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Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025. Epub 2017 Oct 12.

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

Author information

1
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Pharmacology, Brain Korea 21 Program for Leading Universities and Students Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
3
Department of Urology and General Pediatrics, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt.
5
Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia.
6
Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt; Egyptian Group for Orphan Renal Diseases, Cairo, Egypt.
7
Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan.
8
Division of Endocrinology and Nephrology, Department of Internal Medicine, University Clinic Leipzig, Leipzig, Germany.
9
School of Medicine, Department of Pediatrics, Centro Hospitalario Pereira Rossell, Montevideo, Uruguay.
10
Pediatric Nephrology Center of Excellence and Pediatrics Department, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia.
11
Division of Pediatric Nephrology, University of Minnesota, Minneapolis, Minnesota, USA.
12
Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital/The Ohio State University, Columbus, Ohio, USA.
13
Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK.
14
Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
15
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
16
Department of Pediatric Nephrology, Dialysis and Transplantation, Clinical Hospital Center Zagreb, University of Zagreb Medical School, Zagreb, Croatia.
17
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.

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.

KEYWORDS:

monogenic cause; nephrocalcinosis; nephrolithiasis; whole exome sequencing

PMID:
28893421
PMCID:
PMC5750088
DOI:
10.1016/j.kint.2017.06.025
[Indexed for MEDLINE]
Free PMC Article

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