title: Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.
abstract: Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.
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: Juanita
authors.initials: J
authors.lastname: Neira
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: 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: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia.|Instituto de Referencia Andino, Bogotá, Colombia.|Facultad de Medicina, Universidad de La Sabana, Chía, Colombia.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Briceño
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Elsea
authors.affiliation: Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia.|Instituto de Referencia Andino, Bogotá, Colombia.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gómez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.|Texas Children's Hospital, 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. jlupski@bcm.edu.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA. jlupski@bcm.edu.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA. jlupski@bcm.edu.|Texas Children's Hospital, Houston, TX, 77030, USA. jlupski@bcm.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D057895:Haploinsufficiency / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics*; D058496:Smith-Magenis Syndrome / Q000235:genetics* / Q000503:physiopathology; 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