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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Resources for Genetics Professionals — Epigenetic Signature Analysis

, MD, , MD, and , PhD.

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Initial Posting: ; Last Revision: June 30, 2022.

Estimated reading time: 12 minutes

An introduction to epigenetic signature analysis and comparison of gene-specific genome-wide methylation analysis and epigenetic modifications to specific regions of the genome

I. Introduction to Epigenetic Modifications

All human nucleated cells have a nuclear genome (sequence of DNA nucleotides) that encodes the proteins and other gene products responsible for the development of a single-cell zygote into an embryo and then a complex multicellular organism. This developmental process requires that the nuclear genome control the following:

  • The timing of nuclear gene expression during embryonic development
  • The location of nuclear gene expression to enable the differentiation of tissues and organs with specialized functions

Control over timing and location of gene expression occurs through epigenetic modifications – chemical alterations to DNA nucleotides or proteins that control gene expression but do not alter the DNA sequence itself. Histones, the proteins around which DNA is wound, are often targets for modifications that allow accessibility of the DNA for transcription. (See Table 1 for mechanisms of known epigenetic modifications in normal human cells.)

Table 1.

Mechanisms of Known Epigenetic Modifications in Normal Human Development

TargetEpigenetic ModificationMechanism
DNAMethylation patternAddition of methyl groups near promotors & enhancers to directly suppress or indirectly activate/promote transcription
Methylation modificationAddition (methylation) or removal (oxidation) of methyl groups to refine transcription control
HistonesAcetylationAddition of acetyl groups to lysine residues to activate transcription by relaxing the interaction between histones & DNA
ADP ribosylationAddition of ADP-ribose moieties to activate transcription
MethylationAddition of methyl groups to lysine residues to activate or suppress transcription
PhosphorylationAddition of phosphate groups to serine, threonine, or tyrosine residues to activate transcription
SumoylationAddition of small ubiquitin-related modifier (SUMO) proteins to suppress transcription
UbiquitinationAddition of ubiquitin or ubiquitin chains to lysine residues to activate or suppress transcription
NucleosomesATP-dependent chromatin remodelingAlteration of the nucleosome positioning on DNA & histones present in the nucleosomes & disassembly of nucleosomes to increase or decrease the accessibility of DNA for transcription
Proteins & DNA via noncoding RNA 1Methylation (indirect)Facilitation of modifications to DNA & proteins to activate or suppress transcription
Acetylation (indirect)
1.

Of note, noncoding RNAs (ncRNAs) play an important indirect role in controlling epigenetic modifications. Examples include the long ncRNA Xist (which coats the inactive X chromosome marking it for methylation) and small ncRNAs including siRNAs, miRNAs and piRNAs (which regulate proteins such as DNA methyltransferases, methyl CpG binding proteins, and histone methyl and acetyl transferases).

II. Epigenetic Modifications to Specific Regions of the Genome

Epigenetic modifications that occur early in embryogenesis to specific regions of the genome result in imprinting, the process by which maternally and paternally derived regions of chromosomes are uniquely chemically modified, leading to different expression of a certain gene or genes depending on their parental origin. Patterns of gene expression and repression vary between imprinted regions on a chromosome. DNA methylation is thought to be the principal mechanism of imprinting.

Genetic Alterations That Affect Epigenetic Modifications to Specific Regions of the Genome

Disease-associated alterations affecting methylation patterns in specific regions of the genome (see Table 2) include:

  • Disruption of normal imprinting at a specific chromosome locus (e.g., heterozygous deletions or duplications of an imprinted region, uniparental disomy, and pathogenic variants that alter an imprinting control region, thereby disrupting imprint reprogramming during gametogenesis);
  • Hypermethylation (silencing) of an abnormally expanded repeat region;
  • Acquired promoter methylation of tumor suppressor genes; and
  • Skewed X-chromosome inactivation in females due to or in the presence of a disease-causing variant on one X chromosome.

An assay designed to detect the DNA methylation pattern at a specific chromosome locus (e.g., methylation-sensitive multiplex ligation probe analysis [MS-MLPA], methylation-sensitive quantitative PCR [MS-qPCR], Southern blotting using methyl-sensitive DNA restriction enzymes) is necessary to identify epigenetic imprinting alterations. Identification of an epigenetic imprinting alteration typically requires the clinician to suspect a specific imprinting disorder and order the appropriate diagnostic test:

  • First-tier testing (ordered based on clinical suspicion) is often a locus-specific DNA methylation assay to determine if an individual has a disorder caused by an abnormal methylation pattern at a specific chromosome locus (e.g., Prader-Willi/Angelman DNA methylation panel).
  • Second-tier testing may be necessary to identify the cause of the abnormal methylation pattern at a specific chromosome locus (e.g., FISH testing to identify deletion of the Prader-Willi critical region).

Table 2.

Disorders with an Abnormal DNA Methylation Pattern at a Specific Chromosome Locus

Chromosome
Locus		DisorderMechanism(s)
2p21-p16 Lynch syndrome Hypermethylation of MSH2 due to adjacent EPCAM deletion
3p22.2Methylation of MLH1 promoter
4q35 Facioscapulohumeral muscular dystrophy Hypomethylation of the D4Z4 repeat array due to pathogenic variant of SMCHD1 or DNMT3B
6q24.2 Transient neonatal diabetes mellitus, 6q24 related Paternal UPD of chr 6
Paternal 6q24 duplication
Maternal hypomethylation of PLAGL1 TSS alt-DMR due to imprinting defect
Chr 7 Silver-Russell syndrome Maternal UPD of chr 7
11p15.5Paternal hypomethylation of IC1 at 11p15.5
Maternal 11p15.5 duplication
Beckwith-Wiedemann syndrome Maternal hypomethylation of IC2
Paternal UPD of 11p15.5
Maternal hypermethylation of IC1
Isolated Wilms tumor (See Wilms Tumor Predisposition.)Paternal UPD of 11p15.5
Maternal hypermethylation of IC1
Maternal H19 DMR deletion
Maternal H19 DMR duplication
14q32Temple syndrome (OMIM 616222)Maternal UPD of 14q32
Kagami-Ogata syndrome (OMIM 608149)Paternal UPD of 14q32
15q11.2-q13 Prader-Willi syndrome Paternal 15q11.2-q13 deletion
Maternal UPD of 15q11.2-q13
Paternal hypermethylation due to imprinting defect
Angelman syndrome Maternal 15q11.2-q13 deletion
Paternal UPD of 15q11.2-q13
Maternal hypermethylation due to imprinting defect
20q13Pseudohypoparathyroidism 1B (See Disorders of GNAS Inactivation.)Maternal hypomethylation due to imprinting defect
Maternal 20q13 deletion
Paternal UPD of 20q
Chr 20UPD(20)mat 1Maternal UPD of chr 20
Xq27.3 FMR1-related disorders Maternal hypermethylation of FMR1 promoter caused by abnormal CGG repeat expansion.

chr = chromosome; DMR = differentially methylated region; IC1 = imprinting center 1; IC2 = imprinting center 2; TSS alt = alternative transcription start site; UPD = uniparental disomy

1.

III. Gene-Specific Genome-Wide DNA Methylation Analysis (Epigenetic Signature Analysis)

In contrast to locus-specific DNA methylation analysis, an assay has been developed that detects the DNA methylation pattern at ~1000 different loci across the genome of a specific cell type (e.g., leukocytes). The genome-wide DNA methylation pattern in control individuals was compared to the genome-wide DNA methylation pattern in individuals with disorders known to be associated with alteration of genes that regulate DNA methylation. A unique gene-specific genome-wide DNA methylation pattern ("epigenetic signature") was identified for each of several single-gene disorders that could be distinguished from other known single-gene epigenetic signatures and the reference genome-wide DNA methylation pattern (see Table 3) [Kernohan et al 2016, Butcher et al 2017, Aref-Eshghi et al 2019].

Of note, determination of the so-called "epigenetic signature" for a specific single-gene disorder required DNA methylation analysis of a large number of individuals with known pathogenic variants in a specific gene responsible for the genome-wide epigenetic modifications. This led to the development of epigenetic signature analysis as a method that compares the genome-wide DNA methylation pattern from an individual with the altered DNA methylation pattern characteristic of each gene listed in Table 3 in a specific cell type (e.g., leukocytes).

To date, epigenetic signature analysis may be useful as a second-tier test when first-tier gene-specific molecular genetic testing has not established a molecular diagnosis. Epigenetic signature analysis is not appropriate as a first-tier test due to the limited number of single-gene disorders with an identified epigenetic signature, to date. In addition, although identification of an epigenetic signature characteristic of one of the genes listed in Table 3 is suggestive of a diagnosis, further gene-specific molecular genetic testing to identify a causative pathogenic variant is recommended to confirm the diagnosis and allow the appropriate family studies.

Table 3.

Genes in Which Pathogenic Variants Result in a Gene-Specific Genome-Wide Epigenetic Signature Identified on DNA Methylation Analysis of a Blood Sample

Gene(s)DisorderMOIReferences
ADNP ADNP-related disorder 1ADAref-Eshghi et al [2019], Aref-Eshghi et al [2020]
ARID1A
ARID1B
SMARCA2
SMARCA4
SMARCB1 		BAFopathies (ARID1B-related disorder, Coffin-Siris syndrome 2, Nicolaides-Baraitser syndrome)ADAref-Eshghi et al [2018], Aref-Eshghi et al [2020]
SOX11 Coffin-Siris syndrome 2AD Levy et al [2021]
ATRX Alpha-thalassemia X-linked intellectual disability syndrome XLAref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
BRWD3 Intellectual developmental disorder, XL 93 (OMIM 300659)XLAref-Eshghi et al [2020], Levy et al [2021]
CHD2 CHD2-related neurodevelopmental disorders ADAref-Eshghi et al [2020], Levy et al [2021]
CHD7 CHD7 disorder (e.g., CHARGE syndrome)ADButcher et al [2017], Aref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
CHD8 CHD8-related neurodevelopmental disorder with overgrowth ADAref-Eshghi et al [2020], Levy et al [2021]
CREBB
EP300 		Rubinstein-Taybi syndrome ADAref-Eshghi et al [2020], Levy et al [2021]
DNMT1 DNMT1-related disorder ADKernohan et al [2016], Levy et al [2021]
DNMT3A Tatton-Brown-Rahman syndrome ADAref-Eshghi et al [2020], Smith et al [2021], Levy et al [2021]
DNMT3B Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (ICF1) (OMIM 242860) 3ARAref-Eshghi et al [2020], Levy et al [2021]
CDCA7
HELLS
ZBTB24 		ICF2 (OMIM 614069), ICF3 (OMIM 616910), ICF4 (OMIM 616911)
EHMT1 Kleefstra syndrome ADAref-Eshghi et al [2020], Levy et al [2021]
EED
EZH2 		EED-related overgrowth, EZH2-related overgrowthADAref-Eshghi et al [2020], Levy et al [2021]
FAM50A Intellectual developmental disorder, Armfield type (OMIM 300261)XL Levy et al [2021]
H1-4 (formerly HIST1H1E) HIST1H1E syndrome ADBurkardt et al [2019], Levy et al [2021]
KANSL1 Koolen-de Vries syndrome ADAref-Eshghi et al [2020], Cherik et al [2022], Levy et al [2021]
KAT6A Arboleda-Tham syndrome (OMIM 616268)AD Levy et al [2021]
KAT6B Genitopatellar syndrome  4 ADAref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
Say-Barber-Biesecker-Young-Simpson syndrome 4
KDM2B KDM2B-related syndromeYokotsuka-Ishida et al [2021], Levy et al [2021]
KDM4B Intellectual developmental disorder, AD 65 (OMIM 619320)AD Levy et al [2021]
KDM5C Claes-Jensen syndrome (OMIM 300534)XLAref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
KDM6A KMT2D Kabuki syndrome ADButcher et al [2017], Aref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
KMT2A Wiedemann-Steiner syndrome ADAref-Eshghi et al [2020], Levy et al [2021]
KMT2B KMT2B-related dystonia AD Levy et al [2021]
KMT5B Intellectual developmental disorder, AD 51 (OMIM 617788)ADAref-Eshghi et al [2020], Levy et al [2021]
NIPBL
RAD21
SMC3
SMC1A 		Cornelia de Lange syndrome 5AD/XL 6Aref-Eshghi et al [2020], Levy et al [2021]
NSD1 Sotos syndrome ADAref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
PHF6 Börjeson-Forssman-Lehmann syndrome (OMIM 301900) 7XLAref-Eshghi et al [2020], Levy et al [2021]
PQBP1 Renpenning syndrome (OMIM 309500)XL Levy et al [2021]
SETD1B SETD1B-related neurodevelopmental disorder ADAref-Eshghi et al [2020], Levy et al [2021]
SETD2 SETD2 neurodevelopmental disorders AD Levy et al [2021]
SETD5 Intellectual developmental disorder, AD 23 (OMIM 615761)AD Levy et al [2021]
SMS Snyder-Robinson syndrome XLAref-Eshghi et al [2020], Levy et al [2021]
SRCAP Floating-Harbor syndrome ADAref-Eshghi et al [2019], Aref-Eshghi et al [2020], Levy et al [2021]
TET3 Beck-Fahrner syndrome Levy et al [2021]
UBE2A Intellectual disability disorder, Nascimento-type (OMIM 300860)XLAref-Eshghi et al [2020], Levy et al [2021]
YARS2 Myopathy, lactic acidosis, and sideroblastic anemia 2 (OMIM 613561)AR Levy et al [2021]
YY1 Gabriele-de Vries syndrome AD Levy et al [2021]
ZNF711 Intellectual developmental disorder, XL 97 (OMIM 300803)XLAref-Eshghi et al [2020], Levy et al [2021]
1.

Two distinct gene-specific genome-wide DNA methylation patterns were identified in individuals with an ADNP pathogenic variant: The pattern associated with ADNP pathogenic variants between c.2000 and c.2340 differed from that of pathogenic variants outside c.2000-2340 [Aref-Eshghi et al 2019].

2.

Rarely, individuals with clinical features of Coffin-Siris syndrome have been found to have biallelic pathogenic variants in ARID2, DPF2, PHF6, SMARCC2, SMARCE1, or SOX4; To date, distinct epigenetic signatures have not been reported in individuals with Coffin-Siris syndrome attributed to pathogenic variants in one of these genes.

3.

The DNA methylation pattern in individuals with ICF1 could be fully distinguished from the DNA methylation pattern of those with ICF2, ICF3, and ICF4 [Aref-Eshghi et al 2020].

4.

Individuals with the allelic disorders genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome were found to have distinct epigenetic methylation patterns.

5.

To date, individuals with Cornelia de Lange syndrome attributed to pathogenic variants in BRD4, or HDAC8 have not been found to have a distinct epigenetic signature.

6.

NIPBL-, RAD21-, and SMC3-Cornelia de Lange syndrome are inherited in an autosomal dominant manner; SMC1A-Cornelia de Lange syndrome is inherited in an X-linked manner.

7.

To date, a distinct epigenetic signature has been identified in affected males; affected heterozygous females have not been found to have the same epigenetic pattern [Kerkhof et al 2022]

Examples of Clinical Use of Gene-Specific Genome-Wide Epigenetic Signature Analysis

An individual with clinical features suggestive of CHD7-related disorder (e.g., CHARGE syndrome) without an identified CHD7 pathogenic variant was found to have a gene-specific genome-wide DNA methylation pattern consistent with the epigenetic signature of CHD7 disorder – further supporting (but not confirming) the clinical diagnosis.

Another individual with a CHD7 variant of uncertain significance (VUS) was found to have a gene-specific genome-wide DNA methylation pattern consistent with the epigenetic signature of ADNP-related intellectual disability and autism spectrum disorder, a diagnosis subsequently confirmed by molecular genetic testing [Aref-Eshghi et al 2019].

What Are the Clinical Uses of Gene-Specific Genome-Wide Epigenetic Signature Analysis in Single-Gene Disorders?

Gene-specific genome-wide epigenetic signature analysis can suggest a molecular diagnosis in individuals with clinical features of one of the disorders in Table 3 when:

What Are the Current Limitations of Gene-Specific Genome-Wide Epigenetic Signature Analysis in Single-Gene Disorders?

Epigenetic signature analysis has only been reported for the diagnosis of disorders that have a known distinct genome-wide epigenetic signature (see Table 3). Additional single-gene disorders with genome-wide epigenetic signatures may exist; however, data to date have not been sufficient to delineate them.

Of note, the epigenetic signature identified in males with an X-linked disorder may or may not be present in affected or unaffected females with a heterozygous pathogenic variant associated with the disorder [Kerkhof et al 2022].

Importantly, epigenetic signature analysis requires a specific sample type as DNA methylation patterns vary by cell and tissue type. For example, DNA from amniocytes, chorionic villi, and/or fibroblasts may not be appropriate to test for a gene-specific genome-wide epigenetic signature previously characterized only in peripheral blood samples. (Because DNA banking methods do not interfere with analysis of epigenetic signature from peripheral blood, DNA banked from a blood sample can be used for gene-specific genome-wide epigenetic signature analysis previously characterized in blood samples [Hjorthaug et al 2018].)

Individuals mosaic for a disorder with a known epigenetic signature may not be identified on epigenetic signature analysis if the pathogenic variant is either absent or present at a very low level in peripheral leukocytes. Testing affected tissue may not be helpful if a known epigenetic signature has not been reported or described for the affected tissue.

Possible Future Developments

Despite identification of known mechanisms of genome-wide epigenetic modification (Table 1), DNA methylation is, to date, the only method for which sufficient data exist to enable construction of a reference genome-wide pattern of epigenetic modification. It is anticipated that in the future, unique genome-wide epigenetic signatures associated with variants in additional genes will likely be identified. New assays may also be developed to identify other mechanisms associated with gene-specific genome-wide epigenetic modification.

Revision History

References

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