First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing

Neurogenetics. 2018 Jan;19(1):55-59. doi: 10.1007/s10048-017-0531-7. Epub 2017 Dec 2.

Abstract

Familial cerebral cavernous malformations (CCMs) predispose to seizures and hemorrhagic stroke. Molecular genetic analyses of CCM1, CCM2, and CCM3 result in a mutation detection rate of up to 98%. However, only whole genome sequencing (WGS) in combination with the Manta algorithm for analyses of structural variants revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial CCMs. Its breakpoints were fine-mapped, and quantitative analysis on RNA confirmed reduced CCM2 expression. Our data expand the spectrum of CCM mutations and indicate that the existence of a fourth CCM disease gene is rather unlikely.

Keywords: CCM2; Cerebral cavernous malformation; Genomic inversion; Whole genome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / diagnostic imaging
  • Brain / pathology
  • Carrier Proteins / genetics*
  • Child
  • Chromosome Inversion*
  • Genome-Wide Association Study
  • Hemangioma, Cavernous, Central Nervous System / diagnostic imaging
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Hemangioma, Cavernous, Central Nervous System / pathology
  • Humans
  • Male
  • Pedigree
  • Whole Genome Sequencing

Substances

  • CCM2 protein, human
  • Carrier Proteins