1. Hum Mutat. 2021 Oct;42(10):1221-1228. doi: 10.1002/humu.24251. Epub 2021 Jul 26.

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

Olinger E(1), Alawi IA(1)(2), Al Riyami MS(3), Salmi IA(4), Molinari E(1), 
Faqeih EA(5)(6), Al-Hamed MH(7), Barroso-Gil M(1), Powell L(1), Al-Hussaini 
AA(5), Rahim KA(5), Almontashiri NAM(8)(9), Miles C(1), Shril S(10), Hildebrandt 
F(10), Consortium GER, Wilson IJ(11), Sayer JA(12)(13).

Author information:
(1)Translational and Clinical Research Institute, Faculty of Medical Sciences, 
Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.
(2)National Genetic Center, Ministry of Health, Oman.
(3)The Department of Child Health, The Royal Hospital, Muscat, Oman.
(4)The Department of Renal Medicine, The Royal Hospital, Muscat, Oman.
(5)Division of Pediatric Gastroenterology, Children's Specialized Hospital, King 
Fahad Medical City, Riyadh, Saudi Arabia.
(6)College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
(7)Centre for Genomic Medicine, King Faisal Specialist Hospital and Research 
Center, Riyadh, Saudi Arabia.
(8)Center for Genetics and Inherited Diseases, Taibah University, Almadinah 
Almunwarah, Saudi Arabia.
(9)Faculty of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, 
Saudi Arabia.
(10)Division of Nephrology, Department of Pediatrics, Boston Children's 
Hospital, Harvard Medical School, Boston, Massachusetts, USA.
(11)Biosciences Institute, Faculty of Medical Sciences, Newcastle University, 
Newcastle upon Tyne, UK.
(12)Renal Services, Newcastle Upon Tyne Hospitals NHS Foundation Trust, 
Newcastle upon Tyne, UK.
(13)NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK.

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 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.

© 2021 The Authors. Human Mutation published by Wiley Periodicals LLC.

DOI: 10.1002/humu.24251
PMCID: PMC8434971
PMID: 34212438 [Indexed for MEDLINE]

Conflict of interest statement: Conflicts of Interest The authors declare no 
conflict of interest.