Beckwith–Wiedemann syndrome in sibs discordant for IC2 methylation

Genetically heterogeneous imprinting disorders include Beckwith–Wiedemann syndrome (BWS) and multiple maternal hypomethylation syndrome (MMHS). Using DNA sequencing, quantitative PCR, SNuPE, pyrosequencing, and hybridization to the Illumina GoldenGate Methylation Cancer Panel 1 array, we characterized the genomic DNA of two brothers with BWS who were discordant for loss of methylation at several differentially methylated regions (DMR), including imprinting center 2 (IC2) on chromosome band 11p15.5, which is often hypomethylated in BWS. In keeping with MMHS, the elder child had hypomethylation of SGCE and PLAGL1 as well as of IC2, whereas the younger brother demonstrated no loss of methylation at these DMRs. Although this discordance is consistent with the observation that 15–20% of individuals with BWS do not have detectable genetic or epigenetic alterations of 11p15.5, this is the first report of familial recurrence of BWS with discordance for chromosomal 11p15.5 alterations. We hypothesize that this apparent discordance arises either from mosaicism precluding identification of IC2 hypomethylation in blood or buccal mucosa DNA of the younger child, or from hypomethylation at a site not interrogated by our molecular studies. © 2012 Wiley Periodicals, Inc.

[1]  Colin A. Johnson,et al.  Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. , 2011, American journal of human genetics.

[2]  M. Peñaherrera,et al.  The utility of quantitative methylation assays at imprinted genes for the diagnosis of fetal and placental disorders , 2011, Clinical genetics.

[3]  S. Mansour,et al.  An atypical case of hypomethylation at multiple imprinted loci , 2011, European Journal of Human Genetics.

[4]  C. Boerkoel,et al.  Methylation profiling in individuals with Russell–Silver syndrome , 2010, American journal of medical genetics. Part A.

[5]  R. Weksberg,et al.  Beckwith–Wiedemann syndrome , 2010, European Journal of Human Genetics.

[6]  S. Scherer,et al.  Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell–Silver syndrome , 2009, American journal of medical genetics. Part A.

[7]  R. Yuen,et al.  Human Placental-Specific Epipolymorphism and its Association with Adverse Pregnancy Outcomes , 2009, PloS one.

[8]  N. Vora,et al.  Genetic considerations in the prenatal diagnosis of overgrowth syndromes , 2009, Prenatal diagnosis.

[9]  I. Temple,et al.  Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome , 2009, European Journal of Human Genetics.

[10]  D. Bonthron,et al.  Genetic and Epigenetic Analysis of Recurrent Hydatidiform Mole , 2009, Human mutation.

[11]  W. Reik,et al.  Germline Mutation in NLRP2 (NALP2) in a Familial Imprinting Disorder (Beckwith-Wiedemann Syndrome) , 2009, PLoS genetics.

[12]  W. Reik,et al.  Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies. , 2008, Human reproduction.

[13]  A. Hattersley,et al.  Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57 , 2008, Nature Genetics.

[14]  B. Olsen,et al.  Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings , 2008, European Journal of Human Genetics.

[15]  R. Weksberg,et al.  Severe presentation of Beckwith–Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15 , 2007, American journal of medical genetics. Part A.

[16]  D. Amor,et al.  Tumour surveillance in Beckwith–Wiedemann syndrome and hemihyperplasia: A critical review of the evidence and suggested guidelines for local practice , 2006, Journal of paediatrics and child health.

[17]  C. Gicquel,et al.  The epigenetic imprinting defect of patients with Beckwith—Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region , 2006, Journal of Medical Genetics.

[18]  M. Maizels,et al.  Prenatal diagnosis of Beckwith–Wiedemann syndrome , 2005, Prenatal diagnosis.

[19]  W. Reik,et al.  Molecular subtypes and phenotypic expression of Beckwith–Wiedemann syndrome , 2005, European Journal of Human Genetics.

[20]  Rosanna Weksberg,et al.  Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. , 2003, Human molecular genetics.

[21]  T. Meitinger,et al.  The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted , 2003, European Journal of Human Genetics.

[22]  I. Lerer,et al.  Wiedemann-Beckwith syndrome: further prenatal characterization of the condition. , 2002, American journal of medical genetics.

[23]  R. Weksberg,et al.  Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. , 2001, Genomics.

[24]  A. Reeve,et al.  Proportion of cells with paternal 11p15 uniparental disomy correlates with organ enlargement in Wiedemann-beckwith syndrome. , 2000, American journal of medical genetics.

[25]  R. Weksberg,et al.  Molecular genetics of Wiedemann-Beckwith syndrome. , 1998, American journal of medical genetics.

[26]  A. Pazarbasi,et al.  [Prenatal diagnosis]. , 1994, Revista chilena de obstetricia y ginecologia.

[27]  Nan Faion T. Wu,et al.  The Beckwith-Wiedemann Syndrome , 1974, Clinical pediatrics.