[en] 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 were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (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 that 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 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.
Disciplines :
Oncology
Author, co-author :
Daly, Adrian ; Université de Liège > Département des sciences cliniques > Endocrinologie
Yuan, Bo
Fina, Frederic
CABERG, Jean-Hubert ; Centre Hospitalier Universitaire de Liège - CHU > Service de génétique
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, Chan CY, Kayserili H, Avci S, et al. 2014 Genetic heterogeneity in Cornelia de Lange syndrome (CdLS)and CdLS-like phenotypes with observed and predicted levels of mosaicism. Journal of Medical Genetics 51 659-668. (doi:10.1136/jmedgenet-2014-102573)
Asa SL, Kovacs K, Stefaneanu L, Horvath E, Billestrup N, Gonzalez-Manchon C & Vale W 1992 Pituitary adenomas in mice transgenic for growth hormone-releasing hormone. Endocrinology 131 2083-2089.
Ballif BC, Rorem EA, Sundin K, Lincicum M, Gaskin S, Coppinger J, Kashork CD, Shaffer LG & Bejjani BA 2006 Detection of low-level mosaicism by array CGH in routine diagnostic specimens. American Journal of Medical Genetics A 140 2757-2767.
Bates B, Zhang L, Nawoschik S, Kodangattil S, Tseng E, Kopsco D, Kramer A, Shan Q, Taylor N, Johnson J, et al. 2006 Characterization of Gpr101 expression and G-protein coupling selectivity. Brain Research 1087 1-14. (doi:10.1016/j.brainres.2006.02.123)
Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH, Verrua E, et al. 2015 X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocrine-Related Cancer 22 353-367. (doi:10.1530/ERC-15-0038)
Boone PM, Bacino CA, Shaw CA, Eng PA, Hixson PM, Pursley AN, Kang SH, Yang Y, Wiszniewska J, Nowakowska BA, et al. 2010 Detection of clinically relevant exonic copy-number changes by array CGH. Human Mutation 31 1326-1342. (doi:10.1002/humu.21360)
Borson-Chazot F, Garby L, Raverot G, Claustrat F, Raverot V, Sassolas G & group GTE 2012 Acromegaly induced by ectopic secretion of GHRH: a review 30 years after GHRH discovery. Annales d'Endocrinologie 73 497-502.
Campbell IM, Stewart JR, James RA, Lupski JR, Stankiewicz P, Olofsson P & Shaw CA 2014a Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. American Journal of Human Genetics 95 345-359.
Campbell IM, Yuan B, Robberecht C, Pfundt R, Szafranski P, McEntagart ME, Nagamani SC, Erez A, Bartnik M, Wisniowiecka-Kowalnik B, et al. 2014b Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. American Journal of Human Genetics 95 173-182.
Campbell IM, Shaw CA, Stankiewicz P & Lupski JR 2015 Somatic mosaicism: implications for disease and transmission genetics. Trends in Genetics 31 382-392. (doi:10.1016/j.tig.2015.03.013)
Castinetti F, Daly AF, Stratakis CA, Caberg JH, Castermans E, Trivellin G, Rostomyan L, Saveanu A, Jullien N, Reynaud R, et al. 2016 GPR101 mutations are not a frequent cause of congenital isolated growth hormone deficiency. Hormone and Metabolic Research [in press]. (doi: 10.1055/s-0042-100733)
Cheung SW, Shaw CA, Scott DA, Patel A, Sahoo T, Bacino CA, Pursley A, Li J, Erickson R, Gropman AL, et al. 2007 Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. American Journal of Medical Genetics A 143A 1679-1686. (doi:10.1002/ajmg.a.31740)
Conlin LK, Thiel BD, Bonnemann CG, Medne L, Ernst LM, Zackai EH, Deardorff MA, Krantz ID, Hakonarson H & Spinner NB 2010 Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Human Molecular Genetics 19 1263-1275. (doi:10.1093/hmg/ddq003)
Daly AF & Beckers A 2015 Familial isolated pituitary adenomas (FIPA)and mutations in the aryl hydrocarbon receptor interacting protein (AIP)gene. Endocrinology and Metabolism Clinics of North America 44 19-25. (doi:10.1016/j.ecl.2014.10.002)
Daly AF, Lysy PA, Desfilles C, Rostomyan L, Mohamed A, Caberg JH, Raverot V, Castermans E, Marbaix E, Maiter D, et al. 2016 GHRH excess and blockade in X-LAG syndrome. Endocrine-Related Cancer 23 161-170. (doi:10.1530/ERC-15-0478)
Drost JB & Lee WR 1995 Biological basis of germline mutation: comparisons of spontaneous germline mutation rates among drosophila, mouse, and human. Environmental and Molecular Mutagenesis 25 (Supplement 26)48-64.
Gahete MD, Duran-Prado M, Luque RM, Martinez-Fuentes AJ, Quintero A, Gutierrez-Pascual E, Cordoba-Chacon J, Malagon MM, Gracia-Navarro F & Castano JP 2009 Understanding the multifactorial control of growth hormone release by somatotropes: lessons from comparative endocrinology. Annals of the New York Academy of Sciences 1163 137-153. (doi:10.1111/j.1749-6632.2008.03660.x)
Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, et al. 2014 Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. New England Journal of Medicine 371 2477-2487. (doi:10.1056/NEJMoa1409405)
Gu S, Posey JE, Yuan B, Carvalho CM, Luk HM, Erikson K, Lo IF, Leung GK, Pickering CR, Chung BH, et al. 2016 Mechanisms for the generation of two quadruplications associated with split-hand malformation. Human Mutation 37 160-164. (doi:10.1002/humu.22929)
Handsaker RE, Van Doren V, Berman JR, Genovese G, Kashin S, Boettger LM & McCarroll SA 2015 Large multiallelic copy number variations in humans. Nature Genetics 47 296-303. (doi:10.1038/ng.3200)
Hastings PJ, Ira G & Lupski JR 2009 A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genetics 5 e1000327.
Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, et al. 2011 High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Analytical Chemistry 83 8604-8610. (doi:10.1021/ac202028g)
Huisman SA, Redeker EJ, Maas SM, Mannens MM & Hennekam RC 2013 High rate of mosaicism in individuals with Cornelia de Lange syndrome. Journal of Medical Genetics 50 339-344. (doi:10.1136/jmedgenet-2012-101477)
Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, Daly A, Scott C, Harris J, Smillie BJ, et al. 2011 An activating mutation of AKT2 and human hypoglycemia. Science 334 474. (doi:10.1126/science.1210878)
Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, Hutchinson A, Deng X, Liu C, Horner MJ, et al. 2012 Detectable clonal mosaicism and its relationship to aging and cancer. Nature Genetics 44 651-658. (doi:10.1038/ng.2270)
Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, et al. 2014 Somatic mutations in cerebral cortical malformations. New England Journal of Medicine 371 733-743. (doi:10.1056/NEJMoa1314432)
Lee JA, Carvalho CM & Lupski JR 2007 A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131 1235-1247. (doi:10.1016/j.cell.2007.11.037)
Liehr T, Rautenstrauss B, Grehl H, Bathke KD, Ekici A, Rauch A & Rott HD 1996 Mosaicism for the Charcot-Marie-Tooth disease type 1A duplication suggests somatic reversion. Human Genetics 98 22-28. (doi:10.1007/s004390050154)
Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, et al. 2011 A mosaic activating mutation in AKT1 associated with the Proteus syndrome. New England Journal of Medicine 365 611-619. (doi:10.1056/NEJMoa1104017)
Liu P, Gelowani V, Zhang F, Drory VE, Ben-Shachar S, Roney E, Medeiros AC, Moore RJ, DiVincenzo C, Burnette WB, et al. 2014a Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication. American Journal of Human Genetics 94 462-469.
Liu P, Kaplan A, Yuan B, Hanna JH, Lupski JR & Reiner O 2014b Passage number is a major contributor to genomic structural variations in mouse iPSCs. Stem Cells 32 2657-2667.
Lumbroso S, Paris F, Sultan C & European Collaborative Study Group 2004 Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome - a European Collaborative study. Journal of Clinical Endocrinology and Metabolism 89 2107-2113. (doi:10.1210/jc.2003-031225)
Lupski JR 2013 Genetics. Genome mosaicism - one human, multiple genomes. Science 341 358-359.
Mayo KE, Hammer RE, Swanson LW, Brinster RL, Rosenfeld MG & Evans RM 1988 Dramatic pituitary hyperplasia in transgenic mice expressing a human growth hormone-releasing factor gene. Molecular Endocrinology 2 606-612. (doi:10.1210/mend-2-7-606)
Naves LA, Daly AF, Dias LA, Yuan B, Zakir JC, Barra GB, Palmeira L, Villa C, Trivellin G, Junior AJ, et al. 2015 Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. Endocrine 51 236-244. (doi:10.1007/s12020-015-0804-6)
Pham J, Shaw C, Pursley A, Hixson P, Sampath S, Roney E, Gambin T, Kang SH, Bi W, Lalani S, et al. 2014 Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases. European Journal of Human Genetics 22 969-978.
Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK, Hills LB, Heinzen EL, Hill A, Hill RS, et al. 2012 Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74 41-48. (doi:10.1016/j.neuron.2012.03.010)
Poduri A, Evrony GD, Cai X & Walsh CA 2013 Somatic mutation, genomic variation, and neurological disease. Science 341 1237758.
Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Al Turki S, Dominiczak A, Morris A, Porteous D, Smith B, et al. 2016 Timing, rates and spectra of human germline mutation. Nature Genetics 48 126-133.
Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, et al. 2015 Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocrine-Related Cancer 22 745-757. (doi:10.1530/ERC-15-0320)
Sakofsky CJ, Ayyar S, Deem AK, Chung WH, Ira G & Malkova A 2015 Translesion polymerases drive microhomology-mediated break-induced replication leading to complex chromosomal rearrangements. Molecular Cell 60 860-872. (doi:10.1016/j. molcel.2015.10.041)
Steinmann K, Cooper DN, Kluwe L, Chuzhanova NA, Senger C, Serra E, Lazaro C, Gilaberte M, Wimmer K, Mautner VF, et al. 2007 Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. American Journal of Human Genetics 81 1201-1220. (doi:10.1086/522089)
Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, et al. 2014 Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New England Journal of Medicine 371 2363-2374. (doi:10.1056/NEJMoa1408028)
Trivellin G, Bjelobaba I, Daly A, Larco D, Faucz F, Thiry A, Wu T, Stojilkovic S, Feldman B & Costanzi S 2016 Characterization of GPR101 transcripts structure, expression and signaling. InAbstract: book - Keystone Symposia on GPCRs. Presented at Keystone, Colorado. 21-25 February, 2016. Silverthorne, CO, USA: Keystone Symposia on Molecular and Cellular Biology.
Vasilev V, Daly AF, Thiry A, Petrossians P, Fina F, Rostomyan L, Silvy M, Enjalbert A, Barlier A & Beckers A 2014 McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient. Journal of Clinical Endocrinology and Metabolism 99 E2029-E2038.
Veldhuis JD, Iranmanesh A, Erickson D, Roelfsema F & Bowers CY 2012 Lifetime regulation of growth hormone (GH)secretion. In Handbook of Neuroendocrinology, pp 237-257. Eds G Fink, DW Pfaff & J Levine. San Diego, CA, USA: Academic Press.
Weaver S, Dube S, Mir A, Qin J, Sun G, Ramakrishnan R, Jones RC & Livak KJ 2010 Taking qPCR to a higher level: Analysis of CNV reveals the power of high throughput qPCR to enhance quantitative resolution. Methods 50 271-276. (doi:10.1016/j.ymeth.2010.01.003)
Yuan B, Harel T, Gu S, Liu P, Burglen L, Chantot-Bastaraud S, Gelowani V, Beck CR, Carvalho CM, Cheung SW, et al. 2015 Nonrecurrent 17p11.2p12 rearrangement events that result in two concomitant genomic disorders: The PMP22-RAI1 contiguous gene duplication syndrome. American Journal of Human Genetics 97 691-707. (doi:10.1016/j.ajhg.2015.10.003)
Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD & Lupski JR 2009 The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nature Genetics 41 849-853. (doi:10.1038/ng.399
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.
