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Endocr Relat Cancer. 2016 Apr;23(4):221-33. doi: 10.1530/ERC-16-0082. Epub 2016 Mar 2.

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

Author information

1
Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasUSA.
3
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.
4
Department of Human Genetics, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium.
5
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.
6
Section of Endocrinology, Department of Medicine, Erasmus University Medical Center Rotterdam and Pituitary Center Rotterdam, Rotterdam, The Netherlands.
7
Department of Endocrinology, University of Brasilia, Brasilia, Brazil.
8
Endocrinology and Diabetes Unit, BC Children's Hospital, Vancouver, British Columbia, Canada.
9
Department of Endocrinology, University Hospital, Nancy, France.
10
Kinderklinik, Technische Universität München, Munich, Germany.
11
Department of Endocrinology, KEM Hospital, Mumbai, India.
12
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila and Neuromed Institute, IRCCS, Pozzilli, Italy.
13
Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
14
Assistance Publique Hôpitaux de Marseille (AP-HM), Hôpital Nord, Service de Transfert d'Oncologie Biologique, Marseille, France.
15
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.
16
Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
17
Laboratory of Molecular Biology, APHM, Hopital la Conception, Aix Marseille Universite, Marseilles, France CRNSCRN2M-UMR 7286, Marseille, France.
18
Laboratoire de Biologie Médicale, and Aix-Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, France.
19
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
20
Department of Endocrinology, Centre Hospitalier Universitaire de Liege, University of Liege, Liege, Belgium albert.beckers@chu.ulg.ac.be.

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.

KEYWORDS:

X-LAG syndrome; gigantism; molecular genetics; mosaicism; pituitary

PMID:
26935837
PMCID:
PMC4877443
DOI:
10.1530/ERC-16-0082
[Indexed for MEDLINE]
Free PMC Article

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