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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
High-throughput sequencing of a 4.1Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy
Human Mutation, Volume 31, No. 10, Year 2010
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Description
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. © 2010 Wiley-Liss, Inc.
Authors & Co-Authors
Thomas, Sophie
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Encha-Razavi, Ferechte
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Devisme, Louise
France, Lille
Chu Lille
Etchevers, Heather C.
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Bessieres-Grattagliano, Bettina
France, Paris
Institut de Puériculture et de Périnatalogie
Goudefroye, Géraldine
France, Paris
Hôpital Necker Enfants Malades
Elkhartoufi, Nadia
France, Paris
Hôpital Necker Enfants Malades
Pateau, Emilie
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Ichkou, Amale
France, Paris
Hôpital Necker Enfants Malades
Bonnière, Maryse
France, Paris
Hôpital Necker Enfants Malades
France, Lille
Laboratoire Nord Pathologie
Marcorelle, Pascale
France, Brest
Hopital Morvan
Parent, P.
France, Brest
Hopital Morvan
Manouvríer-Hanu, Sylvie
France, Lille
Université de Lille
Holder, Muriel
France, Lille
Université de Lille
Laquérrière, Annie
France, Rouen
Hôpital de Rouen
Loeuillet, Laurence
France, Poissy
Centre Hospitalier Intercommunal Poissy-st-germain-en-laye
Roume, Joëlle
France, Poissy
Centre Hospitalier Intercommunal Poissy-st-germain-en-laye
Martinovic, Jéléna
France, Paris
Hôpital Necker Enfants Malades
Mougou, S.
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Tunisia, Sousse
Hopital Farhat Hached Sousse
Gonzalès, Marie Françoise
France, Paris
Hôpital Armand-trousseau
Meyer, Vincent
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Wessner, Marc
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Feysot, Christine Bole
France, Paris
Hôpital Necker Enfants Malades
Nitschké, Patrick
France, Paris
Université Paris
Leticee, Nadia
France, Paris
Hôpital Necker Enfants Malades
Münnich, Arnold
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Lyonnet, Stanislas L.
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Wookey, Peter
Australia, Melbourne
University of Melbourne
Gyapay, Gábor
France, Gif-sur-yvette
Commissariat a L'energie Atomique et Aux Energies Alternatives
Foliguet, Bernard
France, Nancy
Laboratoire de Biologie de la Reproduction et du Développement Maternité de Nancy
Vekemans, Michel J.J.
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Attié-Bitach, Tania
France, Paris
Hôpital Necker Enfants Malades
France, Paris
Université Paris Cité
Statistics
Citations: 32
Authors: 32
Affiliations: 15
Identifiers
Doi:
10.1002/humu.21329
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Cancer
Genetics And Genomics
Health System And Policy