Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies

Hiura, Hitoshi; Okae, Hiroaki; Miyauchi, Naoko; Sato, Fumi; Satô, Akiko; Pette, Mathew Van de; Roshan, John; Kagami, Masayo; Nakai, Kunihiko; Soejima, Hidenobu; Ogata, Tsutomu; Arima, Takahiro

doi:10.1093/humrep/des197

Cited by 116 publications

(123 citation statements)

References 46 publications

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“…It is well know that BWS is more common among patients conceived by artificial reproduction technique; [36][37][38] we encountered a 4.4% prevalence of this phenomenon, confirming data from previous reports and showing a higher prevalence than that reported in the Italian population (1.7%). 39 As concerns tumor risk, the overall prevalence of cancer approximates 8%, consistent with other studies.…”

Section: Phenotypes In Beckwith-wiedemann Syndromesupporting

confidence: 91%

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

et al. 2015

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Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n = 190), IC1 gain of methylation (IC1-GoM, n = 31), chromosome 11p15 paternal uniparental disomy (UPD, n = 87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n = 10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (Po0.001). Exomphalos was more common in IC2/CDKN1C patients (Po0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (Po0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (Po0.001). Macroglossia was less common among UPD patients (Po0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (Po0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P = 0.009).In conclusion, (epi)genotype-phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.

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Section: Phenotypes In Beckwith-wiedemann Syndromesupporting

confidence: 91%

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

et al. 2015

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“…MLID has been identified in BWS patients at frequencies of up to 30% in patients with LOM at ICR2 [6–14], while it is very rare among cases with GOM at ICR1 [15]. Some BWS patients with MLID show LOM or GOM at both maternal and paternal DMRs [8,15], while others have a hypomethylation syndrome restricted to maternally imprinted genes [16–18].…”

Section: Introductionmentioning

confidence: 99%

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

et al. 2018

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The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

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“…Furthermore, several authors have described an increased prevalence of imprinting disorders in ART offspring, although this link has never been successfully proven (DeBaun et al 2003, Gicquel et al 2003, Chang et al 2005, Sutcliffe et al 2006, Kobayashi et al 2009, Zheng et al 2011, Hiura et al 2012, 2014, Cocchi et al 2013. A meta-analysis has nevertheless found an increased OR for the prevalence of imprinted disorders in children born after ART compared with those born after spontaneous conception (Lazaraviciute et al 2014).…”

Section: Sperm Dna Methylation Infertility and Art Outcomementioning

confidence: 99%

On the origin of sperm epigenetic heterogeneity

2016

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The influence of epigenetic modifications on reproduction and on the function of male germ cells has been thoroughly demonstrated. In particular, aberrant DNA methylation levels in sperm have been associated with abnormal sperm parameters, lower fertilization rates and impaired embryo development. Recent reports have indicated that human sperm might be epigenetically heterogeneous and that abnormal DNA methylation levels found in the sperm of infertile men could be due to the presence of sperm populations with different epigenetic quality. However, the origin and the contribution of different germ cell types to this suspected heterogeneity remain unclear. In this review, we focus on sperm epigenetics at the DNA methylation level and its importance in reproduction. We take into account the latest developments and hypotheses concerning the functional significance of epigenetic heterogeneity coming from the field of stem cell and cancer biology and discuss the potential importance and consequences of sperm epigenetic heterogeneity for reproduction, male (in)fertility and assisted reproductive technologies (ART). Based on the current information, we propose a model in which spermatogonial stem cell variability, either intrinsic or due to external factors (such as endocrine action and environmental stimuli), can lead to epigenetic sperm heterogeneity, sperm epimutations and male infertility. The elucidation of the precise causes for epimutations, the conception of adequate therapeutic options and the development of sperm selection technologies based on epigenetic quality should be regarded as crucial to the improvement of ART outcome in the near future.Reproduction (2016) 151 R71-R78

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Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies

Cited by 116 publications

References 46 publications

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

On the origin of sperm epigenetic heterogeneity

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