Introduction:
Many patients with a cystic kidney disease phenotype remain unsolved after initial analysis of whole genome sequencing (WGS) data, highlighting the need for improved variant filtering and annotation.
Methods:
In a genetically unsolved non-consanguineous family, in whom the affected proband presented with cystic kidney disease, progressive chronic kidney disease and renal biopsy evidence of nephronophthisis, we used a gene specific targeted approach of WGS data analysis. We examined kidney biopsy tissue from the proband, and human urine derived renal epithelial cells (hURECs) from a younger affected sibling to compare in vivo and ex vivo renal epithelial cell primary ciliary morphology. In addition, we performed bulk RNAseq on hURECs to look for disease signatures.
Results:
We detected a homozygous NPHP1 whole gene deletion in the proband which is consistent with the disease phenotype. Genetic screening of the two other siblings, who both had evidence of progressive kidney disease, confirmed the same molecular genetic diagnosis. Both the kidney biopsy and the hURECs demonstrated renal epithelial cells with an elongated primary ciliary phenotype, with hURECs also showing increased ciliary axonemal tortuosity. Bulk RNAseq of patient hURECs showed a disease signature of extracellular matrix interactions and adherens junctions in keeping with the original description of the role of nephrocystin-1 as an adapter protein at adherens junctions.
Conclusions:
We conclude that homozygous NPHP1 deletions may be missed by routine WGS pipelines and that NPHP1 whole gene deletion remains an important genetic diagnosis. hURECS allow deep phenotyping of kidney diseases, replicate human kidney biopsy findings, and can be used to develop disease pathway signatures to allow insights into disease pathogenesis and therapies.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.