Journal
CLINICAL GENETICS
Volume 87, Issue 4, Pages 373-377Publisher
WILEY
DOI: 10.1111/cge.12383
Keywords
ADPKD; germline mosaicism; PKD1 gene; somatic mosaicism; truncation mutation
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Funding
- Rockefeller University Center for Clinical Translational Science (New York, NY)
- National Center for Research Resources (NCRR), a component of the NIH (Bethesda, MD) [UL1 RR024143-01]
- NIH Roadmap for Medical Research
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024143] Funding Source: NIH RePORTER
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Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by loss of function mutations of PKD1 or PKD2 genes. Although PKD1 is highly polymorphic and the new mutation rate is relatively high, the role of mosaicism is incompletely defined. Herein, we describe the molecular analysis of ADPKD in a 19-year-old female proband and her father. The proband had a PKD1 truncation mutation c.10745dupC (p.Val3584ArgfsX43), which was absent in paternal peripheral blood lymphocytes (PBL). However, very low quantities of this mutation were detected in the father's sperm DNA, but not in DNA from his buccal cells or urine sediment. Next generation sequencing (NGS) analysis determined the level of this mutation in the father's PBL, buccal cells and sperm to be approximate to 3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in approximate to 10% of her father's sperm indicates that it probably occurred early in embryogenesis. In ADPKD cases where a de novo mutation is suspected because of negative PKD gene testing of PBL, additional evaluation with more sensitive methods (e.g. NGS) of the proband PBL and paternal sperm can enhance detection of mosaicism and facilitate genetic counseling.
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