title: Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.
abstract: Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal phenotypes range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4L618P, which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Weinstein
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles.
authors.forename: Taekyu
authors.initials: T
authors.lastname: Kang
authors.affiliation: International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle.|University of Washington Center for Mendelian Genomics, University of Washington, Seattle.|Department of Pediatrics, University of Washington, Seattle.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle.|University of Washington Center for Mendelian Genomics, University of Washington, Seattle.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles.|Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles.|Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles.|Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles.|International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles.|Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles.|Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D000483:Alleles; D004252:DNA Mutational Analysis; D004392:Dwarfism / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D009030:Mosaicism; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D010808:Physical Examination; D011859:Radiography; D050916:TRPV Cation Channels / Q000235:genetics*
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human
keywords: TRPV4; metatropic dysplasia; skeletal dysplasia; somatic mosaicism