Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis. Issue 5 (25th September 2017)

• Record Type: Journal Article
• Authors: Papazachariou, L.; Papagregoriou, G.; Hadjipanagi, D.; Demosthenous, P.; Voskarides, K.; Koutsofti, C.; Stylianou, K.; Ioannou, P.; Xydakis, D.; Tzanakis, I.; Papadaki, A.; Kallivretakis, N.; Nikolakakis, N.; Perysinaki, G.; Gale, D.P.; Diamantopoulos, A.; Goudas, P.; Goumenos, D.; Soloukides, A.; Boletis, I.; Melexopoulou, C.; Georgaki, E.; Frysira, E.; Komianou, F.; Grekas, D.; Paliouras, C.; Alivanis, P.; Vergoulas, G.; Pierides, A.; Daphnis, E.; Deltas, C.;
• Is Part Of: Clinical genetics. Volume 92:Issue 5(2017)
• Page Start: 517
• Page End: 527
• Publication Date: 2017-09-25
• Subjects: Alport syndrome -- COL4A3/COL4A4/COL4A5 -- end‐stage renal disease (ESRD) -- familial microscopic hematuria -- focal segmental glomerulosclerosis (FSGS) -- later‐onset Alport‐related nephropathy (LOAN) -- next generation sequencing -- thin basement membrane nephropathy (TBMN); Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.13077
• Languages: English
• ISSNs: 0009-9163

Abstract

Abstract : Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen‐IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end‐stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1 . In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X‐linked COL4A5 mutations. Even more patients developed later‐onset Alport‐related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50‐years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X‐linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen‐IV glomerulopathies, frequently averting the need for invasive renal biopsies. Abstract : Amongst 42 patients in 12 families with heterozygous COL4A3 / A4 mutations, 5 (12%) developed ESRD. According to the current knowledge these patients with thin basement membrane nephropathy, develop a form of late‐onset Alport‐related nephropathy, mostly above 50 years. The former term of "familial benign hematuria" should be entirely abandoned.