GATA2 at 10: Emergence of Genotype-Phenotye correlations

GATA2 mutations cause adult-onset bone-marrow failure characterized by cytopenias, infections and increased risk of leukemia. We reviewed hospital records and referrals from 232 GATA2 mutation positive individuals from 122 families to gather hematopoietic and syndromic features. Mutations were categorized by effect on GATA2 protein: missense after the 2nd Zinc-finger (C-term, n = 10); missense in the 2nd Zinc-Finger (2nd Zf, n = 104); mutations producing stable truncated protein (truncation, n = 26); null alleles (mRNA instability, large deletions, n = 42); or enhancer (n = 50). Median age at first symptom presentation for the cohort was 20 years. Kaplan-Meier analysis for symptom onset showed differences in age at presentation across truncation and null mutations (median 15 and 18 years, respectively), 2nd Zf (22 years) and enhancer mutations (45 years). A similar analysis of four recurrently mutated 2nd ZF amino acids revealed later symptom onset for R361 and R398 mutations (median 22 and 34 years, respectively) compared to R396 or T354 (16 and 19 years, respectively). Mixed-effect Cox regression analysis corrected for relatedness across patients and confirmed these findings. There was decreased penetrance in enhancer (27/50, 54% symptomatic) and 2nd Zf (85/104, 81.7%) compared to truncation (24/26, 92.3%) and null (39/40, 97.5%) mutation patients. Grouping mutations by median onset before (null, truncation, R396, T354) or after (R361, R398, enhancer) age 20 revealed significantly increased incidence of cytopenias, HPV, myelodysplastic syndrome and hearing loss among the early onset mutation group. Additionally, age of cytopenia or myelodysplasia syndrome diagnosis was significantly younger in the early onset group (P = 0.0019, P = 0.0012 respectively). Males had more monosomy 7 (11/92 males, 4/142 females, P < 0.0001). Nontuberculous mycobacterial infection was the presenting symptom in 14/92 males vs 7/142 females (P = 0.0188). Warts/anogenital HPV were common (93/234, 39.7%). Non-hematologic manifestations included hearing loss (46/232; 19.8%), lymphedema (30/232; 12.8%), and non-hematologic malignancies (46/232, 19.8%), the majority being HPV-related ano-genital cancers. Hematologic malignancy occurred in 26/234 patients (11%). This comprehensive analysis demonstrates that GATA2 mutation type, and specific mutations, affect penetrance and expression. Gender is an independent risk for specific infectious complications and cytogenetic abnormalities.