Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders

Mallett, Andrew J., McCarthy, Hugh J., Ho, Gladys, Holman, Katherine, Farnsworth, Elizabeth, Patel, Chirag, Fletcher, Jeffery T., Mallawaarachchi, Amali, Quinlan, Catherine, Bennetts, Bruce, and Alexander, Stephen I. (2017) Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders. Kidney International, 92. pp. 1493-1506.

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Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment individualized to the patient’s phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.

Item ID: 67883
Item Type: Article (Research - C1)
ISSN: 1523-1755
Copyright Information: (C) Kidney International
Funders: Children’s Hospital, Westmead, Alport Foundation of Australia, Magdalene Foundation, Conjoint Renal Genetics Service - Royal Brisbane and Women’s Hospital, Genetic Health Queenland
Date Deposited: 16 Jul 2021 01:38
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320213 Medical genetics (excl. cancer genetics) @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 60%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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