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Genotype-phenotype correlations
Short report
Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study
  1. Merlin G Butler1,
  2. Samantha N Hartin1,
  3. Waheeda A Hossain1,
  4. Ann M Manzardo1,
  5. Virginia Kimonis2,
  6. Elisabeth Dykens3,
  7. June Anne Gold4,
  8. Soo-Jeong Kim5,
  9. Nicolette Weisensel6,
  10. Roy Tamura7,
  11. Jennifer L Miller8,
  12. Daniel J Driscoll8
  1. 1 Departments of Psychiatry, Behavior Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, Kansas, USA
  2. 2 Department of Pediatrics, University of California-Irvine, Irvine, California, USA
  3. 3 Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee, USA
  4. 4 Department of Pediatrics, Loma-Linda University, Loma-Linda, California, USA
  5. 5 Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, Washington, USA
  6. 6 College of Arts, Sciences and Letters, Marian University, Fond du Lac, Wisconsin, USA
  7. 7 Health Informatics Institute, University of South Florida, Tampa, Florida, USA
  8. 8 Department of Pediatrics, University of Florida School of Medicine, Gainesville, Florida, USA
  1. Correspondence to Professor Merlin G Butler, Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA; mbutler4{at}kumc.edu

Abstract

Background Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects.

Methods High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age.

Results We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200).

Conclusions We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.

  • Prader-Willi syndrome
  • molecular genetic classification
  • pws deletion subtypes
  • PWS maternal disomy subclasses
  • maternal age effects

https://doi.org/10.1136/jmedgenet-2018-105301

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    Footnotes

    • Contributors MGB planned the study design, recruited individuals, collected natural histories and biological samples and served as the primary author of the manuscript. SNH performed genetic analysis of individuals, compiled data from the different sites and contributed to the manuscript. WAH performed genetic analysis of individuals and compiled data from the different sites. AMM and RT performed statistical analyses and contributed to the manuscript. VK recruited individuals, collected natural histories and biological samples and served as an author of the manuscript. ED and DJD planned the study design, recruited individuals, collected natural histories and biological samples and served as an author of the manuscript. JAG and JLM compiled data and contributed to the manuscript. SJK performed genetic analysis of individuals and compiled data. NW recruited individuals, collected natural histories and biological samples and contributed to the manuscript.

    • Funding This study was funded by the Prader-Willi Syndrome Association (USA) and the National Center for Advancing Translational Sciences grant number (U54 HD06122).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval University of Kansas Medical Center Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.