Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Mallawaarachchi, Amali; Lundie, Ben; Hort, Yvonne; Schönrock, Nicole; Senum, Sarah R.; Gayevskiy, Velimir; Minoche, André E.; Hollway, Georgina E.; Ohnesorg, Thomas; Hinchcliffe, Marcus; Patel, Chirag; Tchan, Michel; Mallett, Andrew; Dinger, Marcel E.; Rangan, Gopala K.; Cowley, Mark J.; Harris, Peter C.; Burnett, Leslie; Shine, John; Furlong, Timothy J.

doi:10.1038/s41431-020-00796-4

Cited by 32 publications

(53 citation statements)

References 35 publications

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“…This is consistent with the larger number of identified IFT140 pedigrees described here than for any other ADPKD-spectrum gene, apart from PKD1 and PKD2. [11][12][13][14]17,22,[70][71][72][73] The phenotype is also very consistent, reflective of a monogenic disease; a few large kidney cysts resulting in increased htTKV, renal insufficiency just in older individuals but rarely ESKD, and liver cysts rare or not present. Nevertheless, UK Biobank participants with IFT140 LoF variants were enriched for CKD 4 and 5, indicating that it is not an entirely benign phenotype.…”

Section: Discussionmentioning

confidence: 99%

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

Senum

Benson

et al. 2022

The American Journal of Human Genetics

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Section: Discussionmentioning

confidence: 99%

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

Senum

Benson

et al. 2022

The American Journal of Human Genetics

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“…The largest disease groups for which positive disease-causing genetic findings were identified were ADPKD and Alport syndrome (collagen 4A disorders), reflecting findings in other cohorts of CKD patients referred for genetic testing [3, 10]. Testing for monogenic causes of ADKPD can enable diagnosis when ultrasound criteria alone cannot exclude individuals without a family history, in individuals with atypical presentation, or in younger patients with fewer or smaller cysts [18]. As variants in additional genes, such as GANAB and DNAJB11 have been implicated in atypical presentation of ADPKD or can have phenotypic overlap with non-ADPKD disorders, diagnoses based on ultrasound alone have become more complicated [18].…”

Section: Discussion/conclusionmentioning

confidence: 97%

“…Testing for monogenic causes of ADKPD can enable diagnosis when ultrasound criteria alone cannot exclude individuals without a family history, in individuals with atypical presentation, or in younger patients with fewer or smaller cysts [18]. As variants in additional genes, such as GANAB and DNAJB11 have been implicated in atypical presentation of ADPKD or can have phenotypic overlap with non-ADPKD disorders, diagnoses based on ultrasound alone have become more complicated [18]. Knowledge of the underlying genetic component can influence prognosis and treatment of ADPKD [19].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel

et al. 2022

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Introduction: Chronic kidney disease (CKD) is a major public health issue in the USA. Identification of monogenic causes of CKD, which are present in ∼10% of adult cases, can impact prognosis and patient management. Broad gene panels can provide unbiased testing approaches, which are advantageous in phenotypically heterogeneous diseases. However, the use and yield of broad genetic panels by nephrologists in clinical practice is not yet well characterized. Methods: Renal genetic testing, ordered exclusively for clinical purposes, predominantly by general and transplant nephrologists within the USA, was performed on 1,007 consecutive unique patient samples. Testing was performed using a commercially available next-generation sequencing-based 382 gene kidney disease panel. Pathogenic (P) and likely pathogenic (LP) variants were reported. Positive findings included a monoallelic P/LP variant in an autosomal dominant or X-linked gene and biallelic P/LP variants in autosomal recessive genes. Results: Positive genetic findings were identified in 21.1% (212/1,007) of cases. A total of 220 positive results were identified across 48 genes. Positive results occurred most frequently in the PKD1 (34.1%), COL4A5 (10.9%), PKD2 (10.0%), COL4A4 (6.4%), COL4A3 (5.9%), and TTR (4.1%) genes. Variants identified in the remaining 42 genes comprised 28.6% of the total positive findings, including single positive results in 26 genes. Positive results in >1 gene were identified in 7.5% (16/212) of cases. Conclusions: Use of broad panel genetic testing by clinical nephrologists had a high success rate, similar to results obtained by academic centers specializing in genetics.

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“… 62 GS has been found to efficiently circumvent these challenges, 62 with this now being revealed in clinical contexts. 63 …”

Section: The Multidisciplinary Teammentioning

confidence: 99%

“…62 GS has been found to efficiently circumvent these challenges, 62 with this now being revealed in clinical contexts. 63 The genotype of patients with ADPKD is predictive of the clinical course. Compared with patients with PKD2, those with PKD1 gene mutations progress to KF on average 20 years earlier and die at a younger age.…”

Section: Common Gkdsmentioning

confidence: 99%

The Evolving Role of Diagnostic Genomics in Kidney Transplantation

Soraru

Chakera

Isbel

et al. 2022

Kidney International Reports

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Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Cited by 32 publications

References 35 publications

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype

Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel

The Evolving Role of Diagnostic Genomics in Kidney Transplantation

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