title: Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism.
abstract: 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 ∼3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in ∼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.
authors.affiliation: Department of Pathology and Laboratory Medicine, New York, NY, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Tan
authors.forename: J
authors.initials: J
authors.lastname: Blumenfeld
authors.forename: A
authors.initials: A
authors.lastname: Michaeel
authors.forename: S
authors.initials: S
authors.lastname: Donahue
authors.forename: W
authors.initials: W
authors.lastname: Bobb
authors.forename: T
authors.initials: T
authors.lastname: Parker
authors.forename: D
authors.initials: D
authors.lastname: Levine
authors.forename: H
authors.initials: H
authors.lastname: Rennert
mesh_terms: D000328:Adult; D001483:Base Sequence; D019295:Computational Biology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D007690:Polycystic Kidney Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D011859:Radiography; D050396:TRPP Cation Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: D050396:TRPP Cation Channels
keywords: ADPKD; PKD1 gene; germline mosaicism; somatic mosaicism; truncation mutation