TY - JOUR
TI - 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. and
AU - Demosthenous, P.
AU - Voskarides, K.
AU - Koutsofti, C.
AU - Stylianou, K.
AU - and Ioannou, P.
AU - Xydakis, D.
AU - Tzanakis, I.
AU - Papadaki, A. and
AU - Kallivretakis, N.
AU - Nikolakakis, N.
AU - Perysinaki, G.
AU - Gale, D. P.
AU - and Diamantopoulos, A.
AU - Goudas, P.
AU - Goumenos, D.
AU - Soloukides,
AU - A.
AU - Boletis, I.
AU - Melexopoulou, C.
AU - Georgaki, E.
AU - Frysira, E.
AU - and Komianou, F.
AU - Grekas, D.
AU - Paliouras, C.
AU - Alivanis, P. and
AU - Vergoulas, G.
AU - Pierides, A.
AU - Daphnis, E.
AU - Deltas, C.
JO - Application of Clinical Genetics
PY - 2017
VL - 92
TODO - 5
SP - 517-527
PB - Wiley
SN - null
TODO - 10.1111/cge.13077
TODO - 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)
TODO - 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.
ER -