Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing
- 547 Downloads
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.
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.
KeywordsImprinting disorders Genetic testing Multi-locus methylation defects Chromosomal imbalances Uniparental disomies
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).
The authors declare no conflict of interests related to this study.
- 1.Howard MS (2011) Russell-Silver syndrome. Gene reviews, Initial posting: November 2, 2002; Last update: June 2, 2011Google 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 34:595–602PubMedGoogle 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 34:1172–1180PubMedCrossRefGoogle 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 161:2174–2182PubMedCrossRefGoogle 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 18:4724–4733PubMedCrossRefGoogle 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 17:648–655Google 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 40:949–951PubMedCrossRefGoogle 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 50:635–639PubMedCrossRefGoogle 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)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 48:308–311PubMedCrossRefGoogle 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 46:192–197PubMedCrossRefGoogle Scholar