Systematic assessment of monogenic etiology in adult‐onset kidney stone formers undergoing urological intervention–evidence for genetic pretest probability

Abstract

Kidney stone disease (KSD) is a prevalent condition associated with high morbidity, frequent recurrence, and progression to chronic kidney disease (CKD). The etiology is multifactorial, depending on environmental and genetic factors. Although monogenic KSD is frequent in children, unbiased prevalence data of heritable forms in adults is scarce. Within 2 years of recruitment, all patients hospitalized for urological kidney stone intervention at our center were consecutively enrolled for targeted next generation sequencing (tNGS). Additionally, clinical and metabolic assessments were performed for genotype-phenotype analyses. The cohort comprised 155 (66%) males and 81 (34%) females, with a mean age at first stone of 47 years (4-86). The diagnostic yield of tNGS was 6.8% (16/236), with cystinuria (SLC3A1, SLC7A9), distal renal tubular acidosis (SLC4A1), and renal phosphate wasting (SLC34A1, SLC9A3R1) as underlying hereditary disorders. While metabolic syndrome traits were associated with late-onset KSD, hereditary KSD was associated with increased disease severity in terms of early-onset, frequent recurrence, mildly impaired kidney function, and common bilateral affection. By employing systematic genetic analysis to a less biased cohort of common adult kidney stone formers, we demonstrate its diagnostic value for establishing the underlying disorder in a distinct proportion. Factors determining pretest probability include age at first stone (<40 years), frequent recurrence, mild CKD, and bilateral KSD.

Prevalence and characteristics of genetic disease in adult kidney stone formers

“…In this exome-sequencing study in a large, unselected European cohort of 787 adult KSF, we detected a Mendelian kidney stone disease in 23 patients (2.9 %) using stringent diagnostic criteria. This diagnostic yield is significantly lower compared to previous studies conducted in selected groups of KSF 10,17,42 . Yet the fraction of additional individuals (8.13%) with LP/P variants predisposing to nephrolithiasis is substantial, especially when considering the broad inclusion criteria, the high prevalence of the disease and the potential rate of false-negatives due to stringent molecular genetic diagnosis criteria and technical limitations of exome sequencing, such as inability to detect deep intronic or difficulty in reliably calling copy-number variants.…”

“…This diagnostic yield is lower compared to most previous studies with selected groups of kidney stone formers 10,13,31 . Yet it is substantial, especially when considering the broad inclusion criteria, the high prevalence of the disease and the potential rate of false-negatives due to stringent molecular genetic diagnosis criteria and technical limitations of exome sequencing such as inability to detect deep intronic or difficulty in reliably calling copy-number variants.…”

Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting

“…In 7% of adult KSD patients from our in-house registry of hereditary kidney stone disease (n = 236), a diagnostic variant with molecular diagnosis could be identified [30]. Among these, 19% had pathogenic variants in either SLC34A1, SLC34A3, or NHERF1.…”

Genomic Approaches for Monogenic Kidney Diseases: A Comparative Review of Diagnostic Methods and Precision Medicine Implications

“…Table 1 reports diagnostic yields for targeted panels which are disease-specific, ranging from 6.8% for patients with renal stones [28] to 81% for patients with a clinical diagnosis of Autosomal Dominant Polycystic Kidney Disease (ADPKD) [26]. In the case of non-specific CKD clinical presentations, diagnostic yield from panels range from 28 to 40% for pediatric cases [37,38], 21 to 65% for pediatric/adult cases [39][40][41] and 12 to 56% for adult cases.…”

“…The difference in yield, however, is largely related to the clinical presentation investigated: three studies on cystic patients observed an overlapping yield (70-80%) independent of whether the study was conducted on a small or a broad-spectrum panel. In contrast, there are disorders, such as hypophosphatemia, in which a panel of 13 genes leads to a yield of 63% [25] and renal stones disorders in which a panel of 45 has a yield of 7% [28].…”