Papazachariou, L;
Papagregoriou, G;
Hadjipanagi, D;
Demosthenous, P;
Voskarides, K;
Koutsofti, C;
Stylianou, K;
... Deltas, C; + view all
(2017)
Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.
Clinical Genetics
, 92
(5)
10.1111/cge.13077.
Preview |
Text
2017 Papazachariou et al Clinical Genet accepted 2017.pdf - Accepted Version Download (8MB) | Preview |
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 five genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, nine of them novel. In five 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, eight (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-yrs, 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.
| Type: | Article |
|---|---|
| Title: | Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis |
| Location: | Denmark |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/cge.13077 |
| Publisher version: | http://doi.org/10.1111/cge.13077 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| 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) |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1560088 |
Archive Staff Only
 |
View Item |
