title: Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.
abstract: Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Daly
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasUSA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital Nord, Service de Transfert d'Oncologie Biologique, Marseille, France Laboratoire de Biologie Médicale, and Aix-Marseille UniversitéInserm, CRO2 UMR_S 911, Marseille, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Fina
authors.affiliation: Department of Human Genetics, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Jean-Hubert
authors.initials: JH
authors.lastname: Caberg
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Trivellin
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Liliya
authors.initials: L
authors.lastname: Rostomyan
authors.affiliation: Section of Endocrinology, Department of Medicine, Erasmus University Medical Center Rotterdam and Pituitary Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: Department of Endocrinology, University of Brasilia, Brasilia, Brazil.
authors.forename: Luciana A
authors.initials: LA
authors.lastname: Naves
authors.affiliation: Endocrinology and Diabetes Unit, BC Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Department of Endocrinology, University Hospital, Nancy, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cuny
authors.affiliation: Kinderklinik, Technische Universität München, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rabl
authors.affiliation: Department of Endocrinology, KEM Hospital, Mumbai, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila and Neuromed Institute, IRCCS, Pozzilli, Italy.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Jaffrain-Rea
authors.affiliation: Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.affiliation: Department of Human Genetics, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Castermans
authors.affiliation: Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital Nord, Service de Transfert d'Oncologie Biologique, Marseille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nanni-Metellus
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.affiliation: Section of Endocrinology, Department of Medicine, Erasmus University Medical Center Rotterdam and Pituitary Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Ammar
authors.initials: A
authors.lastname: Muhammad
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Leonor
authors.initials: L
authors.lastname: Palmeira
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium Department of Human GeneticsCentre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Iulia
authors.initials: I
authors.lastname: Potorac
authors.affiliation: Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.affiliation: Section of Endocrinology, Department of Medicine, Erasmus University Medical Center Rotterdam and Pituitary Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Neggers
authors.affiliation: Department of Endocrinology, University Hospital, Nancy, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Klein
authors.affiliation: Laboratory of Molecular Biology, APHM, Hopital la Conception, Aix Marseille Universite, Marseilles, France CRNSCRN2M-UMR 7286, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.affiliation: Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital Nord, Service de Transfert d'Oncologie Biologique, Marseille, France.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Laboratoire de Biologie Médicale, and Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, France.
authors.forename: L'Houcine
authors.initials: L
authors.lastname: Ouafik
authors.affiliation: Department of Human Genetics, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium albert.beckers@chu.ulg.ac.be.
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
mesh_terms: D000328:Adult; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D005877:Gigantism / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D016133:Polymerase Chain Reaction; D013577:Syndrome; D055815:Young Adult
keywords: X-LAG syndrome; gigantism; molecular genetics; mosaicism; pituitary