COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

BMC Nephrology
Konstantinos VoskaridesConstantinos Deltas

Abstract

About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includ...Continue Reading

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Citations

Feb 7, 2019·American Journal of Physiology. Renal Physiology·Steven D FunkJeffrey H Miner
May 3, 2019·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Ashima GulatiAlda Tufro
Feb 29, 2020·Genes·K M Tahsin Hassan Rahit, Maja Tarailo-Graovac
Feb 28, 2019·BMC Nephrology·S DagaA M Pinto
Jun 30, 2019·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Erol Demir, Yasar Caliskan
May 31, 2019·Molecular Genetics & Genomic Medicine·Shunlai ShangXiang M Chen
Feb 18, 2020·Clinical Science·Holly Mabillard, John A Sayer
Jul 28, 2020·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Clifford E Kashtan
Apr 4, 2021·Genes·Zureesha SajidZubair M Ahmed
Jul 11, 2021·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Judy Savige, Philip Harraka
May 11, 2020·American Journal of Human Genetics·Dimitrios Vitsios, Slavé Petrovski

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Methods Mentioned

BETA
biopsy
Exome Sequencing

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