Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease

Abstract

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

“…Interestingly, identified molecular diagnoses pertained to only three distinct disorders: (a) cystinuria, (b) dRTA, and (c) renal phosphate wasting. Analogous to previous data on adult and adolescent cohorts, dominant genes predominated their recessive counterparts (Braun et al, 2016;Cogal et al, 2021;Halbritter et al, 2015). While in cystinuria both modes of inheritance were observed, we only found…”

“…However, the question of whom to subject to genetic testing is still unresolved. Most of the previous studies focused on childhood KSD (Braun et al, 2016; Cogal et al, 2021; Daga et al, 2018) and available prevalence data is difficult to interpret. A main limitation of most studies constitute their preselection of patients based on an upfront clinical suspicion of monogenic KSD (Cogal et al, 2021; Halbritter et al, 2015).…”

“…Most of the previous studies focused on childhood KSD (Braun et al, 2016; Cogal et al, 2021; Daga et al, 2018) and available prevalence data is difficult to interpret. A main limitation of most studies constitute their preselection of patients based on an upfront clinical suspicion of monogenic KSD (Cogal et al, 2021; Halbritter et al, 2015). Lessons from the introduction of broad genetic testing in other medical fields, however, have taught us to expect genetic causes also in unsuspected clinical situations (Splinter et al, 2018; Sun et al, 2022).…”

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

“…Others identified that diagnosable phenocopy disorders may be more common, representing up to one in five genetic diagnoses in suspected hereditary kidney disease and that an approach rigidly applying very strictly targeted gene panels rather than broader or cascade panels does not identify such instances [ 30 ▪ ]. For complex phenotypes such as urinary stone disease, the evidence for broadened gene panels is further reflecting this concept that application of a very targeted gene panel approach will fail to identify a genetic diagnosis that is present and directly related to the patient phenotype in 10–20% of instances [ 31 ].…”

Genotype Phenotype Correlation in Dent Disease 2 and Review of the Literature: OCRL Gene Pleiotropism or Extreme Phenotypic Variability of Lowe Syndrome?

“…Twenty-three patients were referred for molecular diagnosis to the Laboratory of histomorphology and molecular biology of the kidney (Italy) and 12 were referred to the Rare Kidney Stone Consortium (RKSC) in the USA. Sanger sequencing was used to determine and verify the pathogenic variants in OCRL in our cohort [16]. OCRL variants were classified as pathogenic or likely pathogenic according to American College of Medical Genetics and American College of Pathologists (ACMG/AMP) guidelines [17].…”