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

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

Author information

1
Instituto de Ensino e Pesquisa Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil.
2
Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
3
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
5
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
6
Texas Children's Hospital, Houston, Texas.
7
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
8
Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.

Abstract

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

PMID:
28631899
PMCID:
PMC5561000
DOI:
10.1002/ajmg.a.38315
[Indexed for MEDLINE]
Free PMC Article

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