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Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability

Overview of attention for article published in Orphanet Journal of Rare Diseases, May 2016
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  • Above-average Attention Score compared to outputs of the same age (58th percentile)
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Citations

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19 Dimensions

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Title
Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability
Published in
Orphanet Journal of Rare Diseases, May 2016
DOI 10.1186/s13023-016-0439-6
Pubmed ID
Authors

Valerie Maduro, Barbara N. Pusey, Praveen F. Cherukuri, Paul Atkins, Christèle du Souich, Rosemarie Rupps, Marjolaine Limbos, David R. Adams, Samarth S. Bhatt, Patrice Eydoux, Amanda E. Links, Anna Lehman, May C. Malicdan, Christopher E. Mason, Marie Morimoto, James C. Mullikin, Andrew Sear, Clara Van Karnebeek, Pawel Stankiewicz, William A. Gahl, Camilo Toro, Cornelius F. Boerkoel

Abstract

Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. To address the relationship between mutation of these transcripts and phenotype, we report a three-generation family segregating mild intellectual disability with a chromosomal translocation disrupting TCF4. Using whole genome sequencing, we detected a complex unbalanced karyotype disrupting TCF4 (46,XY,del(14)(q23.3q23.3)del(18)(q21.2q21.2)del(18)(q21.2q21.2)inv(18)(q21.2q21.2)t(14;18)(q23.3;q21.2)(14pter®14q23.3::18q21.2®18q21.2::18q21.1®18qter;18pter®18q21.2::14q23.3®14qter). Subsequent transcriptome sequencing, qRT-PCR and nCounter analyses revealed that cultured skin fibroblasts and peripheral blood had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Although the derivative chromosome generated a PLEKHG3-TCF4 fusion transcript, the increased levels of TCF4 mRNA arose from transcript variants originating distal to the translocation breakpoint, not from the fusion transcript. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS are partially rescued by overexpression of those short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain.

Twitter Demographics

The data shown below were collected from the profiles of 4 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 35 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 35 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 20%
Student > Bachelor 6 17%
Student > Master 6 17%
Professor > Associate Professor 3 9%
Professor 3 9%
Other 3 9%
Unknown 7 20%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 9 26%
Neuroscience 4 11%
Agricultural and Biological Sciences 4 11%
Medicine and Dentistry 4 11%
Psychology 2 6%
Other 2 6%
Unknown 10 29%

Attention Score in Context

This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 May 2016.
All research outputs
#7,542,491
of 14,102,693 outputs
Outputs from Orphanet Journal of Rare Diseases
#805
of 1,547 outputs
Outputs of similar age
#108,288
of 264,256 outputs
Outputs of similar age from Orphanet Journal of Rare Diseases
#22
of 38 outputs
Altmetric has tracked 14,102,693 research outputs across all sources so far. This one is in the 46th percentile – i.e., 46% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,547 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.2. This one is in the 47th percentile – i.e., 47% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 264,256 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 58% of its contemporaries.
We're also able to compare this research output to 38 others from the same source and published within six weeks on either side of this one. This one is in the 36th percentile – i.e., 36% of its contemporaries scored the same or lower than it.