1. Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis
- Author
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Deborah R. Stein, Weizhen Tan, Amar J. Majmundar, Richard P. Lifton, David Schapiro, Daniela A. Braun, Jan Halbritter, Christian Hanna, John A. Sayer, Margarita Halty, Avram Z. Traum, Sherif M. El-Desoky, Velibor Tasic, Shrikant Mane, Friedhelm Hildebrandt, Asaf Vivante, Michelle A. Baum, Shirlee Shril, Seema Hashmi, Michael A. J. Ferguson, Zoran Gucev, Caleb P. Nelson, Avi Katz, Ghaleb Daouk, Heon Yung Gee, Neveen A. Soliman, Tilman Jobst-Schwan, Michael J. Somers, Eugen Widmeier, Danko Milosevic, Ari J. Wassner, Jameela A. Kari, Hanan M. Fathy, Ankana Daga, Andrew L. Schwaderer, Jennifer A. Lawson, Jillian K. Warejko, and Nancy Rodig
- Subjects
Genetic Markers ,Male ,0301 basic medicine ,Heredity ,Adolescent ,030232 urology & nephrology ,Disease ,Consanguinity ,Biology ,Nephrolithiasis ,Bioinformatics ,Article ,Young Adult ,Kidney Calculi ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Age of Onset ,Child ,Gene ,Genetic Association Studies ,Exome sequencing ,Ultrasonography ,Genetics ,Phenocopy ,Incidence (epidemiology) ,Infant ,Prognosis ,medicine.disease ,Pedigree ,Nephrocalcinosis ,Phenotype ,030104 developmental biology ,Nephrology ,Child, Preschool ,Mutation ,Mutation (genetic algorithm) ,Disease Progression ,Female ,nephrolithiasis ,nephrocalcinosis, monogenic cause ,whole exome sequencing ,Tomography, X-Ray Computed - Abstract
The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes ( AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1 ), in one dominant gene ( SLC9A3R1 ), and in one gene ( SLC34A1 ) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.
- Published
- 2018