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Short report
Mosaic de novo SNRPN gene variant associated with Prader-Willi syndrome
  1. Yue Huang1,
  2. Katheryn Grand2,
  3. Virginia Kimonis3,
  4. Merlin G Butler4,
  5. Suparna Jain5,
  6. Alden Yen-Wen Huang6,
  7. Julian A Martinez-Agosto1,7,
  8. Stanley F Nelson7,
  9. Pedro A Sanchez-Lara2
  1. 1Department of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  2. 2Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
  3. 3Department of Pediatrics, UCI and Children’s Hospital of Orange County, Irvine, California, USA
  4. 4Departments of Psychiatry and Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, Kansas, USA
  5. 5Pediatric Endocrinology, Department of Pediatrics, Cedar-Sinai Medical Center, Los Angeles, California, USA
  6. 6Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  7. 7Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  1. Correspondence to Dr Pedro A Sanchez-Lara, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Pedro.Sanchez{at}cshs.org

Abstract

Background Prader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects.

Results We report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant.

Conclusions This is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS.

  • imprinting
  • point mutation

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Footnotes

  • Contributors All authors have contributed to this study in data collection and analysis, as well as manuscript preparation.

  • Funding This project was partially supported by the UCLA California Center for Rare Diseases within the Institute of Precision Health.

  • Competing interests None declared.

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

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