TY - JOUR
T1 - Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis
AU - Papazachariou, L.
AU - Papagregoriou, G.
AU - Hadjipanagi, D.
AU - Demosthenous, P.
AU - Voskarides, K.
AU - Koutsofti, C.
AU - Stylianou, K.
AU - Ioannou, P.
AU - Xydakis, D.
AU - Tzanakis, I.
AU - Papadaki, A.
AU - Kallivretakis, N.
AU - Nikolakakis, N.
AU - Perysinaki, G.
AU - Gale, D. P.
AU - Diamantopoulos, A.
AU - Goudas, P.
AU - Goumenos, D.
AU - Soloukides, A.
AU - Boletis, I.
AU - Melexopoulou, C.
AU - Georgaki, E.
AU - Frysira, E.
AU - Komianou, F.
AU - Grekas, D.
AU - Paliouras, C.
AU - Alivanis, P.
AU - Vergoulas, G.
AU - Pierides, A.
AU - Daphnis, E.
AU - Deltas, C.
N1 - Funding Information:
European Regional Development Fund and the Republic of Cyprus through the Research Promotion Foundation (Strategic Infrastructure Project NEW INFRASTRUCTURE/STRATEGIC/0308/24) to C.D.
Funding Information:
All clinical and biological material was accessible through the University of Cyprus Biobank.16 This research project was approved by the Cyprus National Bioethics Committee.
Funding Information:
European Regional Development Fund; Cyprus Research Promotion Foundation
Publisher Copyright:
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - Alport syndrome
KW - COL4A3/COL4A4/COL4A5
KW - end-stage renal disease (ESRD)
KW - familial microscopic hematuria
KW - focal segmental glomerulosclerosis (FSGS)
KW - later-onset Alport-related nephropathy (LOAN)
KW - next generation sequencing
KW - thin basement membrane nephropathy (TBMN)
UR - http://www.scopus.com/inward/record.url?scp=85030258937&partnerID=8YFLogxK
U2 - 10.1111/cge.13077
DO - 10.1111/cge.13077
M3 - Article
C2 - 28632965
AN - SCOPUS:85030258937
SN - 0009-9163
VL - 92
SP - 517
EP - 527
JO - Clinical Genetics
JF - Clinical Genetics
IS - 5
ER -