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 authors have declared no competing interest.

This study was funded in part by Fondo Europeo de Desarrollo Regional (FEDER), Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Subdirección General de Investigacion Sanitaria, Ministerio de Ciencia e Innovacion (GA: PI14/01107, PI18/01107, PI22/01946), and by donations from the FHHNC patient advocacy group HIPOFAM. CM is suppor-ted by the Miguel Servet program from the Instituto de Salud Carlos III, Subdireccion General de Investigacion Sanitaria, Ministerio de Ciencia e Innovacion (CP18/00116). MV-P and JT are supported by HIPOFAM.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All patients or their caregivers provided written informed consent before participation in the study. This study was approved by the Ethics Committee of our institution the Vall dHebron Hospital (PR(AMI)280/2015). Patient records were consulted only to obtain relevant patient data. The described research adhered to the Declaration of Helsinki.

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Availability of data and materials: De-identified data will be made available upon request from qualified investigators studying the molecular basis of renal rare disorders. Datasets can be obtained via the corresponding author.