Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings

Boonen, Susanne E.; Pörksen, Sven; Mackay, Deborah J G; Oestergaard, E; Olsen, Birthe Susanne; Brøndum‐Nielsen, Karen; Temple, I. Karen; Hahnemann, Johanne M D

doi:10.1038/sj.ejhg.5201993

Cited by 52 publications

(49 citation statements)

References 22 publications

(29 reference statements)

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“…This phenomenon, known as multiple maternal hypomethylation syndrome, has previously been described for BWS [7,16,17]. Only two studies reported on MLID as GOM at paternally methylated iDMRs in BWS patients [8,15]; however, also in these cases, MLID was supposed to arise as a consequence of a methylation defect of the maternal allele.…”

Section: Discussionmentioning

confidence: 96%

“…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]. MLID has less frequently been described in patients with SRS (~ 15%) [8].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

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 only non consanguineous patient was a compound heterozygote. The disorder was seen in one sib pair [29]. This is thus a rare example of an autosomal gene having a role in the epigenetic regulation for a disorder compatible with life and sibs have a 25% recurrence risk.…”

Section: Genetics and Epigenetics Of 6q24 Transient Neonatal Diabetesmentioning

confidence: 89%

6q24 transient neonatal diabetes

Temple

Shield

2010

Rev Endocr Metab Disord

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Transient Neonatal Diabetes (type 1) is the commonest cause of diabetes presenting in the first week of life. The majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes in later life. It is associated with low birth weight but rapid catch up by 1 year of life. The condition is usually due to genetic or epigenetic aberrations at an imprinted locus on chromosome 6q24 and can be sporadic or inherited. Early diagnosis alters medical treatment strategies and differentiates it from other types of early onset diabetes. In some individuals, diabetes may be the initial presentation of a more complex imprinting disorder due to recessive mutations in the gene ZFP57 and may be associated with other developmental problems.

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“…12 Since these two reports, other groups have described multilocus imprinting defects in BWS and in TNDM patients. [13][14][15][16] More recently, we revealed that about 10% of RSS patients exhibit multilocus LOM at both paternally and maternally methylated loci and that over two-thirds of these patients exhibit LOM at DLK1/GTL2 IG-DMR 14q34 in addition to that at ICR1 11p15. These regions are two of the three paternally methylated ICRs.…”

Section: Human Multilocus Imprinting Disordersmentioning

confidence: 95%

Lessons from imprinted multilocus loss of methylation in human syndromes: A step toward understanding the mechanisms underlying these complex diseases

Azzi¹,

Rossignol²,

Bouc³

et al. 2010

Epigenetics

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Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings

Cited by 52 publications

References 22 publications

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

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

6q24 transient neonatal diabetes

Lessons from imprinted multilocus loss of methylation in human syndromes: A step toward understanding the mechanisms underlying these complex diseases

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