title: A cryptic familial rearrangement of 11p15.5, involving both imprinting centers, in a family with a history of short stature.
abstract: Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. Both hypomethylation of the telomeric imprinting control region 1 (ICR1) at 11p15.5 and maternal duplication of 11p15.5 have been implicated in the etiology of this disorder. Here we report the origin and segregation of the first reported between-arm intrachromosomal insertion of 11p15.5 that encompasses both ICR1 and ICR2 in a multigenerational family with a history of short stature. One (or any odd number) crossover within the centromeric segment during meiosis would produce recombinant chromosomes; one with a duplication of the inserted segment and the other a deletion. In this 4-generation family, there were six instances of transmission of the recombinant chromosome with duplication of the11p15.5 segment, which leads to a SRS phenotype when maternally inherited and a Beckwith-Wiedemann phenotype when paternally transmitted. The size of the duplicated region is ~1.9 Mb as determined by microarray analysis. This study provides further evidence that maternally inherited duplications of 11p15.5 result in a SRS phenotype that includes short stature and other variable features. The methylation status of the extra copy of the duplicated region of 11p15.5 ultimately predicts the resulting phenotype. Thus, the different phenotype based on parental mode of transmission is of importance in the genetic counseling of these patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Brown
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Rupps
authors.forename: Maria S
authors.initials: MS
authors.lastname: Peñaherrera
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
authors.forename: Millan S
authors.initials: MS
authors.lastname: Patel
authors.forename: Patrice
authors.initials: P
authors.lastname: Eydoux
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation; D019066:Facies; D005190:Family; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D056730:Silver-Russell Syndrome / Q000235:genetics*
keywords: 11p15 duplication; Beckwith-Wiedemann syndrome; Silver-Russell syndrome; imprinting