High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy

Hum Mutat. 2010 Oct;31(10):1134-41. doi: 10.1002/humu.21329.


Rare lethal disease gene identification remains a challenging issue, but it is amenable to new techniques in high-throughput sequencing (HTS). Cerebral proliferative glomeruloid vasculopathy (PGV), or Fowler syndrome, is a severe autosomal recessive disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels leading to hydranencephaly. In three multiplex consanguineous families, genome-wide SNP analysis identified a locus of 14 Mb on chromosome 14. In addition, 280 consecutive SNPs were identical in two Turkish families unknown to be related, suggesting a founder mutation reducing the interval to 4.1 Mb. To identify the causative gene, we then specifically enriched for this region with sequence capture and performed HTS in a proband of seven families. Due to technical constraints related to the disease, the average coverage was only 7×. Nonetheless, iterative bioinformatic analyses of the sequence data identified mutations and a large deletion in the FLVCR2 gene, encoding a 12 transmembrane domain-containing putative transporter. A striking absence of alpha-smooth muscle actin immunostaining in abnormal vessels in fetal PGV brains, suggests a deficit in pericytes, cells essential for capillary stabilization and remodeling during brain angiogenesis. This is the first lethal disease-causing gene to be identified by comprehensive HTS of an entire linkage interval.

Publication types

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

MeSH terms

  • Brain / blood supply
  • Chromosomes, Human, Pair 14 / genetics
  • Consanguinity
  • Fetus / blood supply
  • Genetic Linkage
  • High-Throughput Screening Assays / methods*
  • Humans
  • Hydranencephaly / genetics*
  • Hydrocephalus / genetics
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / genetics*
  • Mutation*
  • Neovascularization, Pathologic
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Receptors, Virus / chemistry
  • Receptors, Virus / genetics*
  • Sequence Analysis, DNA
  • Sequence Deletion*
  • Vascular Diseases / genetics*


  • FLVCR2 protein, human
  • Membrane Transport Proteins
  • Receptors, Virus