Investigation of the monogenic causes of chronic kidney disease
Citation:
CONNAUGHTON, DERVLA, Investigation of the monogenic causes of chronic kidney disease, Trinity College Dublin.School of Medicine, 2020Download Item:
Abstract:
Chronic Kidney Disease (CKD) is a common chronic condition that affects 15 percent of adults in the Irish healthcare system. End stage kidney disease (ESKD) represents the final stage of CKD which culminates in the need for renal replacement therapy, either in the form of dialysis or kidney transplantation, in order to sustain life. In Ireland, >4000 patients require renal replacement therapy with 400 new patients developing ESKD each year.
Recent research into the genetic causes of CKD suggests that 20-30% of CKD in childhood may have an underlying genetic cause and to date ~450 monogenic (synonymous with single-gene disorders) genes, if mutated, are known to cause CKD. Recently, similar trends have been observed among adult populations with CKD. In an era of precision medicine, understanding the utility of genetic testing in individuals with a suspected inherited nephropathy has important diagnostic and prognostic implications, while detection of monogenic causes of CKD permits molecular genetic diagnosis for patients and families, and open avenues for personalised treatment strategies for CKD.
The aim of this work was firstly to investigate how next-generation sequencing can facilitate molecular genetic diagnostics in individuals with suspected genetic kidney disease (GKD). In Chapter 3, I provide accurate estimates of the genetic contribution of CKD in both adult and paediatric patients with CKD (Connaughton Nephrology Dialysis Transplantation, 35(3):390, 2019).
In Chapter 4 I outline my work demonstrating that a high proportion of patients with CKD report a positive family history. Following recruitment of 1,840 patients with CKD, I demonstrate that a positive family history was reported by 629 participants (34%). Interestingly, CKD of unknown aetiology (CKDu) was common in patients with CKD reporting a positive family history (67 of 629, 11%). Based on these preliminary findings, I hypothesise that examining these families with CKD may reveal an underlying genetic disease.
In Chapters 5 and 6 I therefore focus on the utility of whole exome sequencing (WES) in adults and children with CKD to rapidly identify a high number of both known and novel single-gene causes of CKD.
My research results in Chapter 5 indicate that a mutation in a CKD causing gene can be detected in over one third of adult patients from a select cohort with CKD, a much higher proportion than previously considered (Connaughton Kidney International, 95(4):914, 2019). My work revealed that a monogenic mutation in a gene known to cause CKD was identified in 37% of a sample of 114 families, and increased to almost 50% in patients with CKD of unknown aetiology. Importantly, detection of single-gene causes of CKD translated into tangible benefits for affected patients, allowing in some cases for an early, unequivocal molecular diagnosis in patients who would otherwise remain without a formal diagnosis. In a further 22% of patients, the findings resulted in reclassification of the aetiology of CKD, which in many cases revealed personalized treatment options that were previously unavailable. This represents a major modifiable gap in the treatment of patients with CKD, allowing early precision diagnostics and personalized treatment regimes.
Finally, in Chapter 6, I outline how WES was used to identify a monogenic mutations in genes known to cause congenital anomalies of the kidney and urinary tract (CAKUT) in 14% of patients. In addition, by examining patients with genetically inherited CKD, I highlight how novel disease-causing genes can be identified, which can in turn translate into a better understanding of disease pathogenesis and delineate new disease pathways (Van der Ven and Connaughton J Am Soc Nephrol, 29:2348, 2018).
Knowledge gained from these research discoveries will hopefully allow for improved health outcomes for patients with CKD by making the study of CKD accessible to genetic approaches of ?personalised medicine?, enabling genetic diagnostics in patients who would otherwise remain without a definite diagnosis and permitting the study of ?personalised? disease mechanisms and treatments.
Sponsor
Grant Number
Health Research Board (HRB)
Amgen Irish Nephrology Society Specialist Registrar Research Bursary
International Pediatric Research Foundation Early Investigators? Exchange Program
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:DCONNAUGDescription:
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Author: CONNAUGHTON, DERVLA
Advisor:
Little, MarkPublisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
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