High-throughput Sequencing of a 4.1 Mb Linkage Interval Reveals FLVCR2 Deletions and Mutations in Lethal Cerebral Vasculopathy

Sophie Thomas (1, 2) , Ferechte Encha-Razavi (1, 2) , Louise Devisme (3) , Heather C Etchevers (2, 4) , Bettina Bessieres-Grattagliano (5) , Geraldine Goudefroye (6) , Nadia Elkhartoufi (6) , Emilie Pateau (7) , Amale Ichkou (6) , Maryse Bonniere (8, 9) , Pascale Marcorelles (10) , Philippe Parent (11) , Sylvie Manouvrier (12) , Muriel Holder (6) , Annie Laquerriere (13) , Laurence Loeuillet (14) , Joelle Roume (15) , Jéléna Martinovic (6, 16) , Soumaya Mougou-Zerelli (1, 2, 17) , Marie Gonzales (18) , Vencent Meyer (7) , Marc Wessner (7) , Christine Bole Feysot (19) , Patrick Nitschke (20) , Nadia Leticee (21) , Arnold Munnich (1, 2, 6) , Stanislas Lyonnet (1, 2, 6) , Peter Wookey (22) , Gabor Gyapay (7) , Bernard Folliguet (23) , Michel Vekemans (1, 2, 6) , Tania Attie-Bitach (2, 6, 4)

1 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
2 UPD5 - Université Paris Descartes - Paris 5
3 Pôle de Pathologie, Centre de Biologie Pathologie
4 Genetics
5 Anatomo-foeto-pathologie
6 Service de Génétique Médicale [CHU Necker]
7 GENOSCOPE - Genoscope - Centre national de séquençage [Evry]
8 Embryologie
9 Laboratoire Nord Pathologie
10 Anatomopathologie Pathologique
11 Département de pédiatrie et génétique médicale
12 Hôpital Jeanne de Flandres
13 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
14 Service d'Anatomie et de Cytologie Pathologiques
15 Génétique Médicale
16 Genetics
17 Génétique moléculaire et Biologie de la reproduction
18 UPMC - Université Pierre et Marie Curie - Paris 6
19 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
20 Service de Bioinformatique
21 Service de Gynécologie Obstétrique [CHU Necker]
22 Department of Medicine
23 Laboratoire de Biologie de la Reproduction et du Développement [CHRU Nancy]

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 3 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 4,1Mb. To identify the causative gene, we then specifically enriched for this region with sequence capture and performed HTS in a proband of 7 families. Due to technical constraints related to the disease, the average coverage was only 7X. Nonetheless, iterative bioinformatic analyses of the sequence data identified mutations and a large deletion in the FLVCR2 gene, encoding a twelve 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 stabilisation and remodelling during brain angiogenesis. This is the first lethal disease-causing gene to be identified by comprehensive HTS of an entire linkage interval.

Mots clés: Life Sciences

Sophie Thomas, Ferechte Encha-Razavi, Louise Devisme, Heather C Etchevers, Bettina Bessieres-Grattagliano, et al.. High-throughput Sequencing of a 4.1 Mb Linkage Interval Reveals FLVCR2 Deletions and Mutations in Lethal Cerebral Vasculopathy. Human Mutation, 2010, 31 (10), pp.1134. ⟨10.1002/humu.21329⟩. ⟨hal-00574003⟩