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.

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Keywords Atypical Prader-Willi Syndrome, Blended phenotype, Dual genetic diagnosis, Mosaicism, PTHS
Persistent URL dx.doi.org/10.1002/ajmg.a.38315, hdl.handle.net/1765/100691
Journal American Journal of Medical Genetics. Part A
Jehee, F.S, de Oliveira, V.T. (Valdirene T.), Gurgel-Giannetti, J. (Juliana), Pietra, R.X. (Rafaella X.), Rubatino, F.V.M. (Fernando), Carobin, N.V. (Natália V.), … Carvalho, C.M.B. (Cláudia M. B.). (2017). Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins. American Journal of Medical Genetics. Part A. doi:10.1002/ajmg.a.38315