@article{3176664,
    title = "Frequent COL4 mutations in familial microhematuria accompanied by
later-onset Alport nephropathy due to focal segmental glomerulosclerosis",
    author = "Papazachariou, L. and Papagregoriou, G. and Hadjipanagi, D. and and Demosthenous, P. and Voskarides, K. and Koutsofti, C. and Stylianou, K. and and Ioannou, P. and Xydakis, D. and Tzanakis, I. and Papadaki, A. and and Kallivretakis, N. and Nikolakakis, N. and Perysinaki, G. and Gale, D. P. and and Diamantopoulos, A. and Goudas, P. and Goumenos, D. and Soloukides, and A. and Boletis, I. and Melexopoulou, C. and Georgaki, E. and Frysira, E. and and Komianou, F. and Grekas, D. and Paliouras, C. and Alivanis, P. and and Vergoulas, G. and Pierides, A. and Daphnis, E. and Deltas, C.",
    journal = "Application of Clinical Genetics",
    year = "2017",
    volume = "92",
    number = "5",
    pages = "517-527",
    publisher = "Wiley",
    doi = "10.1111/cge.13077",
    keywords = "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)",
    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."
}