Abstract: SA-PO756
Genome-Wide Copy Number Analysis in 11,754 Trios Identifies Human Gene Knockout Patients Including 12 Patients with NPHP1 Whole Gene Deletions
Session Information
- Genetic Diseases: Cystic - Genetic Analysis and Extrarenal Manifestations
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Sayer, John Andrew, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
- Wilson, Ian J., Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
- Olinger, Eric Gregory, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
Background
Whole genome sequencing (WGS) to detect rare genetic diseases is becoming increasingly common. However, pipelines to analyse copy number variants (CNV) are underutilised.
Methods
Using a bespoke CNV analysis of Genomics England 100,000 Genomes Project (100kGP) WGS data from 11754 parent-child trios, we searched for homozygous deletions overlapping with a gene, or“whole gene”, or contiguous gene deletions across the 22 autosomes. We filtering for frequency (<0.5% in a control cohort of 15440 cancer patients within 100kGP population) and for autosomal recessive inheritance mode. Identified regions of deletions were also analysed in 18877 additional rare disease singletons within the 100kGP.
Results
A homozygous ~150kb whole gene deletion of NPHP1-MALL on chromosome 1, which aligned with a known region containing segmental duplications (SD), was the most frequent observation among all autosomal recessive (AR) OMIM-morbid genes, identified in 3 parent-child trios. Clinical phenotypes were consistent with this genotype including nephronophthisis and retinal dystrophy. We extended our analysis to look for NPHP1 whole gene deletions in 18877 additional singletons within the 100kGP. This reverse genetics approach identified an additional 9 patients with whole gene deletions and matching phenotypes. The frequency of heterozygous NPHP1 whole gene deletion was assessed in a control cohort of 15440 cancer patients within 100kGP and was found to be 0.35%.
Conclusion
In conclusion, NPHP1 was the most frequently observed AR OMIM-morbid gene knockout in our trio analysis. Homozygous whole gene deletions in NPHP1 may be easily missed using standard WGS pipelines which don’t assess fully for CNVs and a targeted read-depth approach to identify CNVs in parent-patient trios and singletons is valuable in identifying these deletions.