Maternal Effect Gene-Related Multilocus Imprinting Disturbances
Zeynep Tümer, MD, PhD, DMSc, Thomas Eggermann, PhD, Saskia Maas, MD, Jet Bliek, PhD, and Deborah Mackay, PhD.
Author Information and AffiliationsInitial Posting: May 15, 2025.
Estimated reading time: 17 minutes
1. Genomic Imprinting
For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care [Caughey et al 2021].
Imprinting is parent-of-origin-specific expression of a gene or genes.
In humans there are approximately 100
imprinted genomic regions; some of the imprinted loci comprise single genes, while others contain clusters of genes [
Monk et al 2019].
In these regions,
gene expression is regulated by
imprinting centers that are differently epigenetically marked (including differential DNA
methylation) in the egg and sperm. Notably, maternally and paternally inherited
imprinted regions have divergent DNA methylation at differentially methylated regions (DMRs).
After fertilization,
imprinted regions maintain these marks through essentially all subsequent cell divisions in the body.
Imprinting disorders. Thirteen loci are known to be associated with imprinting disorders due to various types of genetic or epigenetic changes that disturb parentally restricted expression of imprinted genes [Eggermann et al 2023].
These changes include DNA
methylation disturbance (loss of methylation [LOM] or gain of methylation [GOM]) of
imprinted DMRs, segmental or whole-
chromosome uniparental disomy (UPD), or pathogenic single-nucleotide variants or copy number variants of genes under imprinted control.
Epigenetically, MLID is heterogeneous, meaning it can affect any number and combination of
imprinted loci, including those currently known to be associated with recognized
imprinting disorders and those not known to have any clinical associations at this time. Different imprinting disorders have different observed frequencies of MLID [
Mackay et al 2024,
Urakawa et al 2024].
Maternal effect genes. A proportion MLID are caused by biallelic pathogenic variants in maternal effect genes (MEGs) in the apparently unaffected mother of the affected offspring; such maternal effect genes are highly expressed in the oocyte and are required for the establishment or maintenance of imprinting in the oocyte, zygote, and embryo.
2. Review of Imprinting Disorders in Which Multilocus Imprinting Disturbances Have Been Observed
Multilocus imprinting disturbances (MLID) are most frequently identified in individuals whose initial features are consistent with transient neonatal diabetes mellitus (TNDM), and to a lesser extent in individuals who initially are noted to have features of Beckwith-Wiedemann spectrum (BWSp), pseudohypoparathyroidism (PHP), and/or Silver-Russell syndrome (SRS). MLID appears to be rare in individuals whose initial features are suggestive of other imprinting disorders.
The clinical features of individuals with MLID are not fully predictable from their
imprinting disturbance, as MLID can alter the clinical presentation and progression of a classic imprinting disorder [
Mackay et al 2024].
Some affected individuals have initial symptoms of a classic
imprinting disorder such as TNDM or BWSp, but upon further evaluation, features of other imprinting disorders are subsequently noted.
Some affected individuals have phenotypic features typical of a specific
imprinting disorder (such as BWSp) that are not apparently altered by the presence of MLID. However, some affected individuals have clinical features of more than one imprinting disorder, features that are a blend of one or more imprinting disorder, or features that do not align with any classic imprinting disorder.
As noted in Section 1, imprinting disorders can be due to different molecular alterations, but MLID is identified almost exclusively in imprinting disorders caused by loss of methylation (LOM). To date, it has not been reported in imprinting disorders caused by pathogenic protein-coding single-nucleotide variants (such as pathogenic CDKN1C variants for BWSp), pathogenic protein-coding copy number variants (such as duplication of 11p15.5 in BWSp), or pathogenic regulatory copy number variants, and has very rarely been seen in individuals who also have uniparental disomy (UPD). MLID has not to date been reported in imprinting disorders caused by gain of methylation (GOM), such as Kagami-Ogata syndrome or BWSp due to H19/IGF2:IG (intergenic) differentially methylated region (DMR) [Bilo et al 2023].
Table 1 summarizes imprinting disorders in which MLID has been detected; the chromosomal locus of each imprinting disorder; the DMR that is affected when maternal effect gene (MEG)-related MLID is the cause of the imprinting disturbance; the clinical features of the imprinting disorder (noting that these clinical features may be altered by MLID and may not be classic for that specific imprinting disorder); the frequency of MLID reported for a given imprinting defect; and the MEGs in which pathogenic or likely pathogenic variants were identified. It should be noted that multiple molecular mechanisms cause imprinting disorders (epimutations, deletions, uniparental disomy, and pathogenic gene variants), but only specific epimutations in each entity are associated with MLID and should prompt further evaluation for possible MLID.
Table 1.
Imprinting Disorders in Which MEG-MLID Has Been Observed
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| Imprinting Disorder | Chromosomal Locus | DMR Epimutation 1 | Classic Clinical Features of the Imprinting Disorder | Frequency of MLID Occurrence 2 | Causative Gene(s) for MLID 3 |
|---|
| Beckwith-Wiedemann spectrum (BWSp) | 11p15.5 | KCNQ1OT1:TSS DMR LOM 4 |
| 25% 6 |
NLRP2
NLRP5
NLRP7
PADI6
|
| Disorders of GNAS inactivation, in particular pseudohypoparathyroidism type 1B | 20q13 | Aberrant imprinting at all GNAS DMRs | Resistance to PTH &, in some cases, TSH Mild features of Albright hereditary osteodystrophy, such as brachydactyly 7
| 12.5% 6 | NR |
| Silver-Russell syndrome (SRS) | 11p15.5 | H19/IGR2:IG DMR LOM 8 |
| 7%-10% 6 |
NLRP2
NLRP5
NLRP7
PADI6
|
| Temple syndrome 11 | 14q32 | MEG3/DLK1:IG DMR LOM 12 |
| Single cases | NR |
| Transient neonatal diabetes mellitus (TNDM) | 6q24 | PLAGL1:TSS DMR LOM |
| 60% 13 | NLRP2 14, 15 |
DMR = differentially methylated region, also known as an imprinting center (IC); GOM = gain of methylation; ID = intellectual disability; IG = intergenic; IUGR = intrauterine growth restriction; LOM = loss of methylation; MEG = maternal effect gene; MLID = multilocus imprinting disturbances; NR = none reported; PTH = parathyroid hormone; SGA = small for gestational age; TSH = thyroid-stimulating hormone; TSS = transcriptional start site differentially methylated region
- 1.
- 2.
Frequency of individuals with the specific imprinting disorder who have the imprinting disorder as a result of MLID regardless of the underlying molecular defect.
- 3.
These genes have biallelic causative variants in the mother of the affected offspring; affected offspring may be heterozygous carriers of a pathogenic variant in one of these genes, but the offspring's symptoms are due to aberrant imprinting and not to the pathogenic variant itself.
- 4.
- 5.
- 6.
- 7.
- 8.
- 9.
SGA can involve birth weight and/or length.
- 10.
- 11.
Clinical features may overlap with those of BWSp and SRS.
- 12.
This is the only molecular defect in individuals with Temple syndrome for which MLID has been detected. For other disease mechanisms that lead to Temple syndrome, see Eggermann et al [2023].
- 13.
- 14.
One case has been identified in which the mother had biallelic pathogenic variants in NLRP2.
- 15.
A subset of individuals with TNDM and MLID have biallelic pathogenic variants in ZFP57, but this is not an MEG, and the biallelic pathogenic variants are found in the affected individual, not in the affected individual's mother.
3. Genes of Interest in Maternal Effect Gene-Related Multilocus Imprinting Disturbances
Table 2 summarizes the reported instances of a mother having biallelic pathogenic variants in the listed genes, the reproductive findings, and imprinting disorder(s) noted in affected family members [Eggermann et al 2022].
Note: In some instances, a mother is found to be compound heterozygous for a pathogenic variant in a gene listed below and a second pathogenic variant not identified. These instances are not included in Table 2, as further research is necessary to determine whether these heterozygous variants contribute to the clinical findings and if other genetic or environmental factors remain to be found.
Table 2.
MEG-MLID: Genes and Associated Phenotypes in Offspring
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| Gene 1 | # of Families w/Maternal Biallelic Pathogenic Variants in Gene 1 | Imprinting Disorders Noted in Offspring & Reproductive Findings | OMIM |
|---|
|
KHDC3L
| 1 | Recurrent hydatidiform mole |
611687
|
|
NLRP2
| 3 |
|
609364
|
|
NLRP5
| 7 | Most offspring had BWSp. In 1 family, 1 child had BWSp & 1 had SRS. Features not specific for any classic imprinting disorder 2Maternal infertility due to oocyte/zygote/embryo maturation arrest Miscarriage
|
620333
|
|
NLRP7
| 2 |
|
231090
|
|
PADI6
| 7 |
|
617234
|
SRS = Silver-Russell syndrome; BWSp = Beckwith-Wiedemann spectrum
- 1.
Genes are listed in alphabetic order.
- 2.
Clinical features may be present in the offspring, but the features in the offspring may not be specific for any classic imprinting disorder.
4.
Evaluation Strategies to Identify the Genetic Cause of Maternal Effect Gene-Related Multilocus Imprinting Disturbances in a Family
In genetic terms, the "molecular proband" is the mother who has the pathogenic variants but is asymptomatic with regards to clinical features of an imprinting disorder (though may have reproductive issues), while the clinical impact of these variants with regards to imprinting disorders is on the offspring, who is the "clinical proband" (see ).
Inheritance in multilocus imprinting disturbances (MLID) due to pathogenic variants in a maternally expressed gene (MEG). The "molecular proband" is the asymptomatic female (II;2) who has biallelic pathogenic variants in an MEG. The "clinical proband" (more...)
Establishing a specific genetic cause of MLID:
Usually involves a medical history, physical examination and (where relevant) laboratory testing of the clinical
proband(s), detailed family history, and
genomic/genetic testing of the clinical proband(s) and family members, as warranted.
Medical History
Mothers with biallelic pathogenic variants in a maternal effect gene (MEG) may have offspring with one imprinting disorder, multilocus imprinting disturbances (MLID) (i.e., clinical features of more than one imprinting disorder, features that are a blend of two or more imprinting disorders, or features that do not align with any classic imprinting disorder), or offspring who are clinically healthy; such mothers may also experience reproductive difficulties including pregnancy losses, molar pregnancy, or apparent infertility.
The detection of MLID in more than one child is strongly suggestive of biallelic pathogenic variants in an MEG in the mother. In families with reproductive issues (fertility problems, recurrent miscarriages, or requirement of the use of assisted reproductive technology [ART] to achieve a pregnancy), the birth of a child with features of one or more of the imprinting disorders listed in Table 1 should prompt the clinician to consider a diagnosis of MLID (see Mackay et al [2024] for a general discussion on the association between ART and imprinting disorders).
Physical Examination
Physical examination should not focus solely on the identification of the classic features of each imprinting disorder listed in Table 1 but also take into account atypical clinical features [Mackay et al 2024]. While the offspring of a mother with biallelic pathogenic variants in an MEG may have classic features of one imprinting disorder, the presence of clinical features characteristic of different imprinting disorders in the same person should raise suspicion for MLID.
Family History
A three-generation family history (pedigree) should be taken with specific inquiry about female relatives with infertility, multiple miscarriages, molar pregnancies, offspring with features of one or more imprinting disorders, and multiple different offspring with an imprinting disorder (see ). Documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing, is recommended.
Genomic/Genetic Testing
Molecular genetic testing in a proband with a recognizable imprinting disorder. In a proband with a recognizable imprinting disorder, molecular genetic testing depends on which imprinting disorder is suspected clinically. Genetic testing strategies for Beckwith-Wiedemann syndrome, disorders of GNAS inactivation, Silver-Russell syndrome, and transient neonatal diabetes mellitus (see Diabetes Mellitus, 6q24-Related Transient Neonatal) are already summarized in the GeneReviews chapter for each respective condition. Such disease-focused testing should be the first step in testing and should discriminate between the different molecular subtypes. Only certain molecular subtypes of each imprinting disorder are currently known to be associated with MEG-MLID (see Table 1) [Mackay et al 2024].
Note: Features in the medical and family history may be suggestive of MEG-MLID even when there is a low clinical suspicion that the offspring has a classic imprinting disorder phenotype; in this scenario, testing the mother for biallelic pathogenic variants in MEGs may be considered [Mackay et al 2024].
Molecular genetic testing
in a clinical proband suspected of having MEG-MLID. The method to identify MEG-MLID must be able to show alterations of DNA methylation, which is not possible when only assessing for DNA sequence variants.
Because the
imprinted loci involved in MEG-MLID are unpredictable and epigenotype-
phenotype correlations are variable, all imprinted loci that are known to be associated with an
imprinting disorder should be evaluated through testing.
Several
methylation-specific (MS) assays are available for clinical MEG-MLID testing (e.g., MLPA, pyrosequencing, long-read sequencing), but diagnostic laboratories should confirm their suitability and that the clinically associated
imprinted loci are addressed.
Genome-wide MS assays (e.g., those based on DNA
methylation arrays or massively parallel sequencing) may be used to detect MEG-MLID; however, diagnostic laboratories should ensure that they include all clinically associated
imprinted loci and must assess their
sensitivity to detect mosaic
imprinting disturbances.
Molecular genetic testing for the mother (molecular proband) of a clinical proband with suspected MEG-MLID. The molecular diagnosis of MEG-MLID is established in the mother (molecular proband) of a clinical proband or a female with suggestive family history findings (miscarriages, molar pregnancies) by the identification of biallelic pathogenic (or likely pathogenic) variants in one of the genes in Table 2.
Note: (1) For genetic testing, the molecular proband is the mother (see , II;2) of the clinically affected offspring or clinical proband (, III;3 and III;4). (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (3) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in one of the genes listed in Table 2 does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing), depending on the phenotype of the clinical proband and the family history findings. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.
A multigene panel that includes some or all of the genes listed in
Table 2 is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of
uncertain significance in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Comprehensive
genomic testing (which does not require the clinician to determine which
gene[s] are likely involved) may be considered.
Exome sequencing is most commonly used;
genome sequencing is also possible.
For an introduction to comprehensive
genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
5. Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members of a Molecular Proband
In genetic terms, the molecular proband in a family with maternal effect gene-related multilocus imprinting disturbances (MEG-MLID) is the mother (see , II;2), who has biallelic pathogenic variants in an MEG (see Table 2). The clinical impact (with regards to imprinting disorders) of the pathogenic variants of the mother is on the offspring, who is the "clinical proband" (see , III;3 and III;4) and manifests features of one or more imprinting disorder(s).
A female who is a molecular proband will not have features of an imprinting disorder but may have a reproductive history consistent with MEG-MLID (e.g., pregnancy loses, molar pregnancy, or apparent infertility) and/or (multiple) offspring with features of imprinting disorders [Mackay et al 2024]. The exact risks for these pregnancy and offspring outcomes are currently unknown due to small data sets but appear to be higher than that of the general population.
Parents of a molecular proband. The parents of a molecular proband (the mother) are presumed to be heterozygous for a pathogenic variant in an MEG.
Sibs of a molecular proband. If both parents of a molecular proband are heterozygous for a pathogenic variant in a maternal effect gene:
Sibs are presumed to have a 25% chance of having
biallelic pathogenic variants, a 50% chance of having one
pathogenic variant, and a 25% chance of having neither of the
familial pathogenic variants.
Female sibs who inherit
biallelic pathogenic variants are at risk of MEG-MLID-related reproductive complications (i.e., pregnancy losses, molar pregnancy, apparent infertility, and affected offspring).
Female sibs who inherit one
pathogenic variant are heterozygotes. The risk of MEG-MLID-related reproductive complications is presumed to be low; however, further study is needed to determine if maternal heterozygosity for a pathogenic variant in an MEG may contribute to reproductive complications.
Male sibs who inherit
biallelic or
heterozygous pathogenic variants in an MEG are not at risk for MEG-MLID-related reproductive problems.
Note: The sibs of a molecular proband are not themselves at increased risk of having features of an imprinting disorder but do have the reproductive risks listed above.
Offspring of a molecular proband. A female with biallelic pathogenic variants in an MEG may have:
Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most health care professionals would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
There are limited possibilities for prenatal testing in offspring of a female who has biallelic pathogenic variants in an MEG gene. There is no reliable prenatal test for detection of multilocus methylation changes. For prenatal testing for Beckwith-Wiedemann spectrum or Silver-Russell syndrome, see the respective GeneReviews chapters. Presence of hydatidiform mole can be investigated using ultrasound imaging. Prenatal sequencing of the variant(s) identified in the mother is not warranted, as the offspring will be a heterozygous carrier.
Preimplantation diagnostic testing is not possible.
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