Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia

Am J Med Genet A. 2016 Dec;170(12):3298-3302. doi: 10.1002/ajmg.a.37942. Epub 2016 Aug 17.

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.

Keywords: TRPV4; metatropic dysplasia; skeletal dysplasia; somatic mosaicism.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • DNA Mutational Analysis
  • Dwarfism / diagnosis*
  • Dwarfism / genetics*
  • Exons
  • Genetic Association Studies*
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Mosaicism*
  • Mutation*
  • Osteochondrodysplasias / diagnosis*
  • Osteochondrodysplasias / genetics*
  • Phenotype*
  • Physical Examination
  • Radiography
  • TRPV Cation Channels / genetics*

Substances

  • TRPV Cation Channels
  • TRPV4 protein, human

Supplementary concepts

  • Metatropic dwarfism