title: Mutation screening and array comparative genomic hybridization using a 180K oligonucleotide array in VACTERL association.
abstract: In order to identify genetic causes of VACTERL association (V vertebral defects, A anorectal malformations, C cardiac defects, T tracheoesofageal fistula, E esophageal atresia, R renal anomalies, L limb deformities), we have collected DNA samples from 20 patients diagnosed with VACTERL or with a VACTERL-like phenotype as well as samples from 19 aborted fetal cases with VACTERL. To investigate the importance of gene dose alterations in the genetic etiology of VACTERL association we have performed a systematic analysis of this cohort using a 180K array comparative genomic hybridization (array-CGH) platform. In addition, to further clarify the significance of PCSK5, HOXD13 and CHD7 genes in the VACTERL phenotype, mutation screening has been performed. We identified pathogenic gene dose imbalances in two fetal cases; a hemizygous deletion of the FANCB gene and a (9;18)(p24;q12) unbalanced translocation. In addition, one pathogenic mutation in CHD7 was detected, while no apparent disease-causing mutations were found in HOXD13 or PCSK5. Our study shows that although large gene dose alterations do not seem to be a common cause in VACTERL association, array-CGH is still important in clinical diagnostics to identify disease cause in individual cases.
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Winberg
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Clinical Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Gustavsson
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nikos
authors.initials: N
authors.lastname: Papadogiannakis
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Clinical Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ellika
authors.initials: E
authors.lastname: Sahlin
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Frideborg
authors.initials: F
authors.lastname: Bradley
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Edvard
authors.initials: E
authors.lastname: Nordenskjöld
authors.affiliation: Department of Women's and Children's Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Pär-Johan
authors.initials: PJ
authors.lastname: Svensson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Clinical Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Iwarsson
authors.affiliation: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Clinical Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Department of Women's and Children's Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
mesh_terms: D000595:Amino Acid Sequence; D001003:Anal Canal / Q000002:abnormalities*; D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004947:Esophagus / Q000002:abnormalities*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D005260:Female; D005333:Fetus; D018628:Gene Dosage; D015870:Gene Expression; D005820:Genetic Testing; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D057898:Hemizygote; D006801:Humans; D007668:Kidney / Q000002:abnormalities*; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D013131:Spine / Q000002:abnormalities*; D014132:Trachea / Q000002:abnormalities*; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C515775:FANCB protein, human; D051856:Fanconi Anemia Complementation Group Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human