title: Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.
abstract: 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.
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Malone
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Phelan
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.affiliation: Department of Genetics, Sisli Etfal Training and Research Hospital, Istanbul, Turkey.
authors.forename: Umran
authors.initials: U
authors.lastname: Cetincelik
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Homstad
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Alonso
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ruiji
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Duke Molecular Physiology Institute, Durham, North Carolina, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Lindsey
authors.affiliation: Duke Molecular Physiology Institute, Durham, North Carolina, USA.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sparks
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Smith
authors.affiliation: Department of Pediatric Nephrology and NIHR/Wellcome Trust Children's Clinical Research Facility, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, The University of Manchester, Manchester, UK.
authors.forename: Nicholas J A
authors.initials: NJ
authors.lastname: Webb
authors.affiliation: Hope Hospital, Salford, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Kalra
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Adebowale A
authors.initials: AA
authors.lastname: Adeyemo
authors.affiliation: Department of Pathology and Immunology, Washington University, St Louis, Missouri, USA.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.affiliation: Beaumont Kidney Centre, Beaumont Hospital, Royal College of Surgeons, Dublin, Ireland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Conlon
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Howell
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
authors.affiliation: 1] Duke Molecular Physiology Institute, Durham, North Carolina, USA [2] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Rasheed A
authors.initials: RA
authors.lastname: Gbadegesin
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics*; D002648:Child; D024141:Collagen Type IV / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D050533:Glomerular Basement Membrane / Q000648:ultrastructure; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000235:genetics* / Q000473:pathology; D034381:Hearing Loss / Q000235:genetics; D006417:Hematuria / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D050199:Podocytes / Q000648:ultrastructure; D011507:Proteinuria / Q000209:etiology; D055815:Young Adult
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain