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Thomas, Sophie; Encha-Razavi, Ferechté; Devisme, Louise; Etchevers, Heather; Bessieres-Grattagliano, Bettina; Goudefroye, Géraldine; Elkhartoufi, Nadia; Pateau, Emilie; Ichkou, Amale; Bonniere, Maryse; Marcorelle, Pascale; Parent, Philippe; Manouvrier, Sylvie; Holder, Muriel; Laquerriere, Annie; Loeuillet, Laurence; Roume, Joelle; Martinovic, Jelena; Mougou-Zerelli, Soumaya; Gonzales, Marie; Meyer, Vincent; Wessner, Marc; Feysot, Christine Bole; Nitschke, Patrick; Leticee, Nadia; Munnich, Arnold; Lyonnet, Stanislas; Wookey, Peter; Gyapay, Gabor; Foliguet, Bernard; Vekemans, Michel; Attie-Bitach, Tania
Human mutation, 10/2010, Volume: 31, Issue: 10Journal Article
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 14Mb 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 4.1Mb. 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. Hum Mutat 31:1-8, 2010. © 2010 Wiley-Liss, Inc.
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