title: Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay.
abstract: The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1-BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2-BP3) or uniparental disomy 15. The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.
authors.affiliation: Laboratory Corporation of America, 1904 Alexander Dr., Research Triangle Park, NC 27709, USA. burnsir@labcorp.com
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Burnside
authors.forename: Romela
authors.initials: R
authors.lastname: Pasion
authors.forename: Fady M
authors.initials: FM
authors.lastname: Mikhail
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Nathaniel H
authors.initials: NH
authors.lastname: Robin
authors.forename: Erin L
authors.initials: EL
authors.lastname: Youngs
authors.forename: Inder K
authors.initials: IK
authors.lastname: Gadi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Keitges
authors.forename: Vikram L
authors.initials: VL
authors.lastname: Jaswaney
authors.forename: Peter R
authors.initials: PR
authors.lastname: Papenhausen
authors.forename: Venkateswara R
authors.initials: VR
authors.lastname: Potluri
authors.forename: Hiba
authors.initials: H
authors.lastname: Risheg
authors.forename: Brooke
authors.initials: B
authors.lastname: Rush
authors.forename: Janice L
authors.initials: JL
authors.lastname: Smith
authors.forename: Stuart
authors.initials: S
authors.lastname: Schwartz
authors.forename: James H
authors.initials: JH
authors.lastname: Tepperberg
authors.forename: Merlin G
authors.initials: MG
authors.lastname: Butler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017204:Angelman Syndrome / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D020440:Gene Duplication; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D013064:Speech Disorders / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers