Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene

Bekheirnia, Mir Reza; Bekheirnia, Nasim; Bainbridge, Matthew N.; Gu, Shen; Akdemir, Zeynep H. Coban; Gambin, Tomasz; Janzen, Nicolette; Jhangiani, Shalini N.; Muzny, Donna M.; Michael, Mini; Brewer, Eileen D.; Elenberg, Ewa; Kale, Arundhati S.; Riley, Alyssa A.; Swartz, Sarah J.; Scott, Daryl A.; Yang, Yaping; Srivaths, Poyyapakkam; Wenderfer, Scott E.; Bodurtha, Joann; Applegate, Carolyn D.; Velinov, Milen; Myers, Angela; Borovik, Lior; Craigen, William J.; Hanchard, Neil A.; Rosenfeld, Jill A.; Lewis, Richard A.; Gonzales, Edmond T.; Gibbs, Richard A.; Belmont, John W.; Roth, David R.; Eng, Christine M.; Braun, Michael C.; Lupski, James R.; Lamb, Dolores J.

doi:10.1038/gim.2016.131

Cited by 78 publications

(89 citation statements)

References 37 publications

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“…Indeed, single nucleotide variants (SNVs) in FOXP1 have recently been associated with congenital anomalies of the kidneys and urinary tract 46. An electroencephalogram should be performed if there is any doubt of seizures, and brain MRI should be considered in the presence of epilepsy.…”

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confidence: 99%

FOXP1-related intellectual disability syndrome: a recognisable entity

et al. 2017

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FOXP1-related intellectual disability syndrome: a recognisable entity

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“…For these reasons, WES is emerging as a preferred diagnostic tool for hereditary disorders (12–15, 22, 23). In pediatric cohorts, WES recently identified diagnostic mutations in up to 11.5% of patients with congenital kidney anomalies and 26% of patients with steroid-resistant nephrotic syndrome, supporting its diagnostic utility for early-onset CKD (24, 25). However, the value of this sequencing method for the diagnosis and management of CKD in adults has not been adequately studied.…”

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confidence: 97%

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

et al. 2017

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Background The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown. Objective To study the diagnostic utility of WES in a selected referral population of adults with CKD. Design Observational cohort. Setting A major academic medical center. Patients 92 adults with CKD of unknown cause or familial nephropathy or hypertension. Measurements The diagnostic yield of WES and its potential effect on clinical management. Results Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands diagnosed respectively with tubulointerstitial fibrosis and CKD of unknown cause. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy. Limitation The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population. Conclusion Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted. Primary Funding Source New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

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“…In the research setting, genomic technologies have enabled the identification of new causative genes in GKD, improved delineation of conditions and elucidated novel targets for therapy . Genomic testing technologies are rapidly transitioning from the research to the clinical environment, and it is estimated that genomic data from over 60 000 000 individuals will be generated within healthcare in the next 7 years, worldwide .…”

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Renal genetics in Australia: Kidney medicine in the genomic age

et al. 2018

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There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end‐stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next‐generation sequencing have enabled rapid and cost‐effective sequencing of large amounts of DNA. Next‐generation sequencing‐based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early‐onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at‐risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health‐care systems.

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Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene

Cited by 78 publications

References 37 publications

FOXP1-related intellectual disability syndrome: a recognisable entity

FOXP1-related intellectual disability syndrome: a recognisable entity

Whole-Exome Sequencing in Adults With Chronic Kidney Disease

Renal genetics in Australia: Kidney medicine in the genomic age

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