The Unique Etiology of Imprinting Disorders

In every person there are two copies of each and every gene (with a few exceptions). One copy is inherited from each parent and typically, both copies of a gene are expressed in cells. However, there are certain regions where only a single copy is expressed. The specific copy of a gene that is expressed is determined by the parent that it originated from. So, certain genes within these regions may only be expressed when inherited from the father whereas, other genes may only be expressed when inherited from the mother. This is known as genomic imprinting.

Genomic Imprinting

Imprinting is the process by which one allele of a gene is preferentially and specifically silenced based upon its parental origin. It is thought that ~50% of genomics regions are imprinted and the majority of these are involved in pre- and post-natal growth.

The parental origins of these copies of genes not only determines the expression of certain alleles but often also follows a pattern of paternal growth promotion and maternal growth suppression. Evolutionarily this make sense as it's evolutionarily advantageous for the father to have larger and stronger children which would be more likely to live until an age that they can themselves reproduce, while smaller children increase the chance of the mother surviving child birth and being able to have more children in the future. This defines the conflict hypothesis and acts as a balance between growth promotion and suppression in a healthy individual.

When things go wrong…

When there is an imbalance between the opposing parental alleles it can cause severe congenital disorders which, often occur as paired disorders with opposing presentations depending on which of the two parental alleles predominates. A classic example of this is Beckwith-Weideman syndrome (BWS) and Silver Russel syndrome (SRS). Both syndromes are caused by aberrant expression of alleles on chromosome 11 at position p15 (11p15).

BWS is an overgrowth disorder with common features including increased height and/or weight sometimes asymmetrically, an enlarged tongue (macroglossia), an umbilical hernia or other abdominal wall defects, and ear pits.
Conversely, SRS is an undergrowth disorder with common features including a triangular face, ‘elvish’ features, and what can appear to be a large head in comparison to the rest of the body (relative macrocephaly).

Before we discuss how things go wrong we first need to understand the normal workings of imprinting

The way a cell knows which genes should be expressed or not is based on epigenetic marks which are inherited and ‘tag’ alleles via methylation indicating their parental origin. After fertilization of an egg with a sperm these tags are maintained as a cell grows and divides directing the gene expression within these imprinted regions (illustrated by the dotted pink and blue lines in the graph above). The exception to this are germ cells i.e. sperm or egg cells which must have their parental specific tags changed to reflect the sex of the individual.

How do things go wrong?

Imprinting disorders can arise from one of three unique mechanisms. The first two mechanisms are chromosomal rearrangements i.e. deletions or duplications and epimutations meaning, alternations to these parent specific tags. The third and rather unique mechanism is uniparental disomy.

During cell division, homologous chromosomes (meiosis) or sister chromatids (mitosis) can fail to separate, this is known as non-disjunction. The resulting daughter cells in either case will contain imbalanced numbers of the affected chromosomes. If this happens during meiosis this imbalance is introduced into gamates such that the affected sperm cell or egg cell contains too many or too few chromosomes. Uniparental disomy is where, due to non-disjunction, a gamate inherits both copies of a particular chromosome from a single parent. nondisjunction can either occur at meiosis I and where one parent passes on one copy of each chromosome homologue (heterodisomy) or at meiosis II and one parent passes on 2 copies of the same chromosome (isodisomy). Both cases will disrupt the balance of imprinting tags but isodisomy means both chromatids are identical whereas, with heterodisomy the chromatids are different but with singular parental origin.

Non-disjunction during meiosis: Heterodisomy occurs at meiosis I and results in two daughter cells with two non-identical copies of the same chromosome and two daughter cells with no copies of that chromosome (Image on the left). Isodisomy occurs during meiosis II and results in one daughter cell with two identical chromosomes, one daughter cell with no copies of that chromosome, and two normal cells (Image on the right).

Going back to BWS and SRS

As mentioned previously, BWS and SRS are classic examples of paired imprinting disorders. They are both caused by errors in imprinting to the region 11p15 where methylation patters of the paternal and maternal alleles are the opposite with paternal growth promotion and maternal growth suppression.

11p15 imprinting region: On the paternal allele the first imprinting control region or ICR1 is methylated (CH3) which is its tag to preferentially express insulin-growth factor 2 (IGF2) which is a growth promoter. Within this same region of the maternal strand there is no methylation thus allowing H19, a long non-coding RNA to be preferentially produced. Similarly, on the second ICR, there is no methylation on the paternal strand which encodes another long non-coding sequence of KCNQ1. On the maternal strand of ICR2 there is methylation which results in the skipping out of this non-coding region as well as the repression of CDKN1C. (The 2 ICAs are labeled in reverse order based on when they were discovered.

The overgrowth related to BWS occurs when there is either a disproportionate overexpression of paternal alleles or an under expression of regulatory maternal alleles. Uniparental disomy of the paternal allele would result in doubled expression of IGF2 and no CDKN1C expression. This also increases the risk of developing embryonal tumors e.g. Wilms tumors. Alternatively, an epimutation of the maternal allele resulting in either hypermethylation to ICR1 or hypomethylation of ICR2 would skew gene expression towards the paternal side. The net result of all 3 mechanisms is an imbalance of IGF2/CDK expression favouring IGF2 which produces the characteristic overgrowth.

On the other hand, the undergrowth related to SRS results from converse mechanisms. Uniparental disomy of the maternal allele would cause over expression of CDKN1C and no expression of IGF2. Alternatively, an epimutation to the paternal allele causing hypermethylation of ICR2 or hypomethylation of ICR1 would cause an imbalance towards maternal imprinting patterns. The net result is an imbalance of IGF2/CDKN1C favouring CDKN1C which produces the phenotype of general undergrowth. Additionally, 5-10% of SRS cases have been found to be caused by maternal uniparental disomy of chromosome 7.

Prevalence of disease etiologies for Beckwith-Weideman syndrome and Silver Russel syndrome: These percentages were consolidated by Õunap K. (2) from several studies.

References / Additional Reading

Eggermann, T., Perez de Nanclares, G., Maher, E. R., Temple, I. K., Tümer, Z., Monk, D., Mackay, D. J., Grønskov, K., Riccio, A., Linglart, A., & Netchine, I. (2015). Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. Clinical epigenetics, 7, 123. https://doi.org/10.1186/s13148-015-0143-8.
Õunap K. (2016). Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology. Molecular syndromology, 7(3), 110–121. https://doi.org/10.1159/000447413