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Lookup NU author(s): Dr Eric OlingerORCiD, Dr Elisa MolinariORCiD, Miguel Barroso Gil, Laura Powell, Dr Colin Miles, Dr Ian Wilson, Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 The Authors. Human Mutation published by Wiley Periodicals LLCHalf of patients with a ciliopathy syndrome remain unsolved after initial analysis of whole exome sequencing (WES) data, highlighting the need for improved variant filtering and annotation. By candidate gene curation of WES data, combined with homozygosity mapping, we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family. Analyses on patient-derived RNA shows activation of a cryptic mid-exon splice donor leading to frameshift. Remarkably, the same rare variant was detected in four additional families with hepatorenal disease from UK, US, and Saudi patient cohorts and in addition, another synonymous NPHP3 variant was identified in an unsolved case from the Genomics England 100,000 Genomes data set. We conclude that synonymous NPHP3 variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy syndrome. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.
Author(s): Olinger E, Alawi IA, Al Riyami MS, Salmi IA, Molinari E, Faqeih EA, Al-Hamed MH, Barroso-Gil M, Powell L, Al-Hussaini AA, Rahim KA, Almontashiri NAM, Miles C, Shril S, Hildebrandt F, Consortium GER, Wilson IJ, Sayer JA
Publication type: Article
Publication status: Published
Journal: Human Mutation
Year: 2021
Volume: 42
Issue: 10
Pages: 1221-1228
Print publication date: 01/10/2021
Online publication date: 02/07/2021
Acceptance date: 28/06/2021
Date deposited: 27/06/2022
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/humu.24251
DOI: 10.1002/humu.24251
PubMed id: 34212438
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