title: Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency.
abstract: Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.
authors.affiliation: Service d'Hématologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, 75908 Paris Cedex 15, France. veronique.picard@u-psud.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Picard
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tardy
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Aillaud
authors.forename: Christine
authors.initials: C
authors.lastname: Boiteux-Vergnes
authors.forename: Marie
authors.initials: M
authors.lastname: Dreyfus
authors.forename: Joseph
authors.initials: J
authors.lastname: Emmerich
authors.forename: Cécile
authors.initials: C
authors.lastname: Lavenu-Bombled
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
authors.forename: Nathalie
authors.initials: N
authors.lastname: Trillot
authors.forename: Martine
authors.initials: M
authors.lastname: Aiach
authors.forename: Martine
authors.initials: M
authors.lastname: Alhenc-Gelas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000990:Antithrombin III; D020152:Antithrombin III Deficiency / Q000235:genetics*; D000991:Antithrombins / Q000172:deficiency* / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D000991:Antithrombins; C542513:SERPINC1 protein, human; D000990:Antithrombin III