ena-DATASET-UCAM-GEL-25-06-2019-12:24:20:685-102 - samples

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.EGA dataset EGAD00001005107