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

Abstract

BackgroundAbout 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).MethodsHere, 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.ResultsIn 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 includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts.ConclusionsA modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.Electronic supplementary materialThe online version of this article (10.1186/s12882-018-0906-5) contains supplementary material, which is available to authorized users.

Digenic inheritance and genetic modifiers

“…Mice with a double Lama5 knockout are fatal; however, mice with a hypomorphic Lama5 mutation (Lama5neo) that reduces laminin‐α5 expression, exhibit proteinuria, hematuria and cystic kidneys . It is probable, therefore, that although this might not represent true DI, the LAMA5 ‐p.Pro1243Leu variant behaves as a hypomorphic mutation that adds up to the Alport background…”

“…52 Several reports on renal genetic studies using NGS have identified rare patients with 2 mutations in separate genes but it is not clear whether they act as modifiers to each other or they represent true DI of nephrotic syndrome. 53 In our setup we studied a family where 54 It is probable, therefore, that although this might not represent true DI, the LAMA5-p.Pro1243Leu variant behaves as a hypomorphic mutation that adds up to the Alport background 55 Evidence for true DI was published while this review was in press, in a Libyan patient with distal renal tubular acidosis (dRTA).…”

Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

“…Arrows point to the mutations. Family 7 has one novel mutation, c. 3,782 G > A researches and cases reported that AS patients with COL4A5 mutations who have coinherited with COL4A3/COL4A4, MYO1E and LAMA5 mutations could exacerbated phenotypes (Lennon et al, 2015;Voskarides et al, 2018). These clinical symptoms occur mostly in the late disease stages and are thought to be secondary changes caused by primary GBM defects resulting from abnormalities in the collagen reticular structure (Braunisch et al, 2018).…”

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

“…We looked for references in literature for the top suggested novel genes per disease by mantis-ml and have found supporting evidence for several genes. For instance, LAMA5 has been reported in the last two years to be co-inherited with COL4A5 in familial hematuria 21 and hosting variants that may affect pediatric nephrotic syndrome 22,23 . Moreover, NOS3 and NOS2-although not associated with CKD in OMIM -have already been implicated in Chronic Kidney Disease in a fair amount of studies 24, 25,26,27 , while MEF2C, a gene typically associated with mental disorders, has also been associated with estimated Glomerular Filtration Rate (eGFR) or proteinuria 28 .…”