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, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome 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 findings at diagnosis were 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 glomerular basement membrane, 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.

Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

“…Although most affected individuals develop hematuria in childhood, proteinuria, renal failure, and extrarenal disorders are not observed in patients with TBMN, and the molecular mechanisms responsible for the different clinical courses of ADAS and TBMN remain unclear. Recent studies have revealed correlations between FSGS and heterozygous mutations in COL4A3 or COL4A4 (3,4), and 10% of patients diagnosed with familial FSGS showed heterozygous mutations in these two genes (5). A recent study using next generation sequencing (NGS) analysis revealed high proportions of mutations in COL4A3 and COL4A4 and a higher incidence of ADAS than previously reported (6).…”

Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life

“…Also, we read with interest the work by Malone et al [40 ]who reported on rare hereditary COL4A3/A4 variants in patients who were initially misdiagnosed with FSGS. The authors presented 6 families with heterozygous COL4 mutations and 1 family with classic AS who were amongst 70 families with ‘familial FSGS' that had been analyzed by NGS, including either the whole exome or selected genes [40].…”

“…The authors presented 6 families with heterozygous COL4 mutations and 1 family with classic AS who were amongst 70 families with ‘familial FSGS' that had been analyzed by NGS, including either the whole exome or selected genes [40]. Nine patients reached ESRD at ages 37-83 years (mean ∼50 years) and 2 demonstrated thin basement membranes.…”

Three Novel Heterozygous<b><i> COL4A4</i></b> Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

“…Our findings suggest that COL4A4 gene mutations play a direct role in the development of segmental thinning of GBM and that FSGS may be secondary to the GBM defect. Malone et al [2014] also reported that collagen mutation-associated FSGS may actually be a pathological lesion in kidney disease and secondary to the GBM pathology [Malone et al, 2014]. The patient with TBMN also appeared to undergo an FSGSlike change at 33 years of age.…”