ASXL1 As a Potential Genetic Modifier in a Family with GATA2 Deficiency
Authors: VanDerGraaf Madeline , Dillahunt Kyle , Younger Georgianne , Bayer Diana K , Halyko Michael , Magalhaes-Silverman Margarida , Tung Moon Ley 
Published: December 2024

GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disorder which is classified under inherited bone marrow failure disorders. G2DS is characterized by phenotypic variability ranging from immunodeficiency, monocytopenia and Mycobacterium avium complex (monoMac), bone marrow failure, Emberger syndrome and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It has been hypothesized that patients with germline GATA2 variants have a microenvironment that is predisposed to the selection and clonal expansion of acquired mutations such as ASXL1, CEBPA, SETBP1, and -7/7q.
We describe a family with a heterozygous germline, pathogenic variant in the intronic region of GATA2 (NM_032638.5: c.1017+572C&gt;T). The proband is a 38-year-old woman who was recently diagnosed with AML. She had a history of melanoma diagnosed and excised at age 20, which was preceded by multiple pre-melanoma lesions. She did not report a history of immunodeficiency, abnormal bleeding, or any features of relevant syndromic conditions. Family history was significant for a paternal first cousin diagnosed with AML and passed at age 21. Additional family history included colon and breast cancer on both maternal and paternal sides. Given the young age of presentation with AML, she received genetic counseling and completed germline genetic testing on cultured skin fibroblasts which revealed this intronic, pathogenic variant in the GATA2 gene. Ancillary testing for telomere length and chromosome breakage was not sent due to her leukopenia, the diagnostic finding on next generation sequencing (NGS), and absence of any syndromic features. Her bone marrow karyotype and fluorescence in situ hybridization (FISH) were normal. A NGS AML somatic panel revealed a pathogenic variant in IDH2 (c.419G&gt;A, R140Q) and NPM1 (c.860_863dupTCTG, W288fs) and a variant of uncertain significance (VUS) in ASXL1 (c.4201G&gt;A. G1401R). Interestingly, a repeat NGS AML somatic panel post treatment revealed a persistence of the ASXL1 VUS at a similar variant allele frequency (VAF) of 49.12%. Both the IDH2 and NPM1 variants were not detected on a post-treatment analysis.
As GATA2 variants are considered highly penetrant alleles with a lifetime hematological malignancy risk of greater than 80%, cascade testing was performed in her children. All three children tested positive for the same pathogenic variant in GATA2 but were asymptomatic at diagnosis.
Her oldest son had an abnormal blood count with neutropenia and mild macrocytic anemia on his initial evaluation. A baseline bone marrow exam revealed a hypocellular marrow with 10% cellularity for age, dysmegakaryopoiesis and the presence of monosomy 7. Surprisingly, his NGS AML somatic panel revealed the same ASXL1 VUS at a VAF of 50.75%. His immunological work-up revealed B and NK cell lymphopenia with reduced NK cell function. He is undergoing evaluation for bone marrow transplantation. Her second child had a normal blood count with mild thrombocytosis. Bone marrow exam revealed a hypocellular marrow of 50% cellularity for age with no dysplastic features seen. She also showed the same ASXL1 VUS on her NGS AML somatic panel at a VAF of 51.3%. She does demonstrate functional NK cell deficiency on immunological testing. Her 8-year-old daughter had a relative normal blood count with mild thrombocytosis. Her bone marrow examination was relatively normal with occasional hypolobated megakaryocytes seen. Bone marrow karyotype, FISH study, NGS AML somatic panel and immunological work-up were all unremarkable.
Given the unexpected finding of an ASXL1 VUS at 50% VAF, we hypothesize that this variant may act as a genetic modifier in this family with GATA2 deficiency. Germline variants in ASXL1 are associated with Bohring-Opitz syndrome (MIM #: 605039) which is a malformation syndrome associated with severe intrauterine growth retardation, poor feeding, profound intellectual disability, hirsutism and dysmorphic features. None of the individuals in this family had any clinical phenotype consistent with Bohring-Opitz syndrome. ASXL1 is frequently mutated in patients with GATA2 deficiency and was correlated with the development of chronic myelomonocytic leukemia and poor overall survival. We propose that variants in ASXL1 may be useful as a molecular biomarker to predict the progression to MDS/AML in patients with GATA2 deficiency syndrome.