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GATA2 deficiency French/Belgian cohort
Genotype/phenotype correlation: leukemia was more frequently observed in patients with missense mutations Among the 53 probands, 45 different mutated alleles were identified (Online Supplementary Table S1). Mutations were mainly located in exons 4 and 5 (Figure 5). Four patients (8% of the cohort) had a complete heterozygous GATA2 locus deletion. Five mutations were recurrent in unrelated families (R362X, R361H, A372T, R396W, R398Q). Some residues tended to be mutated: T354 (P or R),R361(GorH),R362(PorX),R396(WorQ),R398(W or Q) (Figure 5). We identified 19 different missense muta- tions in 24 probands and 14 relatives (46%), 7 nonsense mutations in 10 probands and 4 relatives (17%), and 11 small deletions or insertions leading to predicted stop codons (21%). There were 2 splice defects (4%), one in frame duplication (2%) and one intronic variant (2%) located in the regulatory element of intron 4, (Figure 5 and Online Supplementary Table S1). The germline status of the GATA2 mutations was confirmed in 30 probands. The other 23 mutations were highly suspected to be germline as the variant allele frequency was close to 50%. Parental segregation was analyzed in 27 pedigrees. In 6 probands, the GATA2 mutation occurred de novo (P1, P9, P33, P35,
P47 and P52).
There was no significant difference in median age at
diagnosis between probands and relatives. If we consider 2 groups of mutations based on the type of mutation (mis- sense vs. nonsense/frameshift), no genotype/phenotype correlation could be highlighted regarding infection, warts, MDS, neoplasia or inflammatory complications. By contrast, there was a significant risk of developing leukemia in the group of patients with the missense muta- tions (14 of 38) versus the group with nonsense or frameshift mutations (2 of 28; P=0.007, Fisher’s exact test) (Table 2).
Discussion
This large cohort with germline GATA2 mutation has the longest follow up (2249 patients/year) of any study. The homogeneous and exhaustive available clinical and biological data allow key clinical points regarding the dis- ease to be described: the majority of patients (>90%) will present with a life-threatening hematologic and/or infec- tious manifestation by the age of 40. Within the first decade, disease presentation is limited to common bacte- rial infections or lymphoedema. During the second decade, patients may present with infections and/or inflammatory disease and/or hematologic transformation. Monocytopenia was frequent even without any other detectable hematologic disease.
Our study also confirmed that hematologic complica- tions are the major issue of the GATA2 deficiency: the probability of developing MDS and/or AML rapidly increased from 39% at the age of 20 to 80% at the age of
Table 2. Genotype/phenotype associations. The missense mutation group was associated with a significant risk of leukemia (*P=0.007, Fisher's exact test). MDS: myelodysplasia.
Patient pedigree
Missense mutations (n=38)
Leukemia MDS Warts Fungus Mycobacteria
14 27 11 8 6
Frameshift+ 2 20 15 3 8 nonsense
mutations
(n=28)
P 0.007* 0.793 0.081 0.331 0.237
Figure 5. Schematic organiza- tion of the GATA2 locus and protein. The protein is com- posed of 480 amino acids (top) encoded by 1443 nucleotides (bottom). The 5 coding exons (E2 to E6) are separated by blue lines. Forty- one mutations are shown: whole locus deletion including the del3q21 are in orange, nonsense mutation in the top of the schematic protein is in red, missense mutations are in green, small deletion in the bottom of the scheme is in brown, intronic mutation and splice defects are in blue, at the bottom, and mutation of the enhancer is in dark blue. Recurrence of mutations is specified in brackets.
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