Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disabilityReportar como inadecuado

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Orphanet Journal of Rare Diseases

, 11:62

Clinical genetics and genomics


BackgroundMutations 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.

ResultsUsing whole genome sequencing, we detected a complex unbalanced karyotype disrupting TCF4 46,XY,del14q23.3q23.3del18q21.2q21.2del18q21.2q21.2inv18q21.2q21.2t14;18q23.3;q21.214pter®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.

ConclusionsAlthough 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.

KeywordsIntellectual disability Promoter utilization Pitt-Hopkins syndrome TCF4 Gene expression Translocation Transcriptome RNAseq AbbreviationsAD1transcription activation domain 1

AD2transcription activation domain 2

bHLHbasic helix-loop-helix

bpbase pairs

CCDC68coiled-coil domain containing 68

CDPredConserved Domain-based Prediction

CNScentral nervous system

DYNAPdynactin associated protein

FPKMfragments per kilobase of exon per million fragments mapped

HASH1achaete-scute family bHLH transcription factor 1

IDintellectual disability


Math1atonal bHLH transcription factor 1


neuroD2neuronal differentiation 2

NLSnuclear localization signal

Olig2oligodendrocyte lineage transcription factor 2

PLEKHG3pleckstrin homology domain containing, family G

PolyPhen2Polymorphism Phenotyping v2

PTHSPitt-Hopkins syndrome

RAB27BRAB27B, member RAS oncogene family

RefSeqNCBI Reference Sequence Database

RNASeqRNA sequencing

SNVsingle nucleotide variant

TCF4transcription factor 4

Electronic supplementary materialThe online version of this article doi:10.1186-s13023-016-0439-6 contains supplementary material, which is available to authorized users.

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Autor: Valerie Maduro - Barbara N. Pusey - Praveen F. Cherukuri - Paul Atkins - Christèle du Souich - Rosemarie Rupps - Marjolai


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