Premium
High‐throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy
Author(s) -
Thomas Sophie,
EnchaRazavi Ferechté,
Devisme Louise,
Etchevers Heather,
BessieresGrattagliano Bettina,
Goudefroye Géraldine,
Elkhartoufi Nadia,
Pateau Emilie,
Ichkou Amale,
Bonnière Maryse,
Marcorelle Pascale,
Parent Philippe,
Manouvrier Sylvie,
Holder Muriel,
Laquerrière Annie,
Loeuillet Laurence,
Roume Joelle,
Martinovic Jelena,
MougouZerelli 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,
AttiéBitach Tania
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21329
Subject(s) - genetics , linkage (software) , biology , dna sequencing , mutation , throughput , interval (graph theory) , computational biology , gene , computer science , telecommunications , mathematics , combinatorics , wireless
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. Hum Mutat 31:1–8, 2010. © 2010 Wiley‐Liss, Inc.