title: Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion.
abstract: Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of intragenic NIPBL copy number variations (CNVs) in a cohort of 510 NIPBL sequence-negative patients with suspected CdLS. Copy number analysis was performed by custom exon-targeted oligonucleotide array-comparative genomic hybridization and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene. We identified NIPBL CNVs in 13 patients (2.5%) including one intragenic duplication and a deletion in mosaic state. Breakpoint sequences in two patients provided further evidence of a microhomology-mediated replicative mechanism as a potential predominant contributor to CNVs in NIPBL. Patients for whom clinical information was available share classical CdLS features including craniofacial and limb defects. Our experience in studying the frequency of NIBPL CNVs in the largest series of patients to date widens the mutational spectrum of NIPBL and emphasizes the clinical utility of performing NIPBL deletion/duplication analysis in patients with CdLS.
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Tan
authors.affiliation: Department of Pathology, University of Chicago Chicago, Illinois.
authors.forename: Agata
authors.initials: A
authors.lastname: Minor
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Kelly
authors.initials: K
authors.lastname: Arndt
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Latrice
authors.initials: L
authors.lastname: Wysinger
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine St. Louis, Missouri.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine St. Louis, Missouri.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Kozel
authors.affiliation: Department of Genetics, University of Alabama at Birmingham Birmingham, Alabama.
authors.forename: Nathaniel H
authors.initials: NH
authors.lastname: Robin
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Darrel
authors.initials: D
authors.lastname: Waggoner
authors.affiliation: Department of Pathology, University of Chicago Chicago, Illinois.
authors.forename: Carrie
authors.initials: C
authors.lastname: Fitzpatrick
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Human Genetics, University of Chicago Chicago, Illinois.
authors.forename: Daniela
authors.initials: D
authors.lastname: Del Gaudio
keywords: Array-CGH; Cornelia de Lange; MLPA; NIPBL; copy number variation