Deciphering Epigenetic Backgrounds in a Korean Cohort with Beckwith–Wiedemann Syndrome
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background: Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype–phenotype correlations in Korean children with BWS. Methods: Forty children with BWS with proven genetic or epigenetic defects in the 11p15.5 region were included. The phenotype was scored using the BWS consensus scoring system. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), bisulfite pyrosequencing, a single-nucleotide polymorphism microarray, and CDKN1C sequencing were used for confirmative diagnosis. Results: Patients met the criteria for genetic testing, with a mean clinical score of 5.4±2.0. Methylation alterations were consistent between MS-MLPA and bisulfite pyrosequencing in all patients. Twenty-six patients (65.0%) had IC2 loss of methylation (IC2-LoM), 11 (27.5%) had paternal uniparental disomy (patUPD), and one (2.5%) had IC1 gain of methylation. Macroglossia and external ear anomalies were more common in IC2-LoM than in patUPD, and lateralized overgrowth was more common in patUPD than in IC2-LoM (all P<0.05). Methylation levels at IC2 were inversely correlated with birth weight standard deviation score (r=–0.476, P=0.014) and clinical score (r=–0.520, P=0.006) in the IC2-LoM group. Conclusions: Comprehensive molecular analysis of the 11p15.5 region revealed epigenotype–phenotype correlations in our BWS cohort. Bisulfite pyrosequencing can help clarify epigenotypes. Methylation levels were correlated with fetal growth and clinical severity in patients with BWS.
Abstract
Background: Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype–phenotype correlations in Korean children with BWS. Methods: Forty children with BWS with proven genetic or epigenetic defects in the 11p15.5 region were included. The phenotype was scored using the BWS consensus scoring system. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), bisulfite pyrosequencing, a single-nucleotide polymorphism microarray, and CDKN1C sequencing were used for confirmative diagnosis. Results: Patients met the criteria for genetic testing, with a mean clinical score of 5.4±2.0. Methylation alterations were consistent between MS-MLPA and bisulfite pyrosequencing in all patients. Twenty-six patients (65.0%) had IC2 loss of methylation (IC2-LoM), 11 (27.5%) had paternal uniparental disomy (patUPD), and one (2.5%) had IC1 gain of methylation. Macroglossia and external ear anomalies were more common in IC2-LoM than in patUPD, and lateralized overgrowth was more common in patUPD than in IC2-LoM (all P<0.05). Methylation levels at IC2 were inversely correlated with birth weight standard deviation score (r=–0.476, P=0.014) and clinical score (r=–0.520, P=0.006) in the IC2-LoM group. Conclusions: Comprehensive molecular analysis of the 11p15.5 region revealed epigenotype–phenotype correlations in our BWS cohort. Bisulfite pyrosequencing can help clarify epigenotypes. Methylation levels were correlated with fetal growth and clinical severity in patients with BWS.
참고문헌 (36)
- Wang KH, "Diagnosis and management of Beckwith–Wiedemann syndrome", Front Pediatr, 7, pp.562~ (2020)
- Brioude F, "Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement", Nat Rev Endocrinol, 14, pp.229~249 (2018)
- Mussa A, "(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome : a paradigm for genomic medicine", Clin Genet, 89, pp.403~415 (2016)
- Hoeijmakers L, "Epigenetic imprinting during assisted reproductive technologies : the effect of temporal and cumulative fluctuations in methionine cycling on the DNA methylation state", Mol Reprod Dev, 83, pp.94~107 (2016)
- Chang AS, "Association between Beckwith–Wiedemann syndrome and assisted reproductive technology : a case series of 19 patients", Fertil Steril, 83, pp.349~354 (2005)
- Mussa A, "Assisted reproductive techniques and risk of Beckwith–Wiedemann syndrome", Pediatrics, 140, pp.e20164311~ (2017)
- Delaval K, "Epigenetic deregulation of imprinting in congenital diseases of aberrant growth", Bioessays, 28, pp.453~459 (2006)
- Maas SM, "Phenotype, cancer risk, and surveillance in Beckwith–Wiedemann syndrome depending on molecular genetic subgroups", Am J Med Genet A, 170, pp.2248~2260 (2016)
- Mussa A, "Cancer risk in Beckwith–Wiedemann syndrome : a systematic review and meta-analysis outlining a novel(epi)genotype specific histotype targeted screening protocol", J Pediatr, 176, pp.142~149 (2016)
- Brioude F, "Beckwith–Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance", Horm Res Paediatr, 80, pp.457~465 (2013)
- Duffy KA, "Beckwith–Wiedemann syndrome in diverse populations", Am J Med Genet A, 179, pp.525~533 (2019)
- Sasaki K, "Japanese and North American", European patients with Beckwith–Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations, 2007, pp.15, 1205~1210
- Ibrahim A, "Methylation analysis and diagnostics of Beckwith–Wiedemann syndrome in 1,000 subjects", Clin Epigenetics, 6, pp.11~ (2014)
- Lin HY, "Epigenotype, genotype, and phenotype analysis of patients in Taiwan with Beckwith–Wiedemann syndrome", Mol Genet Metab, 119, pp.8~13 (2016)
- Fenton TR, "A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants", BMC Pediatr, 13, pp.59~ (2013)
- 김재현, "The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects", Clinical and Experimental Pediatrics, 61(5), pp.135~149 (2018), 대한소아청소년과학회
- Kalish JM, "Nomenclature and definition in asymmetric regional body overgrowth", Am J Med Genet A, 173, pp.1735~1738 (2017)
- Riggs ER, "Technical standards for the interpretation and reporting of constitutional copy-number variants : a joint consensus recommendation of the American College of Medical Genetics and Genomics(ACMG)and the Clinical Genome Resource(ClinGen)", Genet Med, 22, pp.245~257 (2020)
- Richards S, "Standards and guidelines for the interpretation of sequence variants : a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)
- Romanelli V, "Beckwith–Wiedemann syndrome and uniparental disomy 11p : fine mapping of the recombination breakpoints and evaluation of several techniques", Eur J Hum Genet, 19, pp.416~421 (2011)
- Lee BH, "Quantitative analysis of methylation status at 11p15 and 7q21 for the genetic diagnosis of Beckwith–Wiedemann syndrome and Silver–Russell syndrome", J Hum Genet, 58, pp.604~610 (2013)
- Calvello M, "Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith–Wiedemann syndrome", Epigenetics, 8, pp.1053~1060 (2013)
- Shin CH, "Prospective study of epigenetic alterations responsible for isolated hemihyperplasia", hemihypoplasia and their association with leg length discrepancy, 2021, pp.16, 418~
- Mussa A, "(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome", Eur J Hum Genet, 24, pp.183~190 (2016)
- Weksberg R, "Beckwith–Wiedemann syndrome", Eur J Hum Genet, 18, pp.8~14 (2010)
- Engel JR, "Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome", J Med Genet, 37, pp.921~926 (2000)
- Cooper WN, "Molecular subtypes and phenotypic expression of Beckwith–Wiedemann syndrome", Eur J Hum Genet, 13, pp.1025~1032 (2005)
- Committee for Assisted Reproductive Technology Statistics, "The status of assisted reproductive technology in Korea in 2012", Clin Exp Reprod Med, 44, pp.47~51 (2017)
- Gicquel C, "In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene", Am J Hum Genet, 72, pp.1338~1341 (2003)
- DeBaun MR, "Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19", Am J Hum Genet, 72, pp.156~160 (2003)
- Lim D, "Clinical and molecular genetic features of Beckwith–Wiedemann syndrome associated with assisted reproductive technologies", Hum Reprod, 24, pp.741~747 (2009)
- Gomes MV, "Abnormal methylation at the KvDMR1 imprinting control region in clinically normal children conceived by assisted reproductive technologies", Mol Hum Reprod, 15, pp.471~477 (2009)
- Fraga MF, "Epigenetics and aging : the targets and the marks", Trends Genet, 23, pp.413~418 (2007)
- Matsubara K, "Maternal age effect on the development of Prader-Willi syndrome resulting from upd(15)mat through meiosis 1 errors", J Hum Genet, 56, pp.566~571 (2011)
- Romanelli V, "Constitutional mosaic genome-wide uniparental disomy due to diploidisation : an unusual cancer-predisposing mechanism", J Med Genet, 48, pp.212~216 (2011)
- Azzi S, "Multilocus methylation 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, pp.4724~4733 (2009)