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A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families

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.

Publication metadata

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


DOI: 10.1002/humu.24251

PubMed id: 34212438


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Funder referenceFunder name
KFSHRC RAC# 2160 022
Medical Research Council Discovery Medicine North Training Partnership
Northern Counties Kidney Research Fund
Paed_RP_001_20180925Kidney Research UK (was National Kidney Research Fund)
Research Advisory Council at King Faisal Specialist ...
RP_006_20180227Kidney Research UK (was National Kidney Research Fund)
ST_001_20171120Kidney Research UK (was National Kidney Research Fund)