A Novel EP300 Variant in an African American Girl With Global Developmental Delay and Leukemia.

backgroundPathogenic germline missense and in-frame indel variants in exons 30 or 31 of the EP300 gene are associated with Menke-Hennekam syndrome-2 (MKHK2). The phenotypic spectrum associated with MKHK2 is variable, including neurodevelopmental, respiratory, skeletal, and immunological impairments. Based on their genetic, clinical, and DNA methylation profiles, a recent study proposed three domain-specific subtypes of MKHK: MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4. In somatic cells, EP300 variants have been reported in lymphoma, leukemia, and various solid tumors. We present an African American girl with global developmental delay, failure to thrive, microcephaly, seizure, osteopenia, and T-cell acute lymphoblastic leukemia (T-ALL).

methodWe performed karyotype, FISH, chromosomal microarray, and exome sequencing with probands bone marrow, blood, and buccal swab.

resultComprehensive genetic studies using multiple tissues detected somatic complex cytogenomic changes in blood cells and a de novo germline missense variant (NM_001429.4: c.5258G>A, p.Cys1753Tyr) in the TAZ2 domain of EP300 from her buccal swab, which is consistent with a diagnosis of MKHK2. While in our patient we observed phenotypic overlaps with affected individuals harboring variants in the TAZ2 domain, some phenotypes such as osteopenia and alopecia have not been reported previously. The hematolymphoid malignancy of our patient also raises the question of whether germline EP300 variants are associated with a genetic predisposition to cancer.

conclusionTogether, this case expands the growing body of knowledge regarding the clinical and genetic spectrum of MKHK2. This is the first MKHK individual reported in the literature in an underrepresented population of African American ancestry.