Sequential genetic testing of living‐related donors for inherited renal disease to promote informed choice and enhance safety of living donation

Thomas, Christie P.; Gupta, Sonali; Freese, Margaret E; Chouhan, Kanwaljit K; Dantuma, Maisie I; Holanda, Danniele G.; Katz, Daniel; Darbro, Benjamin W.; Mansilla, M. Adela; Smith, Richard J.H.

doi:10.1111/tri.14133

Cited by 10 publications

(9 citation statements)

References 38 publications

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“…A genetic diagnosis can also help with evaluating risk of disease in asymptomatic family members and can also assist with pre-pregnancy counseling and in preimplantation diagnosis for affected patients who may be considering starting a family. Finally, identifying the genetic cause in an affected individual will allow the targeted evaluation for the familial variant (cascade screening) in a biologically related individual who volunteers to be a kidney donor (Thomas et al, 2021).…”

Section: Benefits Of Genetic Testingmentioning

confidence: 99%

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

Sambharia

Rastogi

Thomas

2022

American J of Med Genetics Pt C

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Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

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Section: Benefits Of Genetic Testingmentioning

confidence: 99%

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

Sambharia

Rastogi

Thomas

2022

American J of Med Genetics Pt C

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“…As such, it may be valuable to attempt to identify a genetic cause of CKD/ESKD in a recipient such that if found, the living related donor can be screened for the same variant (single variant testing would be all that would be necessary). This is particularly of relevance when the donor is younger than the age at which clinical manifestations would become apparent (22,23,(63)(64)(65).…”

Section: Use Of Genetic Testing In Living Related Kidney Donationmentioning

confidence: 99%

“…They show that in some-particularly pediatric-cases, a genetic diagnosis may have an important impact on treatment decisions. A genetic diagnosis can also affect screening of living related donors for transplantation (22,23). For some patients, a significant benefit may come simply from providing an explanation for their condition.…”

Section: Introductionmentioning

confidence: 99%

A Practical Guide to Genetic Testing for Kidney Disorders of Unknown Etiology

Aron

Besse

2022

Kidney360

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Genetic testing is increasingly used in the workup and diagnosis of kidney disease and kidney-related disorders of undetermined cause. Out of pocket costs for clinical genetic testing have become affordable, and logistical hurdles overcome. The interest in genetic testing may stem from the need to make or confirm a diagnosis, guide management, or the patient's desire to have a more informed explanation or prognosis. This poses a challenge for providers who do not have formal training in the selection, interpretation, and limitations of genetic tests. In this manuscript, we provide detailed discussion of relevant cases in which clinical genetic testing using a "kidney gene" panel was applied. The cases demonstrate identification of pathogenic variants for monogenic diseases-contrasting them from genetic risk alleles-and bring up diagnostic limitations and diagnostic utility of these tests in nephrology. This review aims to guide clinicians in formulating pre-test conversations with their patients, interpreting genetic variant nomenclature, and considering follow-up investigations. While providers are gaining experience, there is still risk of testing causing more anxiety than benefit. However, with provider education and support, clinical genetic testing applied to otherwise unexplained kidney-related disorders will increasingly serve as a valuable diagnostic tool with the potential to reshape how we consider and treat many kidney-related diagnoses.

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“…The role of diagnostic genomics in living related kidney donor assessment has also been long proposed as an area for measurable clinical utility. New evidence is demonstrating that this benefit is realizable [ 43 ▪ ] and moreover that the proposed approach of commencing the diagnostic genomic testing cascade with a phenotypically affected relative, usually the proposed kidney transplant recipient [ 44 , 45 ], is appropriate and effective.…”

Section: New Insights Into Utility Of Genomic Sequencing In Chronic K...mentioning

confidence: 99%

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

Mallett

2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewThis review will summarize and synthesize recent findings in regard to monogenic kidney disorders, including how that evidence is being translated into practice. It will add to existing key knowledge to provide context for clinicians in consolidating existing practice and approaches.Recent findingsWhilst there are long established factors, which indicate increased likelihood of identifying a monogenic cause for kidney disease, these can now be framed in terms of the identification of new genes, new indications for genomic testing and new evidence for clinical utility of genomic testing in nephrology. Further, inherent in the use of genomics in nephrology are key concepts including robust informed consent, variant interpretation and return of results. Recent findings of variants in genes related to complex or broader kidney phenotypes are emerging in addition to understanding of de novo variants. Phenocopy phenomena are indicating a more pragmatic use of broader gene panels whilst evidence is emerging of a role in unexplained kidney disease. Clinical utility is evolving but is being successfully demonstrated across multiple domains of outcome and practice.SummaryWe provide an updated framework of evidence to guide application of genomic testing in chronic kidney disease (CKD), building upon existing principles and knowledge to indicate how the practice and implementation of this can be applied today. There are clearly established roles for genomic testing for some patients with CKD, largely those with suspected heritable forms, with these continuing to expand as new evidence emerges.

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Sequential genetic testing of living‐related donors for inherited renal disease to promote informed choice and enhance safety of living donation

Cited by 10 publications

References 38 publications

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

A Practical Guide to Genetic Testing for Kidney Disorders of Unknown Etiology

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

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