Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins

Am J Med Genet A. 2017 Sep;173(9):2451-2455. doi: 10.1002/ajmg.a.38315. Epub 2017 Jun 20.


We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

Keywords: PTHS; atypical Prader-Willi Syndrome; blended phenotype; dual genetic diagnosis; mosaicism.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Base Sequence / genetics
  • Child
  • Chromosome Deletion
  • Chromosomes, Human, Pair 15 / genetics
  • Comparative Genomic Hybridization
  • Exome / genetics
  • Facies
  • Female
  • Humans
  • Hyperventilation / diagnosis
  • Hyperventilation / genetics*
  • Hyperventilation / physiopathology
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Obesity / diagnosis
  • Obesity / genetics
  • Obesity / physiopathology
  • Pathology, Molecular*
  • Phenotype
  • Prader-Willi Syndrome / diagnosis
  • Prader-Willi Syndrome / genetics*
  • Prader-Willi Syndrome / physiopathology
  • Transcription Factor 4 / genetics*
  • Twins, Monozygotic


  • TCF4 protein, human
  • Transcription Factor 4

Supplementary concepts

  • Pitt-Hopkins syndrome