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Molecular genetic diagnosis of kidney ciliopathies: Lessons from interpreting genomic sequencing data and the requirement for accurate phenotypic data

Lookup NU author(s): Dr Eric OlingerORCiD, Sotia Iosifidou, Miguel Barroso Gil, Ruxandra Neatu, Dr Katrina Wood, Dr Ian Wilson, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.Abstract: Introduction: Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis. Methods: Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines. We performed a bespoke reanalysis of Whole Genome Sequencing (WGS) data and coupled this with revised phenotypic data and targeted PCR and Sanger sequencing to provide a precise molecular genetic diagnosis. Results: We detected a heterozygous PKD1 frameshift variant within the WGS data which segregated with the redefined ADPKD phenotypes. An additional heterozygous exon deletion in ALG8 was also found in affected and unaffected individuals, but its precise clinical significance remains unclear. Conclusion: This case illustrates that reanalysis of WGS data in unsolved cases of cystic kidney disease is valuable. Clinical phenotypes must be reassessed as these may have been incorrectly recorded and evolve over time. Undertaking additional studies including genotype-phenotype correlation in wider family members provides useful diagnostic information.

Publication metadata

Author(s): Orr S, Olinger E, Iosifidou S, Barroso-Gil M, Neatu R, Wood K, Wilson I, Sayer JA

Publication type: Article

Publication status: Published

Journal: Annals of Human Genetics

Year: 2024

Volume: 88

Issue: 1

Pages: 76-85

Print publication date: 01/01/2024

Online publication date: 12/04/2023

Acceptance date: 17/03/2023

Date deposited: 15/05/2023

ISSN (print): 0003-4800

ISSN (electronic): 1469-1809

Publisher: John Wiley and Sons Inc


DOI: 10.1111/ahg.12508


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Funder referenceFunder name
Paed_RP_001_20180925Kidney Research UK (was National Kidney Research Fund)