Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.


Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.





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Publication Info

Malone, Andrew F, Paul J Phelan, Gentzon Hall, Umran Cetincelik, Alison Homstad, Andrea S Alonso, Ruiji Jiang, Thomas B Lindsey, et al. (2014). Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int, 86(6). pp. 1253–1259. 10.1038/ki.2014.305 Retrieved from https://hdl.handle.net/10161/11616.

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Matthew A. Sparks

Associate Professor of Medicine

I serve as the Program Director for the Nephrology Fellowship Program. My goal is to work with each fellow to ensure they develop a successful career in whatever direction they choose. I am the lead for the newly established Society for Early Education Scholars (SEEDS) in the Department of Medicine. The SEEDS Program is a year-long mentored education program designed for fellows planning careers as clinician educators or education scholars.

Nephrology Fellowship Program

My interest is in finding ways to promote medical education. My focus is on leveraging social media to enhance learning in nephrology. I serve as the associate director for the Nephrology Social Media Collective (NSMC) internship and member of the board of directors of nephrology journal club (NephJC), a non-profit organization dedicated to enhancing free online medical education in nephrology. I am also co-founder and advisory board member of the first nephrology blog associated with a journal- AJKD blog, the official blog of the American Journal of Kidney Diseases. Co-creator of the popular educational project NephMadness. Past deputy editor of Renal Fellow Network where I continue to remain as faculty lead. I am currently a member of the Nephrology Board of the American Board of Internal Medicine, the Scientific and Clinical Education Lifelong learning Committee Chair, Kidney in Cardiovascular Disease Council of the American Heart Association and am a fellow of the American Society of Nephrology, the American Heart Association, and the National Kidney Foundation. 

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Stephen Richard Smith

Professor of Medicine

Ongoing work focuses on problems of immediate clinical relevance in renal and pancreas transplantation, including issues related to immunosuppression, infection, and cardiovascular events as well as hypertension.

Research methodologies employed include randomized clinical trials, cohort studies, and retrospective multivariable analyses based on the transplant database. 


David Noble Howell

Professor of Pathology

A major focus of both my clinical practice and investigative work is the diagnosis and treatment of disorders affecting solid-organ transplant recipients, particularly infectious complications. For the past 15 years, I have served as the primary pathologist for one of the largest lung transplant programs in the world; in the process contributing to over 20 peer-reviewed publications on complications of lung transplantation, including infections, gastroesophageal reflux, tumors, and antibody-mediated rejection; and writing a major book chapter on the subject (Howell DN and Palmer SM, Pathology of the Lung Transplant. 2006. In: Lynch JP, Ross D, eds. Lung and Heart-Lung Transplantation. Marcel Dekker, Inc., New York, pp. 683-722). I have also been the primary pathologist for Duke's renal and liver transplant programs, authoring or co-authoring a wide variety of journal articles and a book chapter in these areas (e.g., Plumb et al., Transplantation 2006;82:1224-1224; Snyder et al., Am. J. Respir. Crit. Care Med. 2010;181:1391-1396).

A second major area of interest is the pathogenesis of renal glomerular diseases. In collaboration with members of the Division of Nephrology at Duke, I have helped assemble and characterize a large registry of patients with familial focal segmental glomerulosclerosis (FFSGS)(Conlon et al., Kidney Int. 1999;56:1863-1871). Analysis of one of the families in this registry led to the discovery at Duke, in the laboratory of Dr. Michelle Winn, of mutations in the TRPC6 cation channel as a cause of FFSGS (Winn et al., Genomics 1999;58:113-120; Winn et al., Science 2005;308:1801-1804). We are continuing to collect data on additional families with focal segmental glomerulosclerosis. In addition, I have served as principle consultative pathologist for several investigators working in animal models of renal disease and transplantation (e.g., Crowley et al., Hypertension 2010;55:99-108).

Finally, I have devoted considerable time and energy to applications of correlative microscopy to diagnostic pathology, with particular emphasis electron microscopy. I am currently President of the Society for Ultrastructural Pathology, an international organization that promotes the use of ultrastructural examination in both diagnostic pathology and clinical and basic research. Much of my published work in this area involves the role of electron microscopy in the diagnosis of renal diseases (e.g., Howell et al., Ultrastruct. Pathol. 2003;17:295-312; Pavlisko and Howell, Ultrastruct. Pathol., in press), but I have also written extensively, with my colleague Dr. Sara Miller, on the ultrastructural diagnosis of infectious disorders, contributing, among other things, to the first description of a new polyomavirus-induced skin disorder, trichodysplasia spinulosa (Haycox et al., J. Investig. Dermatol. Symp. Proc. 1999;4:268-271).


Rasheed Adebayo Gbadegesin

Wilburt C. Davison Distinguished Professor

Molecular genetics of glomerular disease
Genetic risk factors for childhood onset idiopathic nephrotic syndrome

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