Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Nature Genetics
Kosuke IzumiIan D Krantz

Abstract

Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.

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Datasets Mentioned

BETA
GM03348
GM02036
GM2036

Methods Mentioned

BETA
exome sequencing
chips
ChIP-seq
RNA-seq
immunoprecipitation
transfection
in vitro transcription
PCR
Genotyping
ChIP

Software Mentioned

Ensembl
Affymetrix Command Console
UnifiedGenotyper
SnpEff tool
DROMPA
GATK
Cufflinks
Bowtie
Picard
SAM

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