Abstract: PO1267
Analysis of Somatic Mosaic Mutations in Nephropathy-Associated Genes Reveal Candidate Disease-Causing Mutations in Previously Germline-Negative Cases
Session Information
- Cystic Kidney Disease - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Cocchi, Enrico, Columbia University, New York, New York, United States
- Gharavi, Ali G., Columbia University, New York, New York, United States
Group or Team Name
- Gharavi Lab.
Background
Somatic mosaicism variant (SMV) arises due to postzygotic mutations that results in two genetically distinct populations of cells in the same person. SMVs may be missed by standard search for germline (or inherited) mutations, and the use of dedicated analytic pipelines for SMVs can potentially explain “exome negative” cases.
Methods
We searched for SMVs in 248 patients who underwent exome sequencing for congenital kidney anomalies. Somatic mutations were identified through GATK Mutect2 software, and clinically annotated following the American College of Medical Genetics and Genomics (ACMG) guidelines We focused the analysis on 625 nephropathy-associated genes previously used for the germline analysis.
Results
Previous analyses germline variants had identified 52 diagnostic variants in this cohort (20.9% diagnostic rate). In addition, the SMV pipeline identified candidate disease-related SMVs 4 “exome-negative” patients (1.6% of cases). The SMVs were detected in RET, ENG and COL4A5, and are reported in Table 1. This improved the diagnostic rate of the cohort to 22.5%
Conclusion
Analysis of somatic mosaic variants can increase diagnostic yield in patients with congenital kidney anomalies. Application of the SMV pipeline may increase diagnostic in other forms of kidney disease
SVM identified in congenital anomalies kidney patients
| variant | HGVSc | HGVSp | consequence | gene | ACMG |
| 10-43609070-G-T | c.1826G>T | p.Cys609Phe | missense_variant | RET | P |
| 9-130587518-G-A | c.808C>T | p.Gln270Ter | stop_gained | ENG | P |
| 10-123247552-G-T | c.1942C>A | p.Leu648Ile | missense_variant | FGFR2 | LP |
| X-107939580-G-A | c.5048G>A | p.Arg1683Gln | missense_variant | COL4A5 | P |