Language
English
Publication Date
12-1-2025
Journal
European Journal of Human Genetics
DOI
10.1038/s41431-025-01929-3
PMID
40913078
PMCID
PMC12669671
PubMedCentral® Posted Date
9-6-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Congenital Anomalies of Kidney and Urinary Tract (CAKUT) can occur in isolation or in conjunction with one or more non-CAKUT associated congenital anomalies or neurodevelopmental disorders (CAKUT+). A molecular cause is not identified in most individuals with CAKUT+. This is due, in part, to uncertainty regarding the efficacy of genetic testing and an incomplete understanding of the genes that cause CAKUT+. Here, we use data from 515 individuals with CAKUT+ (n = 500) or isolated CAKUT (n = 15) to determine the efficacy of clinical exome sequencing (cES) and to identify new phenotype expansions that involve CAKUT. We determined that cES established a molecular diagnosis in 27.4% (141/515) of individuals in this cohort. No statistically significant difference in efficacy was seen with regards to age, sex, CAKUT phenotype, or associated organ system abnormality. Only 3.5% (5/144) to 14.6% (21/144) of the individual diagnoses made in our cohort could have been identified using one of four clinically available CAKUT gene panels. We then used a machine-learning approach to confirm that PHIP is a CAKUT gene and to implicate ADNP and SETD5 genes associated with an increased risk of CAKUT. These findings lead us to conclude that cES should be considered in individuals with CAKUT+ for whom a molecular diagnosis has not been identified, that cES has the potential to identify many diagnoses in individuals with CAKUT+ that would be missed using a CAKUT gene panel, and that individuals with ADNP-, PHIP-, and SETD5-related disorders may present with CAKUT phenotypes.
Keywords
Humans, Exome Sequencing, Female, Male, Phenotype, Urogenital Abnormalities, Child, Genetic Testing, Vesico-Ureteral Reflux, Child, Preschool, Adolescent, Adult, Amino Acid Transport Systems, Neutral, Infant, Urinary Tract, Kidney, Genetics research, Genetic testing, Development
Published Open-Access
yes
Recommended Citation
Rivera-Munoz, E Andres; Zhao, Xiaonan E; Rosenfeld, Jill A; et al., "Clinical Exome Sequencing Efficacy and Phenotypic Expansions Involving Non-Isolated Congenital Anomalies of Kidney and Urinary Tract (CAKUT+)" (2025). Faculty and Staff Publications. 5123.
https://digitalcommons.library.tmc.edu/baylor_docs/5123
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