Genetic Disorders
Jeremy R. Jass in Understanding Pathology, 2020
Genomic imprinting may be suspected on clinical grounds when an inherited disease occurs in both males and females but is transmitted only by parents of a particular gender. Genomic imprinting may also be suspected when a disease arises do novo and is associated with parental disomy (in which an individual has two identical chromosomes derived from the same parent). Interestingly, both scenarios have been observed in the case of the Beckwith-Wiedemann syndrome, an inherited disorder associated with organomegaly, hemihypertrophy, gigantism and a propensity to tumours of childhood, notably nephroblastoma or Wilms’ tumour. Underlying this syndrome is the phenomenon of imprinting of the insulin-like growth factor 2 (IGF2)gene in female germ cells. A paternal disomy involving the locus 11p15.5 leads to a double dose of IGF2. This in turn accounts for the organ enlargement. Conversely, mutations or cytogenetic abnormalities involving the 1 lpl5.5 locus are thought to block the process of imprinting in the female germline. Females and their offspring may therefore possess two functioning copies of IGF2 and so express a double dose of the growth factor (Tycko, 1997).
Chromosome abnormalities
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
While deletions of 22q are frequent in specific forms of congenital heart disease, smaller deletions within the area of the common, large deletion are being recognised. While the associated phenotypes are also very variable, they are generally less marked and still in the process of being clarified. In Prader-Willi and Angelman syndromes, the same region of chromosome 15 (15q11-13) has long been implicated; because of genomic imprinting, a different phenotype will result, depending on which parental region is lost. When the loss is from the paternal chromosome, the child will have Prader-Willi syndrome, when the loss is from the maternal chromosome, the child will have Angelman syndrome. Smaller deletions within this region of 15q, and the corresponding duplications, are now being identified with array CGH. The phenotypes associated with these smaller rearrangements are being clarified but include autistic spectrum disorders, intellectual disability, schizophrenia and epilepsy.
Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
Genomic imprinting is the epigenetic process that causes a reversible gamete-of-origin specific marking or an “imprinting” of the genome that is replicated faithfully in somatic cells and ultimately results in mono-allelic gene expression or the inactivation of either the maternal or paternal allele of a particular locus. Although the mechanism of imprinting not fully understood, one modification that is believed to play a role is the reversible addition of methyl groups to specific cytosine residues within the DNA sequence, a process that occurs differently in the production of the egg and the sperm (145). Within the past decade, mutations of imprinted genes on several different chromosomes have been found to cause a wide range of phenotypic effects. This genetic mechanism underlies two well-known genetic disorders, namely, Prader–Willi and Angelman syndromes, the first disorders recognized as occurring because of genomic imprinting(146).
Allogeneic hematopoietic stem cell transplantation in an adolescent with Prader-Willi syndrome – unique considerations
Published in Pediatric Hematology and Oncology, 2022
Tristan E. Knight, Jane Lowry, Sarah Leppington, Donna A. Wall, Jennifer Seelisch
Prader-Willi Syndrome (PWS) is a neurodevelopmental genetic disorder characterized by behavioral, developmental, and endocrine abnormalities, and a characteristic physical phenotype.1 PWS arises due to genomic imprinting errors resulting in loss of expression of paternal genes in the chromosome 15q11-q13 region. This occurs due to de-novo deletions in ∼70%, maternal uniparental disomy of chromosome 15 in ∼25%, and imprinting defects in the remaining ∼5% of patients.1 Profound hyperphagia is a defining characteristic and arises secondary to pathologic lack of satiety, ghrelin signaling dysregulation, and reduced basal metabolic rate.1 Developmental delay and impaired intellectual attainment are expected, as are psychiatric/behavioral comorbidities including anxiety, tantrums, stubbornness, obsessive-compulsive features, and autism-spectrum disorders.1
Assisted reproductive technology (ART) and epigenetic modifications in the placenta
Published in Human Fertility, 2021
Deepali P. Sundrani, Sadhana R. Joshi
Genomic imprinting is an epigenetic process where imprinted genes are expressed in parent-of-origin-specific manner, regulated by DNA methylation or histone modifications during the period of gametogenesis. It is well known that ART procedures occur during this period of epigenetic reprogramming, and these modifications alter the expression of genomic imprinted genes thereby influencing placental growth and development (Barlow & Bartolomei, 2014; Bartolomei & Ferguson-Smith, 2011). Alterations in placental gene expression levels of imprinted genes have been reported in ART pregnancies as compared to naturally conceived pregnancy suggesting that these abnormalities in genomic imprinting could be as a result of ART procedures coinciding with the epigenetic reprogramming events during early pregnancy (Katagiri et al., 2010).
Relevance of sperm imprinted gene methylation on assisted reproductive technique outcomes and pregnancy loss: a systematic review
Published in Systems Biology in Reproductive Medicine, 2021
Rossella Cannarella, Andrea Crafa, Rosita A. Condorelli, Laura M. Mongioì, Sandro La Vignera, Aldo E. Calogero
Overall, the studies included in this qualitative review evaluated methylation of the following genes at the sperm level: H19/IGF2, GTL2/DLK1, PEG1/MEST, PLACL1, LIT1, NESPAS, PEG3, SNRPN, UBE3A, KCNQ1, and KCNQ1OT1. All of them are paternally-expressed imprinted genes except for H19, GTL2, UBE3A, and KCNQ1 that are maternally-expressed imprinted genes (http://www.geneimprint.com/site/genes-by-species). Imprinting is a mechanism that allows monoallelic and parent-specific gene expression since the gene in the other allele is silenced by methylation (Bajrami and Spiroski 2016). Hypermethylation leads to gene silencing, whereas hypomethylation allows gene expression (Bajrami & Spiroski et al., 2016). It has been estimated that ~1% of the human genome has a monoallelic and parent-specific expression (Elbracht et al. 2020). Errors of genomic imprinting have classically been recognized in the pathogenesis of some neurodevelopmental disorders, such as Angelman or Prader–Willi syndrome, which represent the consequence of the loss of paternal or maternal gene expression, respectively (Bajrami and Spiroski 2016).
Related Knowledge Centers
- Allele
- DNA Methylation
- Epigenetics
- Gene Expression
- Germline
- Histone Methylation
- Mendelian Inheritance
- Somatic Cell
- Mitosis
- Gene
- DNA Methylation