1. FrequentCOL4mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis
- Author
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Daniel P. Gale, Eugenios Daphnis, Dimitris Goumenos, Antonia Papadaki, Alkis Pierides, George Vergoulas, Elena Frysira, Konstantinos Voskarides, Constantina Koutsofti, Constantinos Deltas, Despina Hadjipanagi, Petros Ioannou, Dimitrios Grekas, Eleni Georgaki, Ioannis Tzanakis, Christina Melexopoulou, Garyfalia Perysinaki, Athanasios Diamantopoulos, Andreas Soloukides, Alivanis P, Louiza Papazachariou, Gregory Papagregoriou, Dimitris Xydakis, Fifi Komianou, Panagiota Demosthenous, Ioannis Boletis, Nicolaos Nikolakakis, Christos Paliouras, Nicolaos Kallivretakis, Pavlos Goudas, and Kostas Stylianou
- Subjects
Adult ,Collagen Type IV ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,030232 urology & nephrology ,Nephritis, Hereditary ,Penetrance ,urologic and male genital diseases ,Nephropathy ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Focal segmental glomerulosclerosis ,Glomerulopathy ,Internal medicine ,Glomerular Basement Membrane ,Genetics ,medicine ,Humans ,Family ,Age of Onset ,Microhematuria ,Alport syndrome ,Genetics (clinical) ,Aged ,Hematuria ,Aged, 80 and over ,Glomerulosclerosis, Focal Segmental ,Genetic heterogeneity ,business.industry ,High-Throughput Nucleotide Sequencing ,Middle Aged ,medicine.disease ,medicine.icd_9_cm_classification ,Pedigree ,030104 developmental biology ,Endocrinology ,Mutation ,Female ,CFHR5 nephropathy ,business ,CFHR5 - 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.
- Published
- 2017