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Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing

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Abstract

The chromosomal region 11p15 contains two imprinting control regions (ICRs) and is a key player in molecular processes regulated by genomic imprinting. Genomic as well as epigenetic changes affecting 11p15 are associated either with Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS). In the last years, a growing number of patients affected by imprinting disorders (IDs) have reported carrying the diease-specific 11p15 hypomethylation patterns as well as methylation changes at imprinted loci at other chromosomal sites (multi-locus methylation defects, MLMD). Furthermore, in several patients, molecular alterations (e.g., uniparental disomies, UPDs) additional to the primary epimutations have been reported. To determine the frequency and distribution of mutations and epimutations in patients referred as SRS or BWS for genetic testing, we retrospectively ascertained our routine patient cohort consisting of 711 patients (SRS, n = 571; BWS, n = 140). As this cohort represents the typical cohort in a routine diagnostic lab without clinical preselection, the detection rates were much lower than those reported from clinically characterized cohorts in the literature (SRS, 19.9 %; BWS, 28.6 %). Among the molecular subgroups known to be predisposed to MLMD, the frequencies corresponded to that in the literature (SRS, 7.1 % in ICR1 hypomethylation carriers; BWS, 20.8 % in ICR2 hypomethylation patients). In several patients, more than one epigenetic or genetic disturbance could be identified. Our study illustrates that the complex molecular alterations as well as the overlapping and sometimes unusual clinical findings in patients with imprinting disorders (IDs) often make the decision for a specific imprinting disorder test difficult. We therefore suggest to implement molecular assays in routine ID diagnostics which allow the detection of a broad range of (epi)mutation types (epimutations, UPDs, chromosomal imbalances) and cover the clinically most relevant known ID loci because of the following: (a) Multi-locus tests increase the detection rates as they cover numerous loci. (b) Patients with unexpected molecular alterations are detected. (c) The testing of rare imprinting disorders becomes more efficient and quality of molecular diagnosis increases. (d) The tests identify MLMDs. In the future, the detailed characterization of clinical and molecular findings in ID patients will help us to decipher the complex regulation of imprinting and thereby providing the basis for more directed genetic counseling and therapeutic managements in IDs.

Key message

  • Molecular disturbances in patients with imprinting disorders are often not restricted to the disease-specific locus but also affect other chromosomal regions.

  • These additional disturbances include methylation defects, uniparental disomies as well as chromosomal imbalances.

  • The identification of these additional alterations is mandatory for a well-directed genetic counseling.

  • Furthermore, these findings help to decipher the complex regulation of imprinting.

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References

  1. Howard MS (2011) Russell-Silver syndrome. Gene reviews, Initial posting: November 2, 2002; Last update: June 2, 2011

  2. Choufani S, Shuman C, Weksberg R (2013) Molecular findings in Beckwith-Wiedemann syndrome. Am J Med Genet C: Semin Med Genet 163C:131–140

    Article  Google Scholar 

  3. Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, Thibaud N, Faussat AM, Tauber M, Le Bouc Y et al (2013) CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet 50:823–830

    Article  CAS  PubMed  Google Scholar 

  4. Begemann M, Spengler S, Gogiel M, Grasshoff U, Bonin M, Betz RC, Dufke A, Spier I, Eggermann T (2012) Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature. J Med Genet 49:547–553

    Article  PubMed Central  PubMed  Google Scholar 

  5. Bullman H, Lever M, Robinson DO, Mackay DJ, Holder SE, Wakeling EL (2008) Mosaic maternal uniparental disomy of chromosome 11 in a patient with Silver-Russell syndrome. J Med Genet 45:396–399

    Article  CAS  PubMed  Google Scholar 

  6. Court F, Martin-Trujillo A, Romanelli V, Garin I, Iglesias-Platas I, Salafsky I, Guitart M, Perez de Nanclares G, Lapunzina P, Monk D (2013) Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes. Hum Mutat 34:595–602

    CAS  PubMed  Google Scholar 

  7. Perez-Nanclares G, Romanelli V et al (2012) Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus. J Clin Endocrinol Metab 97:E1060–E1067

    Article  CAS  PubMed  Google Scholar 

  8. Maupetit-Méhouas S, Azzi S, Steunou V, Sakakini N, Silve C, Reynes C, Perez de Nanclares G, Keren B, Chantot S, Barlier A et al (2013) Simultaneous hyper- and hypomethylation at imprinted loci in a subset of patients with GNAS epimutations underlies a complex and different mechanism of multilocus methylation defect in pseudohypoparathyroidism type 1b. Hum Mutat 34:1172–1180

    Article  PubMed  Google Scholar 

  9. Poole RL, Docherty LE, Al Sayegh A, Caliebe A, Turner C, Baple E, Wakeling E, Harrison L, Lehmann A, Temple IK et al (2013) International Clinical Imprinting Consortium. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. Am J Med Genet A 161:2174–2182

    Article  PubMed  Google Scholar 

  10. Rossignol S, Steunou V, Chalas C et al (2006) The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J Med Genet 43:902–907

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Bliek J, Verde G, Callaway J et al (2009) Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet 17:611–619

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Azzi S, Rossignol S, Steunou V et al (2009) Multilocus analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet 18:4724–4733

    Article  CAS  PubMed  Google Scholar 

  13. Bliek J, Alders M, Maas SM et al (2009) Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. Eur J Hum Genet 17:1625–1634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Turner CL, Mackay DM, Callaway JL et al (2010) Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci. Eur J Med Genet 17:648–655

    Google Scholar 

  15. Begemann M, Spengler S, Kanber D, Haake A, Baudis M, Leisten I, Binder G, Markus S, Rupprecht T, Segerer H et al (2011) Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues. Clin Genet 80:83–88

    Article  CAS  PubMed  Google Scholar 

  16. Baple EL, Poole RL, Mansour S et al (2011) An atypical case of hypomethylation at multiple imprinted loci. Eur J Hum Genet 19:360–362

    Article  PubMed Central  PubMed  Google Scholar 

  17. Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE, Dayanikli P, Firth HV, Goodship JA, Haemers AP et al (2008) Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 40:949–951

    Article  CAS  PubMed  Google Scholar 

  18. Meyer E, Lim D, Pasha S, Tee LJ, Rahman F, Yates JR, Woods CG, Reik W, Maher ER (2009) Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome). PLoS Genet 5:e1000423

    Article  PubMed Central  PubMed  Google Scholar 

  19. Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B et al (2006) Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet 38:300–302

    Article  CAS  PubMed  Google Scholar 

  20. Begemann M, Leisten I, Soellner L, Zerres K, Eggermann T, Spengler S (2012) Use of multi-locus methylation-specific single nucleotide primer extension (MS SNuPE) technology in diagnostic testing for human imprinted loci. Epigenetics 7:473–481

    Article  CAS  PubMed  Google Scholar 

  21. Eggermann T, Gonzalez D, Spengler S, Arslan-Kirchner M, Binder G, Schönherr N (2009) Broad clinical spectrum in Silver-Russell syndrome and consequences for genetic testing in growth retardation. Pediatrics 123:e929–e931

    Article  PubMed  Google Scholar 

  22. Schönherr N, Meyer E, Roos A, Schmidt A, Wollmann HA, Eggermann T (2007) The centromeric 11p15 imprinting centre is also involved in Silver-Russell syndrome. J Med Genet 44:59–63

    Article  PubMed Central  PubMed  Google Scholar 

  23. Gogiel M, Begemann M, Spengler S, Soellner L, Göretzlehner U, Eggermann T, Strobl-Wildemann G (2013) Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith-Wiedemann syndrome and ovarian steroid cell tumour. Eur J Hum Genet 21:788–791

    Article  CAS  PubMed  Google Scholar 

  24. Schroeder C, Sturm M, Dufke A, Mau-Holzmann U, Eggermann T, Poths S, Riess O, Bonin M (2013) UPDtool: a tool for detection of iso- and heterodisomy in parent–child trios using SNP microarrays. Bioinformatics 29:1562–1564

    Article  CAS  PubMed  Google Scholar 

  25. Eggermann T, Spengler S, Bachmann N, Baudis M, Mau-Holzmann UA, Singer S, Rossier E (2010) Chromosome 11p15 duplication in Silver-Russell syndrome due to a maternally inherited translocation t(11;15). Am J Med Genet A 152A:1484–1487

    Article  PubMed  Google Scholar 

  26. Eggermann T, Schneider-Rätzke B, Begemann M, Spengler S (2013) Isolated hypermethylation of GRB10 (7p12.2) in a Silver-Russell syndrome patient carrying a 20p13 microdeletion. Clin Genet. doi:10.1111/cge.12186

    PubMed  Google Scholar 

  27. Eggermann T, Spengler S, Begemann M, Binder G, Buiting K, Albrecht B, Spranger S (2012) Deletion of the paternal allele of the imprinted MEST/PEG1 region in a patient with Silver-Russell syndrome features. Clin Genet 81:298–300

    Article  CAS  PubMed  Google Scholar 

  28. Begemann M, Spengler S, Kordass U, Schröder C, Eggermann T (2012) Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation. Am J Med Genet A 158A:423–428

    Article  PubMed  Google Scholar 

  29. Bens S, Haake A, Richter J, Leohold J, Kolarova J, Vater I, Riepe FG, Buiting K, Eggermann T, Gillessen-Kaesbach G et al (2013) Frequency and characterization of DNA methylation defects in children born SGA. Eur J Hum Genet 21:838–843

    Article  CAS  PubMed  Google Scholar 

  30. Beygo J, Ammerpohl O, Gritzan D, Heitmann M, Rademacher K, Richter J, Caliebe A, Siebert R, Horsthemke B, Buiting K (2013) Deep bisulfite sequencing of aberrantly methylated Loci in a patient with multiple methylation defects. PLoS One 8:e76953

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Dias RP, Nightingale P, Hardy C, Kirby G, Tee L, Price S, Macdonald F, Barrett TG, Maher ER (2013) Comparison of the clinical scoring systems in Silver-Russell syndrome and development of modified diagnostic criteria to guide molecular genetic testing. J Med Genet 50:635–639

    Article  PubMed  Google Scholar 

  32. Alders M, Maas SM, Kadouch DM, van der Lip K, Bliek J, van der Horst CMAM, Mannes MMAM (2013) Methylation analysis in tongue tissue of BWS patients identifies the (epi)genetic cause in 3 patients with normal methylation levels of H19 and KCNQ1OT1 in blood. Presented at the 63rd Annual Meeting of the American Society of Human Genetics, Date, Location (October, 2013 in Boston, MA)

  33. Demars J, Gicquel C (2012) Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith-Wiedemann and Silver-Russell syndromes. Clin Genet 81:350–361

    Article  CAS  PubMed  Google Scholar 

  34. Alfarawati S, Fragouli E, Colls P, Wells D (2012) Embryos of Robertsonian translocation carriers exhibit a mitotic interchromosomal effect that enhances genetic instability during early development. PLoS Genet 8:e1003025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Grønskov K, Poole RL, Hahnemann JM, Thomson J, Tümer Z, Brøndum-Nielsen K, Murphy R, Ravn K, Melchior L, Dedic A et al (2011) Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation. J Med Genet 48:308–311

    Article  PubMed  Google Scholar 

  36. Binder G, Liebl M, Woelfle J, Eggermann T, Blumenstock G, Schweizer R (2013) Adult height and epigenotype in children with Silver-Russell syndrome treated with GH. Horm Res Paediatr 80:193–200

    Article  CAS  PubMed  Google Scholar 

  37. Kalish JM, Conlin LK, Bhatti TR, Dubbs HA, Harris MC, Izumi K, Mostoufi-Moab S, Mulchandani S, Saitta S, States LJ et al (2013) Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. Am J Med Genet A 161A:1929–1939

    Article  PubMed  Google Scholar 

  38. Behnecke A, Hinderhofer K, Jauch A, Janssen JW, Moog U (2012) Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13). Clin Genet 82:494–498

    Article  CAS  PubMed  Google Scholar 

  39. Bartholdi D, Krajewska-Walasek M, Ounap K, Gaspar H, Chrzanowska KH, Ilyana H, Kayserili H, Lurie IW, Schinzel A, Baumer A (2009) Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. J Med Genet 46:192–197

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the patients and their families as well as the contributing clinicians for participating in this study. The project is supported by the Bundesministerium für Bildung und Forschung (Network “Imprinting Diseases”, 01GM1114) as well as by Merck Serono. The authors are members of the European Network of Congenital Imprinting Disorders (EUCID.net; www.imprinting-disorders.eu), supported by COST (BM1208).

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The authors declare no conflict of interests related to this study.

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Authors and Affiliations

  1. Institute of Human Genetics, RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Germany

    Thomas Eggermann, Ann-Kathrin Heilsberg, Matthias Begemann & Lukas Soellner

  2. Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    Susanne Bens & Reiner Siebert

  3. Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany

    Jasmin Beygo & Karin Buiting

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  1. Thomas Eggermann
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Correspondence to Thomas Eggermann.

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Eggermann, T., Heilsberg, AK., Bens, S. et al. Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing. J Mol Med 92, 769–777 (2014). https://doi.org/10.1007/s00109-014-1141-6

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  • DOI: https://doi.org/10.1007/s00109-014-1141-6

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