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J Am Soc Nephrol. 2018 Sep;29(9):2348-2361. doi: 10.1681/ASN.2017121265. Epub 2018 Aug 24.

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

Author information

1
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
2
Department of Pediatric Nephrology, Institute for Mother and Child Health Care, Belgrade, Serbia.
3
Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Cairo University, Egypt.
4
Egyptian Group for Orphan Renal Diseases, Cairo, Egypt.
5
Department of Pediatrics and.
6
Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
7
Pediatric Nephrology Unit, University of Alexandria, Alexandria, Egypt.
8
University of Zagreb School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia.
9
United Arab Emirates University, Abu Dhabi, United Arab Emirates.
10
Pediatric Nephrology Department, Dubai Kidney Center Of Excellence, Dubai Hospital, Dubai, United Arab Emirates.
11
Department of Pediatric Nephrology, Institute of Child Health and Hospital for Children, The Tamil Nadu Dr. M.G.R. Medical University, Chennai, Tamil Nadu, India.
12
Department of Pediatric Nephrology, Dr. Mehta's Multi-Specialty Hospital, Chennai, Tamil Nadu, India.
13
Division of Nephrology, Columbia University, New York, New York.
14
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
15
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
16
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
17
Rockefeller University, New York, New York.
18
Department of Urology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
19
Renal Section, Department of Medicine and Pathology, Boston University Medical Center, Boston, Massachusetts.
20
Institute of Human Genetics and.
21
Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany; and.
22
Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia.
23
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; friedhelm.hildebrandt@childrens.harvard.edu.

Abstract

BACKGROUND:

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.

METHODS:

We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.

RESULTS:

In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).

CONCLUSIONS:

We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

KEYWORDS:

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT); Vesico-ureteral Reflux (VUR); Whole Exome Sequencing (WES); monogenic disease causation; renal developmental gene

PMID:
30143558
PMCID:
PMC6115658
[Available on 2019-09-01]
DOI:
10.1681/ASN.2017121265

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