Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis

Abstract

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

Keywords: Bartter syndrome; human genetics; hypercalciuria; kidney stones; molecular genetics; renal tubular acidosis.

Figure 1.

Distribution of established molecular genetic causes of NL/NC. (A) Percentage of subjects with identified molecular diagnoses across grouped ages of onset. This percentage is significantly higher in the pediatric cohort (age of onset<18 years) compared with the adult cohort (age of onset≥18 years): 20.8% versus 11.4%. *P≤0.05. In A and B, the green rectangles indicate six individuals with heterozygous SLC7A9 mutations enriched within the age group ≥18–30 years (6 of 19=31.6%). (B) Distribution of age of onset across mutated causative genes. Genes with a dominant mode are annotated in black, whereas genes with a recessive mode are annotated in red. ^†For SLC2A9, SLC22A12, and SLC7A9, detected mutations were primarily dominant, although both modes of inheritance have been reported. Detected mutations in four of six genes with a median onset ≥18 years are in dominant genes (upper right quadrant as indicated by dashed lines), whereas six of eight genes with a median onset of disease <18 years are in recessive genes (lower left quadrant as indicated by dashed lines).