Jae Won Yun1, Jisu Oh2, Ki-O Lee3, Seon Ju Lee4, Jung Oh Kim4, Nam Keun Kim4, Jin Seok Kim5, Youngil Koh6, Sung-Soo Yoon6, Ho-Young Yhim7, Sang-Kyung Jo8, Yong Park8, Jung Eun Lee9, Jinny Park10, Jong Wook Lee11, Sun-Hee Kim1, Hee-Jin Kim12, Doyeun Oh13. 1. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 2. Department of Internal Medicine, School of Medicine, CHA University, Seongnam, Republic of Korea. 3. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. 4. Department of Biomedical Science, CHA University College of Life Science, Seongnam, Republic of Korea. 5. Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. 6. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. 7. Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea. 8. Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea. 9. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 10. Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea. 11. Department of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 12. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: heejinkim@skku.edu. 13. Department of Internal Medicine, School of Medicine, CHA University, Seongnam, Republic of Korea. Electronic address: doh@cha.ac.kr.
Abstract
INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS. MATERIALS AND METHODS: Sixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [CFH, CFB, CFI, CD46, C3, THBD, PLG, and DGKE] and seven candidate genes [CFP, C4BPA, and CHFR1-5]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions. RESULTS: Thirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/CFHR1 homozygous deletions. CONCLUSIONS: The genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS.
INTRODUCTION:Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA), characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and renal failure. In more than half of cases, genetic defects leading to overactivation of the alternative complement system have been identified. In this study, we investigated genetic defects in Korean adult patients with aHUS. MATERIALS AND METHODS: Sixty-six Korean adult patients with aHUS were ascertained from the Korean TMA Registry. Genetic variants of 15 aHUS-related genes (eight core genes [CFH, CFB, CFI, CD46, C3, THBD, PLG, and DGKE] and seven candidate genes [CFP, C4BPA, and CHFR1-5]) were analyzed from exome sequencing data. Multiplex ligation-dependent probe amplification of CFH and related genes was performed to detect hybrid genes or large deletions. RESULTS: Thirty patients (45%) had at least one aHUS-related variant (s) in eight core genes (total 40 variant alleles). The most frequently affected gene was CFH (13/40, 32%), followed by THBD (8/40, 20%) and CD46 (7/40, 18%). The two most common variants were Asp486Tyr of THBD (N = 7) and Tyr1058His-Val1060Leu of CFH (N = 5, linked on the same allele), accounting for 30% (12/40). In seven candidate genes, 19 variants were detected. When combined, 40 patients (61%) had at least one variant in 15 core or candidate genes. No patients had anti-CFH Ab or hybrid gene/CFHR1 homozygous deletions. CONCLUSIONS: The genetic profile of Korean adult aHUS was unique with recurrent missense variants, demonstrating ethnicity- and age-dependent differences in the genetic background of aHUS.
Authors: Maria Helena Vaisbich; Luís Gustavo Modelli de Andrade; Precil Diego Miranda de Menezes Neves; Lílian Monteiro Pereira Palma; Maria Cristina Ribeiro de Castro; Cassiano Augusto Braga Silva; Maria Izabel Neves de Holanda Barbosa; Maria Goretti Moreira Guimarães Penido; Oreste Ângelo Ferra Neto; Roberta Mendes Lima Sobral; Silvana Maria Carvalho Miranda; Stanley de Almeida Araújo; Igor Gouveia Pietrobom; Henrique Mochida Takase; Cláudia Ribeiro; Rafael Marques da Silva; César Augusto Almeida de Carvalho; David José Barros Machado; Ana Mateus Simões Teixeira E Silva; Andreia Ribeiro da Silva; Enzo Ricardo Russo; Flávio Henrique Soares Barros; Jarinne Camilo Landim Nasserala; Luciana Schmitt Cardon de Oliveira; Lucimary de Castro Sylvestre; Rafael Weissheimer; Sueli Oliveira Nascimento; Gilson Bianchini; Fellype de Carvalho Barreto; Valéria Soares Pigozzi Veloso; Patrícia Marques Fortes; Vinicius Sardão Colares; Jaelson Guilhem Gomes; André Falcão Pedrosa Leite; Pablo Girardelli Mendonça Mesquita; Osvaldo Merege Vieira-Neto Journal: Clin Kidney J Date: 2022-04-11