Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene.

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1-4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.

Atypical aHUS: State of the art.

Tremendous advances in our understanding of the thrombotic microangiopathies (TMAs) have revealed distinct disease mechanisms within this heterogeneous group of diseases. As a direct result of this knowledge, both children and adults with complement-mediated TMA now enjoy higher expectations for long-term health. In this update on atypical hemolytic uremic syndrome, we review the clinical characteristics; the genetic and acquired drivers of disease; the broad spectrum of environmental triggers; and current diagnosis and treatment options. Many questions remain to be addressed if additional improvements in patient care and outcome are to be achieved in the coming decade.