Introduction and Pathophysiology

The differential marking or imprinting of specific paternally and maternally inherited alleles during gametogenesis, resulting in differential expression of those genes, is a phenomenon called genomic imprinting

Genomic imprinting refers to the modification of a gene Opens in new window (or a chromosomal region) such that it is expressed differently if it is inherited from one parent as compared to the other parent.

The imprinted copy of the gene is inactivated Opens in new window; therefore, it is not expressed. The imprint is reversible because a man passes on his genes with his own paternal imprint if those genes were inherited with a maternal imprint from his mother (Strachan and Read, 1996).

The mechanism of imprinting appears to involve DNA methylation (the modification of DNA by the addition of a methyl group) and/or histone modification (histones are the protein-spools around which DNA winds), but the details are complex and not well understood. Usually the nonmethylated allele is expressed and the methylated gene is repressed.

Imprinting appears to occur at the level of transcription, most likely in the germline. It is unclear whether imprinting is a critical process in embryonic development and the expression of genetic disease or a property of a limited number of genes (or small chromosomal regions).

Most genes are not subject to imprinting, or we would not so readily recognize simple Mendelian inheritance patterns Opens in new window.

Over 50 genes are known to be imprinted in humans, and many of these genes play a role in growth regulatory pathways and/or behavioral/neurological expression (Weksberg et al., 2007). The imprinted genes tend to cluster together in imprinted chromosomal domains. Duke University has a fascinating website about advances in gene imprinting (human and other species), visit Opens in new window.

Classic examples of imprinting disorders are Prader-Willi syndrome (PWS) Opens in new window and Angelman syndrome Opens in new window. Both of these distinctly different genetic conditions involve altered genetic expression of the same genetic region—a tiny segment of the long (q) arm of chromosome 15 (15q11-q13).

If the altered region is inherited from the father, the child (son or daughter) has PWS. If the same altered region is inherited from the mother, the child (son or daughter) has Angelman syndrome.

Severe developmental delay, limited speech, jerky movements, ataxia, excitable personality with hysterical laughter, and an unusual facial appearance characterize Angelman syndrome Opens in new window.

The hallmark features of PWS Opens in new window are hypotonia in childhood, almond-shaped eyes, small hands, and feet, behavioral difficulties, and a mean IQ of 56. Early feeding difficulties are replaced by overeating and morbid obesity in childhood.

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