Diagnostic Code-Based Screening for Identifying Children with Primary Hyperoxaluria.

PURPOSE: We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying children with this rare condition in PEDSnet, a clinical research network of pediatric health systems that shares electronic health records data. MATERIALS AND METHODS: We conducted a cross-sectional study of children who received care at 7 PEDSnet institutions from January 2009 through January 2021. We developed and applied screening criteria using diagnostic codes that generated 3 categories of the hypothesized probability of PH. Tier 1 had specific diagnostic codes for PH; tier 2 had codes for hyperoxaluria, oxalate nephropathy, or oxalosis; and tier 3 had a combination of ≥2 codes for disorder of carbohydrate metabolism and ≥1 code for kidney stones. We reviewed the electronic health records of patients with possible PH to confirm PH diagnosis and evaluate the accuracy and timing of diagnostic codes. The PPV of the codes was compared across tiers, time, PH type, and site. RESULTS: We identified 341 patients in the screen; 33 had confirmed PH (9.7%). Tier 1 had the highest proportion of PH; however, the PPV was only 20%. The degree to which an institution accurately represented point of care diagnoses in the data extraction process was predictive of higher PPV. The PPV of diagnostic codes was highest for PH3 (100%) and lowest for PH1 (22.8%). CONCLUSIONS: Diagnostic codes for PH have poor PPV. Findings suggest that one should be careful in research using large databases in which source validation is not possible.

Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations.

Signaling by the glial cell line-derived neurotrophic factor (GDNF)-RET receptor tyrosine kinase and SPRY1, a RET repressor, is essential for early urinary tract development. Individual or a combination of GDNF, RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET-null mice. We sequenced GDNF, SPRY1 and RET in 122 unrelated living CAKUT patients to discover deleterious mutations that cause CAKUT. Novel or rare deleterious mutations in GDNF or RET were found in six unrelated patients. A family with duplicated collecting system had a novel mutation, RET-R831Q, which showed markedly decreased GDNF-dependent MAPK activity. Two patients with RET-G691S polymorphism harbored additional rare non-synonymous variants GDNF-R93W and RET-R982C. The patient with double RET-G691S/R982C genotype had multiple defects including renal dysplasia, megaureters and cryptorchidism. Presence of both mutations was necessary to affect RET activity. Targeted whole-exome and next-generation sequencing revealed a novel deleterious mutation G443D in GFRα1, the co-receptor for RET, in this patient. Pedigree analysis indicated that the GFRα1 mutation was inherited from the unaffected mother and the RET mutations from the unaffected father. Our studies indicate that 5% of living CAKUT patients harbor deleterious rare variants or novel mutations in GDNF-GFRα1-RET pathway. We provide evidence for the coexistence of deleterious rare and common variants in genes in the same pathway as a cause of CAKUT and discovered novel phenotypes associated with the RET pathway.