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

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.

SUBMITTER: Jehee FS

PROVIDER: S-EPMC5561000 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Jehee Fernanda S FS de Oliveira Valdirene T VT Gurgel-Giannetti Juliana J Pietra Rafaella X RX Rubatino Fernando V M FVM Carobin Natália V NV Vianna Gabrielle S GS de Freitas Mariana L ML Fernandes Karla S KS Ribeiro Beatriz S V BSV Brüggenwirth Hennie T HT Ali-Amin Roza R White Janson J JJ Akdemir Zeynep C ZC Jhangiani Shalini N SN Gibbs Richard A RA Lupski James R JR Varela Monica C MC Koiffmann Célia C Rosenberg Carla C Carvalho Cláudia M B CMB

American journal of medical genetics. Part A 20170620 9

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 ...[more]

PMID: 28631899

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Project description:Prader-Willi syndrome (PWS) is a complex imprinting disorder related to genomic errors that inactivate paternally-inherited genes on chromosome 15q11-q13 with severe implications on endocrine, cognitive and neurologic systems, metabolism, and behavior. The absence of expression of one or more genes at the PWS critical region contributes to different phenotypes. There are three molecular mechanisms of occurrence: paternal deletion of the 15q11-q13 region; maternal uniparental disomy 15; or imprinting defects. Although there is a clinical diagnostic consensus criteria, DNA methylation status must be confirmed through genetic testing. The endocrine system can be the most affected in PWS, and growth hormone replacement therapy provides improvement in growth, body composition, and behavioral and physical attributes. A key feature of the syndrome is the hypothalamic dysfunction that may be the basis of several endocrine symptoms. Clinical and molecular complexity in PWS enhances the importance of genetic diagnosis in therapeutic definition and genetic counseling. So far, no single gene mutation has been described to contribute to this genetic disorder or related to any exclusive symptoms. Here we proposed to review individually disrupted genes within the PWS critical region and their reported clinical phenotypes related to the syndrome. While genes such as MKRN3, MAGEL2, NDN, or SNORD115 do not address the full spectrum of PWS symptoms and are less likely to have causal implications in PWS major clinical signs, SNORD116 has emerged as a critical, and possibly, a determinant candidate in PWS, in the recent years. Besides that, the understanding of the biology of the PWS SNORD genes is fairly low at the present. These non-coding RNAs exhibit all the hallmarks of RNA methylation guides and can be incorporated into ribonucleoprotein complexes with possible hypothalamic and endocrine functions. Also, DNA conservation between SNORD sequences across placental mammals strongly suggests that they have a functional role as RNA entities on an evolutionary basis. The broad clinical spectrum observed in PWS and the absence of a clear genotype-phenotype specific correlation imply that the numerous genes involved in the syndrome have an additive deleterious effect on different phenotypes when deficiently expressed.

Dataset Information

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

Publications

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

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