High-Throughput Genetic Testing for Thrombotic Microangiopathies and C3 Glomerulopathies.
The thrombotic microangiopathies (TMAs) and C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, C3GN, and dense deposit disease, which share phenotypic similarities and underlying genetic commonalities. Variants in several genes contribute to the pathogenesis of these diseases, and identification of these variants may inform the diagnosis and treatment of affected patients. We have developed and validated a comprehensive genetic panel that screens all exons of all genes implicated in TMA and C3G. The closely integrated pipeline implemented includes targeted genomic enrichment, massively parallel sequencing, bioinformatic analysis, and a multidisciplinary conference to analyze identified variants in the context of each patient's specific phenotype. Herein, we present our 1-year experience with this panel, during which time we studied 193 patients. We identified 17 novel and 74 rare variants, which we classified as pathogenic (11), likely pathogenic (12), and of uncertain significance (68). Compared with controls, patients with C3G had a higher frequency of rare and novel variants in C3 convertase (C3 and CFB) and complement regulator (CFH, CFI, CFHR5, and CD46) genes (P<0.05). In contrast, patients with TMA had an increase in rare and novel variants only in complement regulator genes (P<0.01), a distinction consistent with differing sites of complement dysregulation in these two diseases. In summary, we were able to provide a positive genetic diagnosis in 43% and 41% of patients carrying the clinical diagnosis of C3G and TMA, respectively.
Interdisciplinary PhD Program in Genetics, Molecular Otolaryngology and Renal Research Laboratories.
Fengxiao
F
Bu
Molecular Otolaryngology and Renal Research Laboratories.
Nicolo Ghiringhelli
NG
Borsa
Molecular Otolaryngology and Renal Research Laboratories.
Michael B
MB
Jones
Molecular Otolaryngology and Renal Research Laboratories.
Erika
E
Takanami
Molecular Otolaryngology and Renal Research Laboratories, Iowa Institute of Human Genetics.
Carla
C
Nishimura
Department of Biomedical Engineering.
Jill J
JJ
Hauer
Molecular Otolaryngology and Renal Research Laboratories.
Hela
H
Azaiez
Molecular Otolaryngology and Renal Research Laboratories.
Elizabeth A
EA
Black-Ziegelbein
Molecular Otolaryngology and Renal Research Laboratories.
Nicole C
NC
Meyer
Iowa Institute of Human Genetics.
Diana L
DL
Kolbe
Molecular Otolaryngology and Renal Research Laboratories.
Yingyue
Y
Li
Molecular Otolaryngology and Renal Research Laboratories.
Kathy
K
Frees
Department of Biomedical Engineering.
Michael J
MJ
Schnieders
Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Department of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
Christie
C
Thomas
Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Department of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
Carla
C
Nester
Molecular Otolaryngology and Renal Research Laboratories, Iowa Institute of Human Genetics, Division of Nephrology, Department of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa richard-smith@uiowa.edu.
Richard J H
RJ
Smith
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003176:Complement C3; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007674:Kidney Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000276:immunology; D007678:Kidney Glomerulus; D008297:Male; D057049:Thrombotic Microangiopathies / Q000175:diagnosis* / Q000235:genetics*
D003176:Complement C3
C3 Glomerulopathy; Genetic testing; Thrombotic Microangiopathy