GATA2 at 14: genotype-phenotype correlations

Abstract

GATA2 mutations cause adult-onset bone-marrow failure characterized by cytopenias, infections and increased risk of myeloid malignancy. We reviewed hospital records and referrals of 232 GATA2 mutated individuals from 122 families to gather hematopoietic and syndromic features.

Mutations were categorized by GATA2 protein effect: mutation after the 2nd Zinc-finger (Cterm, n=10); missense in the 2nd Zinc-Finger (ZF2, n=104); mutations producing stable truncated protein (Truncation, n=22); Null alleles (mRNA instability, large deletions, n=46); or Enhancer (n=50).

Regression models for symptom onset identified earlier onset and increased hazard ratios (HR) between Truncation, Null or ZF2 mutations (13 years, HR 5.00; 17 years, 3.60; 22 years, 2.23 respectively) and Enhancer. Commonly mutated ZF2 amino acids stratified: R396 or T354 presented earlier with increased hazard ratios (16 years, HR 2.96; 19 years, HR 2.16) versus R398 (34 years). Mutation groups with median onset <20 years had higher prevalence of cytopenias, infections, HPV, thromboses and hearing loss. Warts/anogenital HPV were common (93/232, 40.1%). Non-hematologic manifestations included hearing loss (45/232; 19.4%), lymphedema (30/232; 12.8%), and non-hematologic malignancies (46/232, 19.8%), the majority being HPV-related ano-genital cancers. Leukemia or lymphoma occurred in 25/232 patients (10.8%). Functional analysis of patient mutations showed impaired transactivation. Males had more monosomy 7 (17/73 males, 6/110 females, P=0.0016). Nontuberculous mycobacterial infection was the presenting symptom in 14/73 males vs 7/110 females (P=0.0151). GATA2 mutation type, and specific mutations, affect penetrance and expression. Sex is an independent risk for specific infectious presentations and cytogenetic abnormalities.