Targeted broad-based genetic testing by next-generation sequencing informs diagnosis and facilitates management in patients with kidney diseases

Autor: Richard J.H. Smith, M. Adela Mansilla, Anne E. Kwitek, Mycah J Kimble, Christie P. Thomas, Colleen A. Campbell, Carla Nishimura, Margaret E. Freese, Ramakrishna Sompallae
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
030232 urology & nephrology
Disease
Ciliopathies
0302 clinical medicine
Copy-number variation
Child
Aged
80 and over
Massive parallel sequencing
medicine.diagnostic_test
massively parallel sequencing
genetic kidney disease
High-Throughput Nucleotide Sequencing
Middle Aged
Phenotype
Nephrology
Child
Preschool
Female
Kidney Diseases
Adult
medicine.medical_specialty
targeted gene panel
Adolescent
DNA Copy Number Variations
Context (language use)
Young Adult
03 medical and health sciences
Clinical Research
Internal medicine
medicine
Humans
Genetic Testing
AcademicSubjects/MED00340
Aged
Genetic testing
Transplantation
business.industry
Infant
Newborn
Infant
Reproducibility of Results
medicine.disease
030104 developmental biology
Mutation
ORIGINAL ARTICLES
business
Tubulointerstitial Disease
Biomarkers
copy number variants
Kidney disease
Zdroj: Nephrology Dialysis Transplantation
ISSN: 1460-2385
0931-0509
DOI: 10.1093/ndt/gfz173
Popis: BackgroundThe clinical diagnosis of genetic renal diseases may be limited by the overlapping spectrum of manifestations between diseases or by the advancement of disease where clues to the original process are absent. The objective of this study was to determine whether genetic testing informs diagnosis and facilitates management of kidney disease patients.MethodsWe developed a comprehensive genetic testing panel (KidneySeq) to evaluate patients with various phenotypes including cystic diseases, congenital anomalies of the kidney and urinary tract (CAKUT), tubulointerstitial diseases, transport disorders and glomerular diseases. We evaluated this panel in 127 consecutive patients ranging in age from newborns to 81 years who had samples sent in for genetic testing.ResultsThe performance of the sequencing pipeline for single-nucleotide variants was validated using CEPH (Centre de’Etude du Polymorphism) controls and for indels using Genome-in-a-Bottle. To test the reliability of the copy number variant (CNV) analysis, positive samples were re-sequenced and analyzed. For patient samples, a multidisciplinary review board interpreted genetic results in the context of clinical data. A genetic diagnosis was made in 54 (43%) patients and ranged from 54% for CAKUT, 53% for ciliopathies/tubulointerstitial diseases, 45% for transport disorders to 33% for glomerulopathies. Pathogenic and likely pathogenic variants included 46% missense, 11% nonsense, 6% splice site variants, 23% insertion–deletions and 14% CNVs. In 13 cases, the genetic result changed the clinical diagnosis.ConclusionBroad genetic testing should be considered in the evaluation of renal patients as it complements other tests and provides insight into the underlying disease and its management.
Databáze: OpenAIRE
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