title: High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy.
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.
authors.affiliation: INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Ferechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Louise
authors.initials: L
authors.lastname: Devisme
authors.forename: Heather
authors.initials: H
authors.lastname: Etchevers
authors.forename: Bettina
authors.initials: B
authors.lastname: Bessieres-Grattagliano
authors.forename: Géraldine
authors.initials: G
authors.lastname: Goudefroye
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhartoufi
authors.forename: Emilie
authors.initials: E
authors.lastname: Pateau
authors.forename: Amale
authors.initials: A
authors.lastname: Ichkou
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonnière
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelle
authors.forename: Philippe
authors.initials: P
authors.lastname: Parent
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerrière
authors.forename: Laurence
authors.initials: L
authors.lastname: Loeuillet
authors.forename: Joelle
authors.initials: J
authors.lastname: Roume
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Soumaya
authors.initials: S
authors.lastname: Mougou-Zerelli
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Vincent
authors.initials: V
authors.lastname: Meyer
authors.forename: Marc
authors.initials: M
authors.lastname: Wessner
authors.forename: Christine Bole
authors.initials: CB
authors.lastname: Feysot
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Nadia
authors.initials: N
authors.lastname: Leticee
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Peter
authors.initials: P
authors.lastname: Wookey
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyapay
authors.forename: Bernard
authors.initials: B
authors.lastname: Foliguet
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D001921:Brain / Q000098:blood supply; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D003241:Consanguinity; D005333:Fetus / Q000098:blood supply; D008040:Genetic Linkage; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D006832:Hydranencephaly / Q000235:genetics*; D006849:Hydrocephalus / Q000235:genetics; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D009389:Neovascularization, Pathologic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011991:Receptors, Virus / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014652:Vascular Diseases / Q000235:genetics*
chemical_list: C553450:FLVCR2 protein, human; D026901:Membrane Transport Proteins; D011991:Receptors, Virus