title: Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype.
abstract: The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described--the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (~3.7 Mb), 13 subjects (~37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability.
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.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Diane
authors.initials: D
authors.lastname: Treadwell-Deering
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Anna
authors.initials: A
authors.lastname: Eifert
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Friedman
authors.forename: Daniel
authors.initials: D
authors.lastname: Glaze
authors.forename: Kevin
authors.initials: K
authors.lastname: Krull
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lee
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.forename: Patricia
authors.initials: P
authors.lastname: Robbins-Furman
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.forename: Xin
authors.initials: X
authors.lastname: Shi
authors.forename: George
authors.initials: G
authors.lastname: Weissenberger
authors.forename: Marjorie
authors.initials: M
authors.lastname: Withers
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D010641:Phenotype; D013577:Syndrome