Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.

TitleWhole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.
Publication TypeJournal Article
Year of Publication2018
AuthorsDaga, A, Majmundar, AJ, Braun, DA, Gee, HYung, Lawson, JA, Shril, S, Jobst-Schwan, T, Vivante, A, Schapiro, D, Tan, W, Warejko, JK, Widmeier, E, Nelson, CP, Fathy, HM, Gucev, Z, Soliman, NA, Hashmi, S, Halbritter, J, Halty, M, Kari, JA, El-Desoky, S, Ferguson, MA, Somers, MJG, Traum, AZ, Stein, DR, Daouk, GH, Rodig, NM, Katz, A, Hanna, C, Schwaderer, AL, Sayer, JA, Wassner, AJ, Mane, S, Lifton, RP, Milosevic, D, Tasic, V, Baum, MA, Hildebrandt, F
JournalKidney Int
Date Published2018 01
KeywordsAdolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult

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.

Alternate JournalKidney Int.
PubMed ID28893421
PubMed Central IDPMC5750088
Grant ListUL1 TR001863 / TR / NCATS NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
S10 OD018521 / OD / NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States
R01 DK064614 / DK / NIDDK NIH HHS / United States