Essam Al Ageeli1, Séverine Drunat2, Catherine Delanoë3, Laurence Perrin2, Clarisse Baumann2, Yline Capri2, Jennifer Fabre-Teste2, Azzedine Aboura2, Céline Dupont2, Stéphane Auvin4, Laila El Khattabi2, Dominique Chantereau2, Anne Moncla5, Anne-Claude Tabet2, Alain Verloes6. 1. Department of Medical Genetics, APHP -- Robert Debré University Hospital, and Paris VII Denis Diderot University, Paris, France; Jazan University, Faculty of Medicine, Jazan, Saudi Arabia. 2. Department of Medical Genetics, APHP -- Robert Debré University Hospital, and Paris VII Denis Diderot University, Paris, France. 3. Department of Physiology, AP-HP, Robert Debré Hospital, Paris, France. 4. Department of Child Neurology, AP-HP, Robert Debré Hospital, Paris, France. 5. Medical Genetic Department, La Timone Hospital, Marseille, France. 6. Department of Medical Genetics, APHP -- Robert Debré University Hospital, and Paris VII Denis Diderot University, Paris, France; INSERM UMR676 "PROTECT", Robert Debré Hospital, Paris, France. Electronic address: alain.verloes@rdb.aphp.fr.
Abstract
BACKGROUND: 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1-BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism. METHODS: Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region. RESULTS: Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader-Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1-BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.
BACKGROUND: 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1-BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism. METHODS: Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region. RESULTS: Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader-Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1-BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autisticpatients without extra material of a neighboring region enhances their likelihood to be genes related to autism.
Authors: Charlotte DiStefano; Rujuta B Wilson; Carly Hyde; Edwin H Cook; Ronald L Thibert; Lawrence T Reiter; Vanessa Vogel-Farley; Joerg Hipp; Shafali Jeste Journal: Am J Med Genet A Date: 2019-10-26 Impact factor: 2.802
Authors: Kesavan Meganathan; Ramachandran Prakasam; Dustin Baldridge; Paul Gontarz; Bo Zhang; Fumihiko Urano; Azad Bonni; Susan E Maloney; Tychele N Turner; James E Huettner; John N Constantino; Kristen L Kroll Journal: BMC Biol Date: 2021-07-28 Impact factor: 7.431