Beckwith-Wiedeman and Prader-Willi Syndromes

The expression of genes can be unbalanced or balanced. In a balanced expression, the two copies of genes have similar expression levels. In an unbalanced form, one gene is expressed more than the other. For example, imagine a recipe seasoned to taste with salt and pepper. Many cooks will add an equal pinch of both. Others will add more salt or pepper. If different genomic factors control the amount of genes to be expressed, just as there are different tastes for different cooks, the result will be a variable amount of one gene or the other.

In genomic imprinting, the factors determining which genes are expressed depend upon genes that generate from male cell lines and those from female cell lines. This process involves silencing genes by factors that do not change the genotype, such as DNA methylation and transcription factors. If we return to our cooking example, despite having both salt and pepper, the male cook only adds salt and the female cook only adds pepper. There are three examples of genomic imprinting disorders, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, and Angelman syndrome (Nussbaum et al., 2015).

Prader-Willi syndrome (PWS) is characterized by a lack of expression of a specific paternally inherited gene on chromosome 15, 15q11-q13. In our cooking example, there is a lack of this specific type of salt. This change in gene expression is typically due to a paternal deletion or maternal disomy; two gene copies are maternal in Chromosome 15. Paternal deletion accounts for 60-70% of cases, and maternal disomy accounts for 25-35% of cases. (The range is due to different percentages in Nussbaum et al. and Butler et al.). Abnormalities in imprinting mechanisms can also cause this disorder and account for the remaining percentage of causality. 

The observable features or phenotype of Prader-Willi include severe weak muscle tone or hypotonia, feeding difficulties, decreased hormone production or hypogonadism, food-seeking behaviors, atypical craniofacial features, and short stature. Other features typically observable in early childhood include delayed motor and language development and marked obesity (Nussbaum et al., 2015). The table from Cassidy et al., 2011 includes the diagnostic criteria for Prader-Willi syndrome.

Beckwith-Wiedemann syndrome (BWS) is also a disorder caused by an imprinting error. The error occurs on chromosome 11 and is an imbalance in the 1-5 region of the long arm. This error involves two noncoding RNAs, KCNQOT1 and H19, and two genes that encode proteins, CDKN1C and IGF2. The two involved genes promote (IGF2) and constrain (CDKN1C) growth (Nussbaum et al., 2015). Prenatal and postnatal overgrowth are phenotypic features of this syndrome.

Typically, KCNQOT1 (noncoding RNA) and IGF2 (encoding for a protein involved with growth) is imprinted and expressed from only the paternal allele of the gene. H19 (noncoding RNA) and CDKN1C (protein-encoding gene which constrains growth) are imprinted and expressed only from the maternal allele. However, in most cases of Beckwith-Wiedemann syndrome, the expression of the maternal version of CDKN1C is lost due to an imprinting error (Nussbaum et al., 2015). Returning to our cooking example, this recipe loses a specific type of pepper. A smaller number of Beckwith-Wiedemann syndrome cases (10-20%) are due to “loss of maternal CDKN1C expression and increased IGF2 expression is caused by paternal isodisomy of 11p15” (Nussbaum et al., 2015). Unlike maternal disomy, where two gene copies are maternal, in paternal isodisomy, there are two copies of the same exact homologues derived from the male line. In typical chromosomes, the homologues are similar but not identical. The figure below from Medline plus genetics depicts uniparental disomy (Beckwith-Wiedemann Syndrome: Medlineplus genetics). “Rare microdeletions in KCNQOT1 or H19 that disrupt imprinting have also been found in BWS” (Nussbaum et al., 2015). 

The observable features or phenotype of Beckwith-Wiedemann syndrome include enlarged tongue or macroglossia, abdominal wall defects or omphalocele, neonatal hypoglycemia or low blood sugar, and cardiomyopathy, which is a disease that makes the heart muscle larger and thicker. The syndrome is characterized by both pre and postnatal overgrowth. In addition, the placentas are significant, and 50% of those with BWS “are premature and large for gestational age at birth” (Nussbaum et al., 2015).

Imprinting explains the phenotypes of BWS and PWS. The genes and noncoding RNAs connected to BWS are involved in growth, and BWS is characterized by overgrowth. Research is ongoing to understand the genes implicated in PWs. However, recent studies of individuals with deletions of the SNORD 116 gene cluster of chromosome 15 have demonstrated that the absence of this paternally derived cluster”plays a major role in the PWS phenotype” (Cassidy et al., 2011). Individuals with this gene cluster deletion also display “neonatal hypotonia, infantile feeding problems, rapid weight gain by 2 years of age, hyperphagia, hypogonadism, developmental delay/intellectual disability, and speech and behavioral problems.” (Cassidy et al., 2011)

References

Butler, M. G., Miller, J. L., & Forster, J. L. (2019). Prader-Willi Syndrome - Clinical Genetics, Diagnosis and Treatment Approaches: An Update. Current pediatric reviews, 15(4), 207–244. https://doi.org/10.2174/1573396315666190716120925

Cassidy, S. B., Schwartz, S., Miller, J. L., & Driscoll, D. J. (2011, September 26). Prader-willi syndrome. Genetics in Medicine. Retrieved September 1, 2022, from https://www.nature.com/articles/gim0b013e31822bead0#citeas

Nussbaum, R. L., McInnes, R. R., & Willard, H. F. (2015). Thompson & Thompson Genetics in medicine. Elsevier.

U.S. National Library of Medicine. (n.d.). Beckwith-Wiedemann Syndrome: Medlineplus genetics. MedlinePlus. Retrieved September 1, 2022, from https://medlineplus.gov/genetics/condition/beckwith-wiedemann-syndrome/#references

U.S. National Library of Medicine. (n.d.). Prader-willi syndrome: Medlineplus genetics. MedlinePlus. Retrieved September 1, 2022, from https://medlineplus.gov/genetics/condition/prader-willi-syndrome/#references