title: Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies.
abstract: Isolated hemihyperplasia (IH) refers to a distinct diagnosis involving asymmetric overgrowth of single or multiple organs or regions of the body and can result from various genomic changes including molecular alterations of 11p15; these are paternal uniparental disomy (UPD), and alterations of methylation at two imprinting centers at 11p15: IC1 (H19) and IC2 (KCNQ1OT1). As little information is available on the molecular basis of tumor development in IH, or on the frequency of tumors in children with different molecular subtypes of IH, molecular testing was undertaken on 51 patients with IH and revealed: 8 (16%) with UPD, 3 (6%) with hypomethylation at KCNQ1OT1, and 0 with hypermethylation at H19. Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma). The 50% tumor frequency in patients with IH and UPD was statistically significantly higher than the 15% tumor frequency in those with IH and no molecular alteration detected (Fisher's exact test P = 0.047, OR 5.67). This is the first demonstration that UPD at 11p15 in patients with IH confers a higher tumor risk than in patients with IH without this molecular change. Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development.
authors.affiliation: Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shuman
authors.forename: Adam C
authors.initials: AC
authors.lastname: Smith
authors.forename: Leslie
authors.initials: L
authors.lastname: Steele
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.forename: Carol
authors.initials: C
authors.lastname: Clericuzio
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Parisi
authors.forename: Anna T
authors.initials: AT
authors.lastname: Meadows
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Kelly
authors.forename: David
authors.initials: D
authors.lastname: Tichauer
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Paul
authors.initials: P
authors.lastname: Sadowski
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics; D002648:Child; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009030:Mosaicism; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D027724:Reproductive Techniques, Assisted / Q000009:adverse effects*; D012307:Risk Factors; D024182:Uniparental Disomy
chemical_list: C094335:H19 long non-coding RNA; C485621:KCNQ1OT1 long non-coding RNA, human; D008565:Membrane Proteins; D024642:Potassium Channels, Voltage-Gated; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D004247:DNA