By:Daga, A (Daga, Ankana)^[ 1 ] ; Majmundar, AJ (Majmundar, Amar J.)^[ 1 ] ; Braun, DA (Braun, Daniela A.)^[ 1 ] ; Gee, HY (Gee, Heon Yung)^[ 2 ] ; Lawson, JA(Lawson, Jennifer A.)^[ 1 ] ; Shril, S (Shril, Shirlee)^[ 1 ] ; Jobst-Schwan, T (Jobst-Schwan, Tilman)^[ 1 ] ; Vivante, A (Vivante, Asaf)^[ 1 ] ; Schapiro, D (Schapiro, David)^[ 1 ] ; Tan, WZ (Tan, Weizhen)^[ 1 ] ...More

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.

Author Keywords:monogenic cause; nephrocalcinosis; nephrolithiasis; whole exome sequencing

KeyWords Plus:SODIUM-PHOSPHATE COTRANSPORTER; PRIMARY HYPEROXALURIA TYPE-1; CHRONIC KIDNEY-DISEASE; MUTATIONS; GENE; PREVALENCE; STONES; CYSTINOSIS; HORMONE

Reprint Address: Hildebrandt, F (reprint author)

Boston Childrens Hosp, Div Nephrol, 300 Longwood Ave, Boston, MA 02115 USA.

Addresses:

	[ 1 ] Harvard Med Sch, Boston Childrens Hosp, Div Nephrol, Dept Med, Boston, MA USA
	[ 2 ] Yonsei Univ, Coll Med, Brain Korea Program Leading Univ & Students Proje, Dept Pharmacol, Seoul, South Korea
	[ 3 ] Harvard Med Sch, Boston Childrens Hosp, Dept Med, Dept Urol & Gen Pediat, Boston, MA USA
	[ 4 ] Alexandria Univ, Pediat Nephrol Unit, Alexandria, Egypt
	[ 5 ] Univ Childrens Hosp, Med Fac Skopje, Skopje, Macedonia
	[ 6 ] Cairo Univ, Kasr Al Ainy Sch Med, Ctr Pediat Nephrol & Transplantat, Dept Pediat, Cairo, Egypt
	[ 7 ] Egyptian Grp Orphan Renal Dis, Cairo, Egypt
	[ 8 ] Sindh Inst Urol & Transplantat, Dept Pediat Nephrol, Karachi, Pakistan
	[ 9 ] Univ Clin Leipzig, Dept Internal Med, Div Endocrinol & Nephrol, Leipzig, Germany
	[ 10 ] Ctr Hosp Pereira Rossell, Dept Pediat, Sch Med, Montevideo, Uruguay
	[ 11 ] King Abdulaziz Univ Hosp, Fac Med, Pediat Nephrol Ctr Excellence, Jeddah, Saudi Arabia
	[ 12 ] King Abdulaziz Univ Hosp, Fac Med, Pediat Dept, Jeddah, Saudi Arabia
	[ 13 ] Univ Minnesota, Div Pediat Nephrol, Minneapolis, MN USA
	[ 14 ] Ohio State Univ, Dept Pediat, Div Nephrol, Columbus, OH 43210 USA
	[ 15 ] Newcastle Univ, Int Ctr Life, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England
	[ 16 ] Harvard Med Sch, Boston Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA USA
	[ 17 ] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA
	[ 18 ] Yale Univ, Sch Med, Yale Ctr Mendelian Genom, New Haven, CT USA
	[ 19 ] Rockefeller Univ, Lab Human Genet & Genom, 1230 York Ave, New York, NY 10021 USA
	[ 20 ] Univ Zagreb, Med Sch, Clin Hosp Ctr Zagreb, Dept Pediat Nephrol Dialysis & Transplant, Zagreb, Croatia

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Research Areas:Urology & Nephrology

Web of Science Categories:Urology & Nephrology