A Study of Multilocus Methylation Abnormalities in Subjects With Imprinting Disorders

Differentially Methylated Regions, Imprinting Disorder, MLID, Molecular Diagnosis, Multi-locus Imprinting Disturbance

Imprinting disorder, MLID, Multi-locus imprinting disturbance, DMR, Differentially methylated regions, Molecular diagnosis

Imprinting disorders may be caused by epimutations. Some subjects exhibit methylation abnormalities in several regions subject to imprinting, a condition known as multilocus imprinting disorder (MLID). The prevalence of MLID is unknown, due to variations in the methodologies used (including technique employed and number of regions studied). The phenotypic consequences of MLID are also poorly understood. Studying the methylation of all the imprinted regions would make it possible to determine the prevalence of MLID as well as its clinical consequences.

Imprinting disorders may be secondary to various molecular mechanisms, including "epimutations", i.e. aberrant methylation levels (gain or loss of methylation) at the level of the ICRs. The 11p15 region in humans contains two genes essential for controlling foetal growth: IGF2, expressed from the paternal allele, and whose expression is controlled by an imprinting centre called H19/IGF2: IG-DMR (or ICR1), methylated on the paternal allele; and CDKN1C, expressed from the maternal allele, and whose expression is controlled by a second imprinting centre called KCNQ1OT1:TSS-DMR (or ICR2), methylated on the maternal allele. (Eggermann et al, 2023) Among the diseases linked to parental imprinting, Beckwith Wiedemann syndrome (BWS, prevalence 1/13,500) is an overgrowth syndrome that, in particular, predisposes to the appearance of embryonic tumours during the first years of life. 80% of subjects with BWS have an alteration in the 11p15 region, which may be a loss of ICR2 methylation (around 50%) or a gain of ICR1 methylation (5 to 10%). (Brioude et al, 2018) Silver Russell syndrome (SRS, prevalence 1/50,000) is a syndrome of fetal and postnatal growth restriction, with preservation of head circumference, severe feeding difficulties and early metabolic complications. Approximately 50% of subjects with SRS have a loss of ICR1 methylation in the 11p15 region. (Wakeling et al, 2017). Temple syndrome (TS14) is a fetal and postnatal growth restriction syndrome similar to SRS with neonatal hypotonia, and associated with a risk of early puberty and obesity. This syndrome is usually caused by abnormalities of the 14q32 region at the MEG3/DLK1 locus which is also imprinted (maternal uniparental disomy, paternal deletion or loss of methylation of the MEG3/DLK1:IG-DMR). (Geoffron et al, 2017) For several years now, it has been shown that some subjects with a methylation anomaly at one locus may have methylation anomalies at other regions subject to parental imprinting. This condition is known as multilocus imprinting disorder (MLID). The prevalence of this multilocus disorder is not precisely known, because the methodologies used vary in terms of the technique used and the number of DMRs studied. In some subjects, symptoms of different diseases linked to these different regions may be present. However, little is currently known about the phenotypic consequences of these multilocus disorders. Finally, although most methylation anomalies occur sporadically, a few familial forms of methylation anomalies have been reported, with the common feature of recurrent miscarriages and the presence of multilocus disease in affected subjects. These familial forms have been associated with the presence in the mother of pathogenic variations in the genes encoding factors in the SCMC (subcortical maternal complex). Among other things, these factors are involved in oocyte maturation and the regulation of epigenetic marks after fertilisation and during the first cell divisions. (MacKay et al, 2024)

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