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Kidney Int. 2019 Apr;95(4):914-928. doi: 10.1016/j.kint.2018.10.031. Epub 2019 Feb 14.

Monogenic causes of chronic kidney disease in adults.

Author information

1
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland; Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
2
Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland.
3
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland.
5
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Department of Nephrology, Belfast-Ulster Hospital, Belfast, Northern Ireland.
7
Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
8
Royal College of Surgeons in Ireland, Dublin, Ireland.
9
Department of Renal Medicine, Cork University Hospital and University College Cork, Cork, Ireland.
10
Department of Nephrology, Galway University Hospital and School of Medicine, National University of Ireland, Galway, Ireland.
11
National Paediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children's University Hospital, Dublin, Ireland.
12
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
13
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Rockefeller University, New York, New York, USA.
14
Department of Nephrology, University Hospital Waterford, Waterford, Ireland.
15
Departments of Nephrology and Internal Medicine, University Hospital Limerick, Limerick, Ireland.
16
Department of Nephrology, St. Vincent's University Hospital, Dublin, Ireland.
17
Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Histopathology, Beaumont Hospital, Dublin, Ireland.
18
Department of Histopathology, Beaumont Hospital, Dublin, Ireland.
19
Trinity Health Kidney Centre, Trinity College Dublin, Tallaght University Hospital, Dublin, Ireland.
20
Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland. Electronic address: peterconlon@beaumont.ie.
21
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.

Abstract

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

KEYWORDS:

chronic kidney disease; genetic kidney disease; whole exome sequencing

PMID:
30773290
PMCID:
PMC6431580
[Available on 2020-04-01]
DOI:
10.1016/j.kint.2018.10.031

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