Identification of Modifier Gene Variants Overrepresented in Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis Patients With a More Aggressive Renal Phenotype

Abstract

Inter- and intra-familial phenotypic variability is a common observation in genetic diseases. In this study we have gathered a highly unique patient cohort suffering from an ultra-rare renal disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, with a deep clinical and genetic characterization. In this cohort, we have previously reported a high phenotypic variability between patients harbouring exactly the same mutation in homozygosis (70% of patients), even between siblings. Patients were stratified at the extremes according to their estimated glomerular filtration rate annual decline and subjected to whole exome sequencing aiming to find candidate phenotype modifier genes. The analysis pipeline applied has allowed us to find, for the first time, 17 putative modifier gene variants associated with a more aggressive renal phenotype. Our results led to a panel of genetic variants in novel candidate modifier genes which will be useful to stratify patients according to their risk of developing renal failure earlier in life and, therefore, direct them to more appropriate and personalized therapeutic options.

The role of claudins in renal transepithelial transport and kidney disease

“…Novel biallelic mutations in Cldn16 causing FHHNC, such as the recently discovered F55/125S mutation (short/long version of human claudin-16, respectively), corroborate the pivotal role of claudin-16 in calcium and magnesium reabsorption [52]. However, symptoms of FHHNC patient may be aggravated by further modifier variants in various genes, as demonstrated by Vall-Palomar et al [53 ▪▪ ]. Interestingly, one of the candidates associated with a more aggressive phenotype in their FHHNC cohort was a variant in CLDN17 .…”