Syndromic Disorders Caused by Disturbed Human Imprinting

Abstract

Imprinting disorders are a group of congenital diseases caused by dysregulation of genomic imprinting, affecting prenatal and postnatal growth, neurocognitive development, metabolism and cancer predisposition. Aberrant expression of imprinted genes can be achieved through different mechanisms, classified into epigenetic - if not involving DNA sequence change - or genetic in the case of altered genomic sequence. Despite the underlying mechanism, the phenotype depends on the parental allele affected and opposite phenotypes may result depending on the involvement of the maternal or the paternal chromosome. Imprinting disorders are largely underdiagnosed because of the broad range of clinical signs, the overlap of presentation among different disorders, the presence of mild phenotypes, the mitigation of the phenotype with age and the limited availability of molecular techniques employed for diagnosis. This review briefly illustrates the currently known human imprinting disorders, highlighting endocrinological aspects of pediatric interest.

Keywords: epimutation; genotype; phenotype; Imprinting disorders.

Figure 1

Schematic representation of the molecular mechanisms responsible for altered imprinted gene expression. At the top normal functioning of a paradigmatic chromosomal region subjected to imprinting is reported: on the allele inherited from parent 1, the imprinting center (IC) is unmethylated and gene A is expressed, while on the allele inherited from parent 2, gene A is silenced by IC methylation. This leads to a balanced expression of gene A, corresponding to the normal phenotype. Conversely, imbalance between the expression of the imprinted gene leads to a pathological phenotype: a deficiency of gene A leads to phenotype 1, while an excess of gene A leads to phenotype 2. Phenotype 1 and phenotype 2 may have antithetical characteristics (mirror phenotypes). In the left column, epigenetic anomalies leading to disturbed expression of imprinted genes are shown. In the middle column, point mutations and in the right column, uniparental disomy, deletion and duplication affecting the imprinted gene are reported. If the point mutation or the deletion/duplication hits the expressed gene, it will lead to a phenotype while, on the opposite, if they involve a normally silenced gene, they will not result in a phenotype: in both cases, the genetic anomaly could be transmitted to the offspring