Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by a distinct set of physical, cognitive, and behavioral features. The genetic abnormality in patients with PWS leads to infantile hypotonia, poor suck reflex with feeding difficulties, hypogonadism and hypogenitalism, growth hormone deficiencies, short stature, hyperphagia with early childhood obesity, mental deficiency, and behavioral problems.1

Causes of Prader-Willi Syndrome

Prader-Willi syndrome is caused by errors in genomic imprinting that involve the long arm of chromosome 15, resulting in the loss of expression of paternally derived genes. The imprinted genes are present on the maternal chromosome 15 but are inactivated.2 The most common event leading to PWS (about 60% of cases) is de novo paternal deletions in the chromosome 15q11-q13 region. Approximately 35% of PWS cases are due to maternal uniparental disomy of chromosome 15, also known as maternal disomy 15. In 5% of patients with PWS, an imprinting center defect is observed, such as a microdeletion or epimutation, as well as other chromosome 15q abnormalities, such as translocations and inversions.1,2

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Patients with PWS presenting with maternal disomy 15, having isodisomy or segmental isodisomy forms, are known to be at risk for the development of secondary genetic conditions that involve recessive genes on chromosome 15 if the mother is a recessive gene carrier. Many recessive genes that are present on chromosome 15 cause health-related issues such as hearing loss or seizures. In addition, female PWS patients with maternal disomy 15 are at risk of developing X-linked genetic conditions.2

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Research points to a correlation between advanced maternal age and trisomic 15 fertilized eggs (zygotes). This occurs due to errors in maternal meiosis and trisomy rescue in early pregnancy.2 Trisomy rescue is one of the mechanisms underlying maternal disomy 15 and PWS. Trisomy rescue causes a reduction of the chromosome count from 47 to 46 in the presence of two chromosome 15s deriving from the mother only, with a loss of the paternal chromosome 15 in subsequent cells in the developing fetus.2 

Previous studies reported a significantly higher maternal age in PWS patients with maternal disomy 15 than in patients with deletions. Additionally, a significantly higher relative frequency of maternal disomy 15 was observed in patients born to mothers over 35 years of age. However, the mechanism leading to maternal disomy 15 in these studies remains unclear.3

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Previous studies suggest that the paternal 15q11-q13 deletion seen in PWS may result from environmental factors, as there is an increased risk for paternal chromosomal deletions due to environmental reasons, such as occupational exposure, drug use, and infections.1,4 

An elevated number of children with PWS whose fathers had known exposure to hydrocarbons has been previously noted, and data suggest that hydrocarbon exposure among these individuals may have a causal relationship with the development of the disease.2 Hydrocarbons are known to induce chromosomal defects in cultures of human cells; highly industrialized and environmentally unregulated areas may therefore represent potential areas with a higher incidence of the disease.2

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Research suggests a correlation between assisted reproductive technology (ART) and imprinting genetic disorders, including Beckwith-Weidemann syndrome (BWS) and PWS.2 Epidemiological studies have reported that the number of pregnancies conceived by ART was higher in patients with diseases such as BWS and PWS than that observed in the general population.5 However, there is still a lack of information as to whether the confounding effect of parental age at childbirth contributed to these numbers.5

A different study was unable to establish an association between ART and PWS but reported a significantly increased proportion of maternal disomy 15 and imprinting defects in the ART-conceived PWS study population. Long-term studies are needed to allow for proper counseling in ART. 6

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  1. Butler MG, Kimonis V, Dykens E, et al. Birth seasonality studies in a large Prader-Willi syndrome cohort. Am J Med Genet A. 2019;179(8):1531-1534. doi:10.1002/ajmg.a.61263
  2. Butler MG, Miller JL, Forster JL. Prader-Willi syndrome – clinical genetics, diagnosis and treatment approaches: an update. Curr Pediatr Rev. 2019;15(4):207-244. doi:10.2174/1573396315666190716120925
  3. Matsubara K, Murakami N, Nagai T, Ogata T. Maternal age effect on the development of Prader-Willi syndrome resulting from upd(15)mat through meiosis 1 errors. J Hum Genet. 2011;56(8):566-571. doi:10.1038/jhg.2011.59
  4. Liu S, Zhang K, Song F, et al. Uniparental disomy of chromosome 15 in two cases by chromosome microarray: a lesson worth thinking. Cytogenet Genome Res. 2017;152(1):1-8. doi:10.1159/000477520
  5. Hara-Isono K, Matsubara K, Mikami M, et al. Assisted reproductive technology represents a possible risk factor for development of epimutation-mediated imprinting disorders for mothers aged ≥ 30 years. Clin Epigenetics. 2020;12(1):111. doi:10.1186/s13148-020-00900-x
  6. Gold JA, Ruth C, Osann K, et al. Frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology. Genet Med. 2014;16(2):164-169. doi:10.1038/gim.2013.97

Reviewed by Kyle Habet, MD, on 7/31/2023.