Monogenic causes of chronic kidney disease in adults

Connaughton, Dervla M.; Kennedy, Claire; Shril, Shirlee; Mann, Nina; Murray, Susan; Williams, Patrick A.; Conlon, Eoin T.; Nakayama, Makiko; Ven, Amelie T. van der; Ityel, Hadas; Kause, Franziska; Kolvenbach, Caroline M.; Dai, Rufeng; Vivante, Asaf; Braun, Daniela A.; Schneider, Ronen; Kitzler, Thomas M.; Moloney, Bróna; Moran, Conor; Smyth, John; Kennedy, Alan; Benson, Katherine; Stapleton, Caragh; Denton, Mark D.; Magee, Colm; O’Seaghdha, Conall M.; Plant, William D.; Griffin, Matthew; Awan, Atif; Sweeney, Clodagh; Mane, Shrikant; Lifton, Richard P.; Griffin, Brenda Walker; Leavey, Sean F.; Casserly, Liam F.; Freitas, D. G. de; Holian, John; Dorman, Anthony; Doyle, Brendan; Lavin, Peter; Little, Mark A.; Conlon, Peter J.

doi:10.1016/j.kint.2018.10.031

Cited by 201 publications

(250 citation statements)

References 31 publications

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“…Variant interpretation was performed by a panel of nephrologists or molecular geneticists with domain expertise in inherited kidney diseases, bioinformaticians, and the clinical molecular geneticists, using the American College of Medical Genetics (ACMG) guidelines for clinical sequence interpretation . In brief, we prioritized variants that occurred in a nephropathy associated genes list (Table S2) and evaluated those variants in other Mendelian disease‐associated genes. Diagnostic variants were defined as “pathogenic” or “likely pathogenic” according ACMG guidelines and included the variants of uncertain significance (VUS) of known disease‐causing genes through discussion combined with genotype and phenotype.…”

Section: Methodsmentioning

confidence: 99%

“…The potential copy‐number variants (CNVs) identified by WES were further examined by chromosomal microarray analysis (CMA) and confirmed by real‐time polymerase chain reaction or PCR‐based gel electrophoresis such as for the NPHP1 deletion. For patients referred with an a clinical diagnosis of nephrotic syndrome, we manually searched for the p.Arg229Gln variant in the NPHS2 gene, because this allele occurs at a frequency of >1% All diagnostic variants were confirmed by Sanger sequencing with segregation. We did not collect the information of incidental findings through WES in the CCGKDD.…”

Section: Methodsmentioning

confidence: 99%

“…Genetic renal disease makes up a significant proportion of chronic kidney disease (CKD) in children . At least 10% of adults and nearly all children who received renal replacement therapy have a genetic renal disease .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2019

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…ADTKD is one such condition, and we have reported separately on the clinical characteristics of Irish individuals with ADTKD . Recently, the use of whole‐exome sequencing has been used to evaluate Irish individuals with a suspected rare genetic cause of kidney disease …”

Section: Discussionmentioning

confidence: 99%

“…20 Recently, the use of whole-exome sequencing has been used to evaluate Irish individuals with a suspected rare genetic cause of kidney disease. 24 There are, at present, no specific therapies to delay CKD progression in patients with ADTKD. Supportive management includes treating complications of CKD, treatment of gout (in patients with mutations in the UMOD gene), and preparation for ESRD.…”

Section: Discussionmentioning

confidence: 99%

Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease

Cormican

Kennedy

Connaughton

et al. 2020

Clinical Transplantation

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Introduction Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure. Methods Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non‐ADTKD renal transplant recipients. Results We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite‐ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow‐up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty‐five transplant biopsies were performed during follow‐up, and none of these showed signs of recurrent ADTKD post‐transplant. Conclusion In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.

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Recessive CHRM5 variant as a potential cause of neurogenic bladder

Schneider

Schierbaum

Burger

et al. 2023

American J of Med Genetics Pt A

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Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.

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Monogenic causes of chronic kidney disease in adults

Cited by 201 publications

References 31 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

Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease

Recessive CHRM5 variant as a potential cause of neurogenic bladder

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