Ezgi Deniz Batu1,2, Can Koşukcu1,2, Ekim Taşkıran1,2, Sezgin Sahin1,2, Sema Akman1,2, Betül Sözeri1,2, Erbil Ünsal1,2, Yelda Bilginer1,2, Ozgur Kasapcopur1,2, Mehmet Alikaşifoğlu1,2, Seza Ozen3,4. 1. From the Department of Pediatrics, Division of Rheumatology, and the Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara; Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, Ankara; Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul; Department of Pediatrics, Division of Nephrology and Rheumatology, Akdeniz University Faculty of Medicine, Antalya; Department of Pediatrics, Division of Rheumatology, Umraniye Training and Research Center, University of Health Sciences, Istanbul; Department of Pediatrics, Division of Rheumatology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey. 2. E.D. Batu, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine; C. Koşukcu, MSc, Department of Medical Genetics, Hacettepe University Faculty of Medicine, and Department of Bioinformatics, Institute of Health Sciences, Hacettepe University; E. Taşkıran, PhD, Department of Medical Genetics, Hacettepe University Faculty of Medicine; S. Sahin, MD, Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine; S. Akman, MD, Department of Pediatrics, Division of Nephrology and Rheumatology, Akdeniz University Faculty of Medicine; B. Sözeri, MD, Department of Pediatrics, Division of Rheumatology, Umraniye Training and Research Center, University of Health Sciences; E. Ünsal, MD, Department of Pediatrics, Division of Rheumatology, Dokuz Eylül University Faculty of Medicine; Y. Bilginer, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine; O. Kasapcopur, MD, Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine; M. Alikaşifoğlu, MD, PhD, Department of Medical Genetics, Hacettepe University Faculty of Medicine; S. Ozen, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine. 3. From the Department of Pediatrics, Division of Rheumatology, and the Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara; Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, Ankara; Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul; Department of Pediatrics, Division of Nephrology and Rheumatology, Akdeniz University Faculty of Medicine, Antalya; Department of Pediatrics, Division of Rheumatology, Umraniye Training and Research Center, University of Health Sciences, Istanbul; Department of Pediatrics, Division of Rheumatology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey. sezaozen@hacettepe.edu.tr. 4. E.D. Batu, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine; C. Koşukcu, MSc, Department of Medical Genetics, Hacettepe University Faculty of Medicine, and Department of Bioinformatics, Institute of Health Sciences, Hacettepe University; E. Taşkıran, PhD, Department of Medical Genetics, Hacettepe University Faculty of Medicine; S. Sahin, MD, Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine; S. Akman, MD, Department of Pediatrics, Division of Nephrology and Rheumatology, Akdeniz University Faculty of Medicine; B. Sözeri, MD, Department of Pediatrics, Division of Rheumatology, Umraniye Training and Research Center, University of Health Sciences; E. Ünsal, MD, Department of Pediatrics, Division of Rheumatology, Dokuz Eylül University Faculty of Medicine; Y. Bilginer, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine; O. Kasapcopur, MD, Department of Pediatrics, Division of Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine; M. Alikaşifoğlu, MD, PhD, Department of Medical Genetics, Hacettepe University Faculty of Medicine; S. Ozen, MD, MSc, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine. sezaozen@hacettepe.edu.tr.
Abstract
OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE. METHODS: We enrolled 7 SLE cases (from different families) with disease onset ≤ 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons of C1QA, C1QB, and C1QC were screened with Sanger sequencing. RESULTS: We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in C1QA in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in C1QC in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in C1QC in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in C1S in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. Further, in 1 patient, we determined a strong candidate variant in HDAC7 (histone decetylase 7). CONCLUSION: Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had DNASE1L3 variant, which functions in the clearance of self-antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE.
OBJECTIVE:Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE. METHODS: We enrolled 7 SLE cases (from different families) with disease onset ≤ 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons of C1QA, C1QB, and C1QC were screened with Sanger sequencing. RESULTS: We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in C1QA in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in C1QC in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in C1QC in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in C1S in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. Further, in 1 patient, we determined a strong candidate variant in HDAC7 (histone decetylase 7). CONCLUSION: Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had DNASE1L3 variant, which functions in the clearance of self-antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE.
Authors: Johannes Hartl; Lee Serpas; Yueyang Wang; Ali Rashidfarrokhi; Oriana A Perez; Benjamin Sally; Vanja Sisirak; Chetna Soni; Alireza Khodadadi-Jamayran; Aristotelis Tsirigos; Ivan Caiello; Claudia Bracaglia; Stefano Volpi; Gian Marco Ghiggeri; Asiya Seema Chida; Ignacio Sanz; Mimi Y Kim; H Michael Belmont; Gregg J Silverman; Robert M Clancy; Peter M Izmirly; Jill P Buyon; Boris Reizis Journal: J Exp Med Date: 2021-05-03 Impact factor: 14.307
Authors: Rebecca W Y Chan; Lee Serpas; Meng Ni; Stefano Volpi; Linda T Hiraki; Lai-Shan Tam; Ali Rashidfarrokhi; Priscilla C H Wong; Lydia H P Tam; Yueyang Wang; Peiyong Jiang; Alice S H Cheng; Wenlei Peng; Diana S C Han; Patty P P Tse; Pik Ki Lau; Wing-Shan Lee; Alberto Magnasco; Elisa Buti; Vanja Sisirak; Nora AlMutairi; K C Allen Chan; Rossa W K Chiu; Boris Reizis; Y M Dennis Lo Journal: Am J Hum Genet Date: 2020-10-05 Impact factor: 11.025