, ³²Rheumatology, Rheumatology department, Bicetre Hospital, Paris-Sud University, Le Kremlin Bicetre, France, ³³Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ³⁴Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Childrens Hospital, Cincinnati, OH, ³⁵Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, USA, Oklahoma City, OK, ³⁶Rheumatology, Cedars Syani Medical Center, Los Angeles, CA, ³⁷Division of Oral and Maxillofacial Surgery, Department of Developmental and Surgical Science, University of Minnesota School of Dentistry, Minneapolis, MN, ³⁸Washington University,, St Louis, MO, ³⁹Rheumatology, Université Paris-Sud, Paris, France

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: genetics and systemic lupus erythematosus (SLE), Sjogren's syndrome, X chromosome

Session Information

Date: Sunday, November 13, 2016

Title: Genetics, Genomics and Proteomics - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Sjögren’s syndrome and systemic lupus erythematosus (SLE) are chronic, autoimmune diseases that are related by clinical and serological manifestations as well as genetic risks. Both diseases are much more commonly found in women compared to men at a ratio of about 10 to 1. We have previously shown that relatively common X chromosome aneuploidies, 47XXY (Klinefelter’s syndrome, 1 in 500 live male births) and 47XXX (1 in 1000 live female births), are enriched among men and women, respectively, with Sjögren’s or SLE. We undertook this study to describe rare X chromosome aneuploidies among large cohorts of patients with these diseases.

Methods: We examined large cohorts of Sjögren’s syndrome or SLE patients with intensity plots of X chromosome single nucleotide polymorphism (SNP) alleles. In addition, we also carried out karyotype of peripheral blood mononuclear cells from Sjögren’s syndrome and SLE subjects.

Results: Among 2,426 women with SLE we found three patients with a triple mosaic consisting of 45X/46XX/47XXX, a statistically significant increase compared to controls and the known birth rate by binomial confidence intervals. Among 2138 women with Sjögren’s syndrome, one patient had 45X/46XX/47XXX with a triplication of the distal p arm of the X chromosome in the 47XXX cells. Neither the triple mosaic nor a partial triplication were found among controls. In fact, the triple mosaic occurs in approximately 1 in 25,000 to 50,000 live female births, while a partial triplication such as the one found is even rarer. In another cohort of Sjögren’s patients, we found a mother-daughter pair in which the mother had an inversion of the proximal region of Xq and the daughter had a Xp isochrome with partial triplication of distal Xp.

Conclusion: Very rare X chromosome abnormalities are present among patients with either Sjögren’s or SLE. These rare variants may be informative as to location of a gene or genes on the X chromosome that mediate a gene dose effect as well as critical cell types in which a gene dose effect is operative.

Disclosure: R. Sharma, None; V. M. Harris, None; J. Cavett, None; B. T. Kurien, None; K. Liu, None; K. A. Koelsch, None; L. Radfar, None; D. M. Lewis, None; D. U. Stone, None; C. E. Kaufman, None; S. Li, None; B. M. Segal, None; D. J. Wallace, None; M. Weisman, None; J. A. Kelly, None; B. Pons-Estel, None; R. Jonsson, None; J. E. Gottenberg, None; J. M. Anaya, None; D. S. Cunninghame-Graham, None; V. P. Bykerk, None; G. Hirschfield, None; G. Xie, None; W. F. Ng, None; G. Nordmark, None; P. Eriksson, None; R. Omdal, None; N. L. Rhodus, None; M. Rischmueller, None; M. D. Rohrer, None; M. Wahren-Herlenius, None; T. Witte, None; X. Mariette, None; C. J. Lessard, None; J. B. Harley, None; K. L. Sivils, None; A. Rasmussen, None; R. H. Scofield, Eli Lilly and Company, 5,UCB, 5; S. Venturopalli, None; X. Lu, None; P. Hughes, None; A. J. W. Huang, None; C. Miceli-Richard, None.

To cite this abstract in AMA style:

Sharma R, Harris VM, Cavett J, Kurien BT, Liu K, Koelsch KA, Radfar L, Lewis DM, Stone DU, Kaufman CE, Li S, Segal BM, Wallace DJ, Weisman M, Kelly JA, Pons-Estel B, Jonsson R, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Bykerk VP, Hirschfield G, Xie G, Ng WF, Nordmark G, Eriksson P, Omdal R, Rhodus NL, Rischmueller M, Rohrer MD, Wahren-Herlenius M, Witte T, Mariette X, Lessard CJ, Harley JB, Sivils KL, Rasmussen A, Scofield RH, Venturopalli S, Lu X, Hughes P, Huang AJW, Miceli-Richard C. Very Rare X Chromosome Abnormalities in SLE and SjöGren’s May Localize X Gene Dose Effect [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/very-rare-x-chromosome-abnormalities-in-sle-and-sjogrens-may-localize-x-gene-dose-effect/. Accessed .

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