Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance

Area of Science:

• Genetics
• Immunology
• Hematology

Background:

• Germline heterozygous mutations in GATA2 are linked to diverse hematological and clinical conditions.
• The specific genetic, immunological, and clinical characteristics of GATA2-deficient individuals experiencing mycobacterial diseases within families are not well understood.

Purpose of the Study:

• To investigate the genetic and clinical features of GATA2-deficient patients with mycobacterial disease.
• To describe the familial context and clinical manifestations in a cohort of GATA2 index cases.

Main Methods:

• Enrolled 15 GATA2 index cases referred for mycobacterial disease.
• Detailed genetic and clinical evaluations were performed on index cases and their relatives.

Main Results:

• Identified 12 distinct heterozygous GATA2 mutations, including two novel ones; 8 were loss-of-function, 4 hypomorphic.
• Mycobacterial infection was the initial symptom in 11 patients (mean age 22.5 years), with incomplete clinical penetrance (32.9% by age 40).
• Three relatives also had mycobacterial disease and heterozygous mutations, totaling 18 affected individuals; many experienced other infections, monocytopenia, or myelodysplasia.

Conclusions:

• Clinical penetrance for mycobacterial disease mirrors other GATA2 deficiency phenotypes, suggesting additional contributing factors.
• Autosomal dominant GATA2 deficiency should be suspected in patients with mycobacterial infections or related phenotypes at any age.
• Genetic testing of GATA2 is recommended for all direct relatives of affected individuals.