GATA2 deficiency phenotype associated with tandem duplication GATA2 and over-expression of GATA2-AS1.

Abstract

A 3-year old girl of non-consanguineous healthy parents presented with cervical and mediastinal lymphadenopathy due to Mycobacterium fortuitum infection. Routine blood analysis showed normal hemoglobin, neutrophils and platelets but profound mononuclear cell deficiency (monocytes <0.1x109/L; B cells 78/µL; NK cells 48/µL). A 548,902bp region containing GATA2 was sequenced by targeted capture and deep sequencing. This revealed a de novo 187Kb duplication of the entire GATA2 locus, containing a maternally inherited copy number variation deletion of 25Kb (GRCh37: esv2725896 and nsv513733). Many GATA2-associated phenotypes have been attributed to amino acid substitution, frameshift/deletion, loss of intronic enhancer function or aberrant splicing. Gene deletion has been described but other structural variation has not been reported in the germline configuration. In this case, duplication of the GATA2 locus was paradoxically associated with skewed, diminished expression of GATA2 mRNA and loss of GATA2 protein. Chimeric RNA fusion transcripts were not detected. A possible mechanism involves increased transcription of the anti-sense long-non-coding (lnc)RNA GATA2-AS1 (RP11-472.220) which was increased several-fold. This case further highlights that evaluation of the allele count is essential in any case of suspected GATA2-related syndrome.