Multilocus imprinting disturbances

Genomic imprinting is an epigenetic mechanism that determines and regulates expression of homologous alleles of genes of different parental origin. Disturbances in this mechanism lead to imprinting disorders (IDs). Imprinting is regulated not only within closely located gene clusters, but also through interactions in imprinted gene networks (IGNs). These interactions may explain some of the observed differences in the phenotypes of various ImpDis and MLID (multilocus imprinting disturbances, in which multiple methylation abnormalities of imprinted regions and genes are observed), where the correlation between the epigenotype and the phenotype is not always obvious. To date, at least 20 IDs have been described in humans, both with independent and with overlapping clinical signs, including minor developmental anomalies, congenital malformations, metabolic disorders, features of intellectual, motor, and physical development. More often, in an individual with a specific ID, one specific imprinted locus is affected, but there are increasing reports of patients with MLID. The causes of MLID are pathogenic variants in genes encoding oocyte and zygotic embryo development factors, 

such as NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6, TLE6, UHRF1, ZFP57, ARID4A, ZAR1, ZNF445, TRIM28. Pathogenic variants of these

genes exhibit a distinct mode of inheritance in that they become functionally significant only in female carriers. They do not affect the health of the carrier herself, but her reproductive prognosis. When providing genetic counseling, it should be taken into account that the phenotype caused by disturbances in the genes for oocyte and zygotic factors of embryo development appears only when the carriers are women. Thus, the variant can be passed on through the father’s side without causing reproductive problems.

MLID is an actively studied problem in clinical and molecular genetics. Due to the possible similarity of the clinical picture of classical ID and MLID, it is advisable for patients with suspected ID to undergo analysis for MLID to establish additional methylation patterns of imprinted DMRs, since in families of patients with MLID it is necessary to conduct medical genetic counseling with a further search for genetic variants in MLID-associated genes, to establish the risk of recurrent birth of children with ID. Also, the study of MLID-associated genes may be relevant for patients with recurrent miscarriage, recurrent hydatidiform mole, and for the study of abortive material, in the absence of chromosomal abnormalities identified in it, to determine the causes of termination and competent planning of a subsequent pregnancy.

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