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

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.

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

“…A genetic cause was determined in 62.3% of cases with renal tubular disease and renal calcinosis or stones, showing the gene distribution of CLCN5 or OCRL detected in Dents disease or Lowe syndrome, AGXT detected in primary hyperoxaluria, SLC12A1 in Gitelman syndrome and SLC4A1 in distal renal tubular acidosis. The factors with higher detection rate including younger age of onset, positive family history and ethnic background should be further analyzed …”

Renal genetics in Australia: Kidney medicine in the genomic age

“…Within a cohort of 1783 unrelated families with SRNS, exon sequencing identified a single gene cause in 29.5% . The advent of WES may have improved the diagnostic yield, with a recent study demonstrating a monogenic causative mutation in 15 out of 51 families who presented with suspected nephrolithiasis or nephrocalcinosis before the age of 25 years . Studies are ongoing in Australia and internationally.…”

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

“…NL, NC, and hypercalciuria are likely to have a genetic basis as up to 65% of kidney stone patients have been reported to have an affected family member and twin studies have estimated that the heritability of hypercalciuria and kidney stones is >50% and >55%, respectively. Moreover, studies of families with rare monogenic disorders associated with hypercalciuric NL and NC, such as Bartter's syndrome, Dent's disease, autosomal dominant hypocalcaemia, and distal renal tubular acidosis, have identified mutations in >30 genes involved in the regulation of calcium transport (Supplemental Table S1) . Furthermore, genome‐wide association studies and targeted sequencing of genes with known roles in calcium and vitamin D metabolism have reported associations for NL and NC with common sequence variants in >10 additional genes (Supplemental Table S1) .…”

“…Moreover, studies of families with rare monogenic disorders associated with hypercalciuric NL and NC, such as Bartter's syndrome, Dent's disease, autosomal dominant hypocalcaemia, and distal renal tubular acidosis, have identified mutations in >30 genes involved in the regulation of calcium transport ( Supplemental Table S1). (3,13,14) Furthermore, genome-wide association studies and targeted sequencing of genes with known roles in calcium and vitamin D metabolism have reported associations for NL and NC with common sequence variants in >10 additional genes ( Supplemental Table S1). (2,(15)(16)(17) However, these account for only $15% to 20% of cases, (3,13) and the identification of further monogenic causes of NL and NC are limited by the availability of large families.…”