IKZF5 RNAseq samples for platelets, neutrophils, monocytes and CD4+ T-cells.
To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.
- DAC: EGAC00001000259
- Technology: Illumina HiSeq 4000
- US DUO:0000026 (version: 2019-01-07)user specific restrictionThis data use modifier indicates that use is limited to use by approved users.
- PS DUO:0000027 (version: 2019-01-07)project specific restrictionThis data use modifier indicates that use is limited to use within an approved project.
- IS DUO:0000028 (version: 2019-01-07)institution specific restrictionThis data use modifier indicates that use is limited to use within an approved institution.
- RTN DUO:0000029 (version: 2019-01-07)return to database or resourceThis data use modifier indicates that the requestor must return derived/enriched data to the database/resource.
- GRU DUO:0000042 (version: 2019-01-07)general research useThis data use permission indicates that use is allowed for general research use for any research purpose.
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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.
| Study ID | Study Title | Study Type |
|---|---|---|
| EGAS00001003736 | Other |