2. Academic Validation
  3. High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy

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.
Sophie Thomas 1,  Ferechté Encha-Razavi,  Louise Devisme,  Heather Etchevers,  Bettina Bessieres-Grattagliano,  Géraldine Goudefroye,  Nadia Elkhartoufi,  Emilie Pateau,  Amale Ichkou,  Maryse Bonnière,  Pascale Marcorelle,  Philippe Parent,  Sylvie Manouvrier,  Muriel Holder,  Annie Laquerrière,  Laurence Loeuillet,  Joelle Roume,  Jelena Martinovic,  Soumaya Mougou-Zerelli,  Marie Gonzales,  Vincent Meyer,  Marc Wessner,  Christine Bole Feysot,  Patrick Nitschke,  Nadia Leticee,  Arnold Munnich,  Stanislas Lyonnet,  Peter Wookey,  Gabor Gyapay,  Bernard Foliguet,  Michel Vekemans,  Tania Attié-Bitach
Affiliations

Affiliation

  • 1 INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
PMID: 20690116 DOI: 10.1002/humu.21329
Abstract

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.

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