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Clin Genet. 2017 Nov;92(5):517-527. doi: 10.1111/cge.13077. Epub 2017 Sep 25.

Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.

Author information

1
Molecular Medicine Research Center & Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
2
Department of Nephrology, University of Crete-Greece, Heraklion, Greece.
3
Department of Nephrology, General Hospital of Chania, Crete, Greece.
4
Division of Nephrology, General Hospital of Rethymno, Crete, Greece.
5
UCL Division of Medicine and Centre for Nephrology, University College London, London, UK.
6
Department of Nephrology, Ayios Andreas Hospital, Patra, Greece.
7
IATOS Dialysis Unit, Patra, Greece.
8
Department of Nephrology, Medical School, University of Patras, Patra, Greece.
9
Protypo Nefrologiko Athinon Dialysis Center, Athens, Greece.
10
Department of Nephrology, Laikon Hospital, Athens, Greece.
11
Pediatric Nephrology Unit, "IASO" Children's Hospital, Athens, Greece.
12
Department of Pediatrics, Athens University Medical School, Agia Sophia Children's Hospital, Athens, Greece.
13
Department of Medical Genetics, Athens University Medical School, Agia Sophia Children's Hospital, Athens, Greece.
14
University Hospital AXEPA, Thessaloniki, Greece.
15
Department of Nephrology, General Hospital of Rhodes, Rhodes, Greece.
16
Organ Transplant Unit, Hippokratio General Hospital, Thessaloniki, Greece.
17
Department of Nephrology, Hippocrateon Hospital, Nicosia, Cyprus.

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.

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)

PMID:
28632965
DOI:
10.1111/cge.13077
[Indexed for MEDLINE]

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