Al Riyami MS

Al-Hamed MH

Al-Hussaini AA

Alawi IA

Almontashiri NAM

Barroso-Gil M

Consortium GER

Faqeih EA

Hildebrandt F

Miles C

Molinari E

Olinger E

Powell L

Rahim KA

Salmi IA

Sayer JA

Shril S

Wilson IJ

\ua9 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

Newcastle University E-Prints

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

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

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