Abstract
Half 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 2 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 4 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 100,000 Genomes dataset. We conclude that synonymous
NPHP3
variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.