Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences

Abstract

Background Imprinting disorders are a group of congenital diseases which are characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting disorders have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects and asymmetry. In general, a single specific DMR is affected in an individual with a given imprinting disorder, but there are a growing number of reports on individuals with so-called multilocus imprinting disturbances (MLID), where aberrant imprinting marks (most commonly loss of methylation) occur at multiple DMRs. However, as the literature is fragmented, we reviewed the molecular and clinical data of 55 previously reported or newly identified MLID families with putative pathogenic variants in maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) and in other candidate genes (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445). Results In 55 families, a total of 68 different candidate pathogenic variants were identified (7 in NLRP2, 16 in NLRP5, 7 in NLRP7, 17 in PADI6, 15 in ZFP57, and a single variant in each of the genes ARID4A, ZAR1, OOEP, UHRF1, KHDC3L and ZNF445). Clinical diagnoses of affected offspring included Beckwith–Wiedemann syndrome spectrum, Silver–Russell syndrome spectrum, transient neonatal diabetes mellitus, or they were suspected for an imprinting disorder (undiagnosed). Some families had recurrent pregnancy loss. Conclusions Genomic maternal effect and foetal variants causing MLID allow insights into the mechanisms behind the imprinting cycle of life, and the spatial and temporal function of the different factors involved in oocyte maturation and early development. Further basic research together with identification of new MLID families will enable a better understanding of the link between the different reproductive issues such as recurrent miscarriages and preeclampsia in maternal effect variant carriers/families and aneuploidy and the MLID observed in the offsprings. The current knowledge can already be employed in reproductive and genetic counselling in specific situations.

Different Mechanisms Cause Hypomethylation of Both H19 and KCNQ1OT1 Imprinted Differentially Methylated Regions in Two Cases of Silver–Russell Syndrome Spectrum

“…For example, the LOM of the GNAS locus has been found associated to 11p15.5 IC2 LOM in MLID patients with BWS and pseudohypoparathyroidism 1B [ 21 ] or hypocalcemia [ 22 ]. In SRS-MLID, the most affected DMRs other than IC1 are MEST :alt-TSS-DMR and GRB10 :alt-TSS-DMR [ 12 ] ( Table 1 ), although we did not find abnormal methylation at these loci in our patient. Some cases of BWS and SRS with MLID have been associated with maternal variants of the SCMC genes [ 9 , 12 , 22 , 23 , 24 , 25 , 26 , 27 ], but the whole-exome sequencing did not identify any such variant in our case.…”

“…As in proband 2, the epigenetic defect is always partial, supporting the hypothesis of errors in imprinting maintenance arising post-zygotically. The resulting epigenetic and gene expression mosaicism probably explain the divergent clinical features as well as the frequent body asymmetry of the affected individuals [ 11 , 12 ]. Most of the IC1 LOM+IC2 LOM patients show the hypomethylation of additional DMRs and have been classified as MLID cases ( Table 1 ).…”

“…In some of these cases, IC1 LOM is detected together with IC2 LOM, which is a hallmark of the overgrowth-associated Beckwith–Wiedemann syndrome spectrum (BWSp) and shows the phenotypic features of either the SRSp or BWSp [ 11 ]. In some families, MLID has been associated with loss-of-function or hypomorphic variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC) [ 12 ].…”

Increased copy number of imprinted genes in the chromosomal region 20q11-q13.32 is associated with resistance to antitumor agents in cancer cell lines

“…NLRP2 (NLR family pyrin domain containing 2) is a maternal effect gene which plays a role in early embryonic implantation and development and has an allelic expression bias in placenta [128,129]. Genetic variants in this gene have been associated with multi-locus imprinting disturbance (MLID) [130,131]. NLRP2 is located near the imprinted MIR371-MIR373 locus at 19q13.42 [132].…”

Identification of differentially methylated regions in rare diseases from a single-patient perspective

“…On the other hand, secondary epivariations are a known alternative mechanism in rare diseases and the detection of these sequence variants has gained popularity in the diagnostic process. That is the case in the group of neurodevelopmental disorders known as the Mendelian disorders of the epigenetic machinery (MDEMs), for which detection of episignatures (i.e., group of DMCs acting as a blueprint for the disease) has been shown to enable patient diagnosis [ 20 – 28 ], or in imprinting disorders [ 29 – 34 ], where DMRs are localized at imprinting control centers. Episignatures and DMRs at imprinting loci are usually linked to a single disease.…”