Identification of modifier gene variants overrepresented in familial hypomagnesemia with hypercalciuria and nephrocalcinosis patients with a more aggressive renal phenotype

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis; Renal phenotype

Hipomagnesèmia familiar amb hipercalciúria i nefrocalcinosi; Fenotip renal

Hipomagnesemia familiar con hipercalciuria y nefrocalcinosis; Fenotipo renal

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an ultra-rare autosomal recessive renal tubular disease with an incidence of <1/1.000.000 individuals, caused by loss-of-function mutations in CLDN16 and CLDN19. Our study includes a unique cohort representing all known FHHNC patients in Spain, with 90% harbouring mutations in CLDN19. Of these, 70% carry the p.G20D mutation in homozygosis. Despite this high genetic homogeneity, our FHHNC cohort display a high phenotypic variability, even among siblings harbouring identical mutations. Patients were stratified at the extremes of the renal phenotype according to their estimated glomerular filtration rate annual decline and subjected to whole exome sequencing (WES) aiming to find candidate phenotype-modifier genes. Initial statistical analysis by SKAT-O identified numerous variants, which were then filtered based on P-value <0.01 and kidney expression. A thorough prioritization strategy was then applied by an exhaustive disease knowledge-driven exploitation of data from public databases (Human Protein Atlas, GWAS catalog, GTEx) to further refine candidate genes. Odds ratios were also calculated to identify potential risk variants. This analysis pipeline suggested several gene variants associated with a higher risk of developing a more aggressive renal phenotype. While these findings hint at the existence of genetic modifiers in FHHNC, further research is needed to confirm their role and potential clinical significance. Clinical decisions should not be based on these preliminary findings, and additional cohorts should be studied to validate and expand upon our results. This exploratory study provides a foundation for future investigations into the genetic factors influencing FHHNC progression and may contribute to our understanding of the disease’s variable expressivity potentially enabling the implementation of more tailored therapeutic strategies.

This study was funded in part by Fondo Europeo de Desarrollo Regional (FEDER), Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Subdirección General de Investigación Sanitaria, Ministerio de Ciencia e Innovación (PI14/01107, PI18/01107, PI22/01946 to GA); by the Fundación Senefro (SEN2023 to AM); and by donations from the FHHNC patient advocacy group HIPOFAM (to GA and AM). AM research group holds the Quality Mention from the Generalitat de Catalunya (Grant No. 2021 SGR 01600 to AM). CMM is supported by the Miguel Servet program from the Instituto de Salud Carlos III, Subdirección General de Investigación Sanitaria, Ministerio de Ciencia e Innovación (CP18/00116).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.