Dataset Information

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

ABSTRACT: 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 with tubulointerstitial fibrosis. 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.

SUBMITTER: Lata S

PROVIDER: S-EPMC5947852 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

Lata Sneh S Marasa Maddalena M Li Yifu Y Fasel David A DA Groopman Emily E Jobanputra Vaidehi V Rasouly Hila H Mitrotti Adele A Westland Rik R Verbitsky Miguel M Nestor Jordan J Slater Lindsey M LM D'Agati Vivette V Zaniew Marcin M Materna-Kiryluk Anna A Lugani Francesca F Caridi Gianluca G Rampoldi Luca L Mattoo Aditya A Newton Chad A CA Rao Maya K MK Radhakrishnan Jai J Ahn Wooin W Canetta Pietro A PA Bomback Andrew S AS Appel Gerald B GB Antignac Corinne C Markowitz Glen S GS Garcia Christine K CK Kiryluk Krzysztof K Sanna-Cherchi Simone S Gharavi Ali G AG

Annals of internal medicine 20171205 2

<h4>Background</h4>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.<h4>Objective</h4>To study the diagnostic utility of WES in a selected referral population of adults with CKD.<h4>Design</h4>Observational cohort.<h4>Setting</h4>A major academic medical c ...[more]

PMID: 29204651

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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein-protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Project description:ImportanceParkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.ObjectiveTo identify genetic variants contributing to disease risk in familial PD.Design, setting, and participantsA 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.Main outcomes and measuresIdentification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.ResultsThe 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.Conclusions and relevanceTNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Project description:IntroductionThe etiology of acute liver failure (ALF) remains an important prognostic factor. The Acute Liver Failure Study Group recently reported that 150 of 2,718 adult patients with ALF (5.5%) had an indeterminate etiology. Our aim was to use whole exome sequencing to identify genetic variants associated with phenotypic, biochemical, and histologic features among patients with indeterminate ALF.MethodsThis effort has defined a cohort of well-pedigreed patients with indeterminate ALF; DNA samples extracted from whole blood samples were obtained from 26 respective patients with indeterminate ALF. These samples were kept at the Acute Liver Failure Study Group repository at the NIDDK, Bethesda. Whole exome sequencing and bioinformatics analysis were performed at the Mayo Clinic Center of Individualized Medicine in Rochester, MN.ResultsOf the 26 patients, 8 survived spontaneously, 6 died, and 12 underwent a liver transplantation; all those transplanted were alive at 21 days after enrollment in the study. Twenty-two of the 26 patients presented as ALF. We found 12 variants associated with 11 genes. The most common variant was rs4940595 in the SERPINB11 gene which was found in 23 of the 26 patients. This variant had a stop codon; no reports of disorders have been associated with this variant. The next most commonly found variant was rs1135840 in the CYP2D6 gene; this mutation is a missense_variant and has been reported to be associated with hepatotoxicity of antituberculous therapy. None of our patients were receiving this therapy. We also found a significant asymmetric distribution of rs1800754 of the CYP2D7 gene and rs1135840 of the CYP2D6 gene between patients who survived spontaneously (75%) and those who died or underwent liver transplantation (30.5% and 25%, respectively).DiscussionWe found 12 variants of 11 genes significantly associated with ALF among adults with indeterminate etiology. We also found a significant asymmetric distribution of 2 variants belonging to the CYP2D7 and CYP2D6 genes, respectively, between those who survived spontaneously and those who died or underwent liver transplantation. The 2 most common variants, rs4940595 and rs1135840, of the SERPINB11 and CYP2D6 genes, respectively, found in our patients with ALF have been described as potentially important in the adaptive response combating the emergence of infectious diseases and associated with hepatotoxicity of antituberculous therapy, respectively. Our findings need to be expanded to include more patients with indeterminate ALF as well as viral, drug toxicity, and autoimmune etiologies to determine whether our findings are associated with the specific etiology, indeterminate, or with the overall ALF syndrome itself.

Dataset Information

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

Publications

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

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