title: Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.
abstract: The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: APHP, Service de génétique et embryologie médicales, CHU Paris Est - Hôpital d'Enfants Armand-Trousseau, Paris, 75571, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.affiliation: APHP, Service de génétique et embryologie médicales, CHU Paris Est - Hôpital d'Enfants Armand-Trousseau, Paris, 75571, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Violet
authors.initials: V
authors.lastname: Gelowani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: University Hospitals, Coventry and Warwickshire NHS Trust, University Hospital, Coventry, West Midlands CV2 2DX, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Coe
authors.affiliation: Département de Génétique, Hôpital Necker-Enfants Malades and Université Paris Descartes, Institute Imagine, Paris, 75015, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Malan
authors.affiliation: Département de Génétique, Hôpital Necker-Enfants Malades and Université Paris Descartes, Institute Imagine, Paris, 75015, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Pilar L
authors.initials: PL
authors.lastname: Magoulas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D025063:Chromosome Disorders / Q000235:genetics* / Q000473:pathology; D058674:Chromosome Duplication / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D005500:Follow-Up Studies; D020440:Gene Duplication; D015321:Gene Rearrangement; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D008957:Models, Genetic; D009185:Myelin Proteins / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011995:Recombination, Genetic; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human; C431552:RAI1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors