Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

Ven, Amelie T. van der; Connaughton, Dervla M.; Ityel, Hadas; Mann, Nina; Nakayama, Makiko; Chen, Jing; Vivante, Asaf; Hwang, Daw-Yang; Schulz, Jan; Braun, Daniela A.; Schmidt, Johanna Magdalena; Schapiro, David; Schneider, Ronen; Warejko, Jillian K.; Daga, Ankana; Majmundar, Amar J.; Tan, Weizhen; Jobst-Schwan, Tilman; Hermle, Tobias; Widmeier, Eugen; Ashraf, Shazia; Amar, Ali; Hoogstraaten, Charlotte A.; Hugo, Hannah; Kitzler, Thomas M.; Kause, Franziska; Kolvenbach, Caroline M.; Dai, Rufeng; Spaneas, Leslie; Amann, Kassaundra; Stein, Deborah R.; Baum, Michelle A.; Somers, Michael J.; Rodig, Nancy; Ferguson, Michael; Traum, Avram Z.; Daouk, Ghaleb H.; Bogdanović, Radovan; Stajić, Nataša; Soliman, Neveen A.; Kari, Jameela A.; Desoky, Sherif El; Fathy, Hanan; Milošević, Danko; Al‐Saffar, Muna; Awad, Hazem S.; Eid, Loai; Selvin, Aravind; Senguttuvan, Prabha; Sanna‐Cherchi, Simone; Rehm, Heidi L.; MacArthur, Daniel G.; Lek, Monkol; Laricchia, Kristen M.; Wilson, Michael W.; Mane, Shrikant; Lifton, Richard P.; Lee, Richard S.; Bauer, Stuart B.; Lu, Weining; Reutter, Heiko; Tasić, Velibor; Shril, Shirlee; Hildebrandt, Friedhelm

doi:10.1681/asn.2017121265

Cited by 153 publications

(160 citation statements)

References 69 publications

(59 reference statements)

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…The diagnostic yield was 17.0% in CAKUT which is close to the reports from an international cohort. 14 17 The diagnostic yields by trio-WES were superior, especially in renal tubular disease and renal calcinosis of our cohort. A significantly higher proportion of de novo mutations were detected early in trio-WES compared with TGS or singleton-WES which could be the limitation of the single patient-based approach, where de novo mutations are confirmed only after segregation.…”

Section: Discussionmentioning

confidence: 65%

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

et al. 2019

View full text Add to dashboard Cite

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole‐exome sequencing (WES) and trio‐WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio‐WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

show abstract

Section: Discussionmentioning

confidence: 65%

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The genetic diagnosis rate of 13.8% is similar to previous studies employing various detection methods. TES achieved a 1-6% positive result in patients with several types of CAKUT [16,17], while whole exome sequencing (WES) studies found causative mutations of known CAKUT genes in 11-14% of patients [14,15,21] and mutations of novel genes in 8% of families [14]. Previous CNV studies reported that 4.5-16.6% of patients with variable CAKUT were carrying pathogenic CNVs [11][12][13]18,19].…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains challenging because of genetic and phenotypic heterogeneity and incomplete penetrance of CAKUT. In the literature, diagnostic yield of genetic testing of patients with CAKUT is approximately 5-20%, representing either single nucleotide variants (SNVs) or CNVs of the relevant genes [11][12][13][14][15][16][17][18][19]. Most of the large studies on CAKUT are from Western countries, therefore genetic background of CAKUT in Asian populations is yet to be elaborated [20,21].…”

Section: Introductionmentioning

confidence: 99%

Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract

Ahn

Lee

Kim

et al. 2020

JCM

View full text Add to dashboard Cite

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5–20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.

show abstract

“…Based on this mapping, it was hypothesized that a biallelic gene mutation residing within a homozygous peak region caused the subject's renal disease. To identify the most probable disease-causing mutation, we used the following criteria for exome 7. variant filtering [40][41][42][43] : (1) exclusion of all variants that did not change the amino-acid sequence or affected canonical splice sites (defined as ± 6 nucleotides surrounding the exon-intron boundary),…”

Section: A Case Of Human Arpkd Associated With Homozygous Cys Mutationmentioning

confidence: 99%

“…Mutation calling was performed in line with proposed guidelines, 41 and the following criteria were employed as previously described 42,43 . The variants included were rare in the population with mean allele frequency <0.1% and with 0 homozygotes in the adult reference genome databases ExAC and gnomAD.…”

Section: Whole Genome Sequencing and Mutation Callingmentioning

confidence: 99%

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Yang¹,

O’Connor²,

Kesterson

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells downregulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect in CYS1.These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene. Translational Statement:The cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

show abstract

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

Cited by 153 publications

References 69 publications

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Contact Info

Product

Resources

About