Genomic imprinting: 10 questions and 10 answers

An epigenetic event

Genomic Imprinting (mother with baby)

Genomic imprinting, although very studied, has many dark sides, even among healthcare professionals. Here are 10 frequently asked questions with relative answers on this phenomenon.

1. What is genomic imprinting?

Genomic imprinting is an epigenetic process that modifies the DNA molecule without changing its nucleotide sequence. Regulator mechanisms of imprinting are not completely known, but it is proven that it is linked to the methylation of cytosines (imprinted regions are usually reach in CpG sequences). Imprinting substantially regulates the transcription of some genes on the basis of their parental origin (maternal or paternal), giving as a result monoallelic expression.

2. Are all genes imprinted?

No, only a few genes are imprinted. Some imprinted regions are on chromosome 15 (critical for the pathogenesis of Prader-Willi and Angelman syndromes), on chromosome 11 (Beckwith-Wiedemann and Silver-Russel syndromes), in 7q31 (PEG/MEST1 genes), in 6q24 (ZAC1 gene), in 6q26 (gene for the IGF receptor type 2), in 14q32 (DLK1/GTL2IGDMR genes) and in 20q13.3 (GNAS locus).

3. Is prenatal diagnosis possible for imprinting disorders?

Yes, but it must be kept in mind that the methylation process of embryonic chromosomes is not complete until about the thirteenth week of gestation. An early villocentesis (around 10-11 weeks) is not recommended for targeted prenatal diagnosis of an imprinting disorder.

4. Which is the reproductive risk in imprinting disorders?

Reproductive risk is not the same in all cases. Depending on the mutation that caused the imprinting abnormality, recurrence risk in the next pregnancies can vary from less than 1% to 100%.  So, for each disorder, it is recommended to consult diagnostic guidelines and undergo genetic counseling.

5. Which are the best-known imprinting disorders?

Angelman syndrome, Prader-Willi syndrome, Silver-Russellsyndrome and Beckwith-Wiedemann syndrome.

6. Which are the molecular pathways underlying an imprinting defect?

Methylation regulates gene expression. Usually, methylated regions are transcriptionally inactive and therefore not expressed, while demethylated regions are expressed.

7. Is imprinting an epigenetic event exclusive to humans or is it also found in other species?

Imprinting is also found in other species. For example, Dolly the sheep, one of the first cloning experiments, is believed to have aged and died prematurely due to the fact that the genetic material contained in its cells, which was of uniparental origin, had substantial abnormalities in the imprinting pattern.

8. Is genomic imprinting the only mechanism that leads to monoallelic expression of a gene?

No. Also other mechanisms, largely unknown, lead to monoallelic expression of a gene, sometimes only in certain cells or at a certain development stage. For instance, genes on chromosome X in females are expressed on a single allele after the random inactivation of one of the two X chromosomes. Another example is given by the immunoglobulin genes in B lymphocytes, by the genes of the T cell receptors, by the IL2 and IL4 genes (interleukins) and by olfactory receptor genes in neurons.

9. Only autosomal genes are imprinted?

Only a few genes of the human genome are imprinted. The vast majority falls on autosomal chromosomes (1-22). However, the XIST gene, which is located on the X chromosome and regulates its inactivation, is imprinted (Amort et al 2012, PMID 23595112).

10. Does assisted insemination increase fetal risk of imprinting disorders?

Several studies support this evidence. It has been proved that Beckwith-Wiedemann syndrome and other imprinting disorders occur more frequently in subjects conceived through artificial insemination (also called ART – Assisted Reproductive Technology). The mechanism by which ART can induce imprinting aberrations with a higher frequency than spontaneous fertilization is not known.


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