Defects in alpha thalassemia/mental retardation syndrome X-linked (ATRX), a gene that encodes a protein involved in chromatin remodeling. ATRX mutation is a marker of astrocytic lineage among the IDH1-mutant gliomas and is mutually exclusive with 1p/19q codeletion. ATRX mutations are most frequently in grade II (67%) and grade III (73%) astrocytomas and secondary glioblastoma multiforme (GBM) (75%), whereas they are uncommon in primary GBMs and oligodendrogliomas. Nearly all diffuse gliomas with IDH and ATRX mutations also harbor TP53 mutation and are associated with the alternative lengthening of telomeres (ALT) phenotype. ATRX mutation also occurs in many other types of human tumors, such as neuroendocrine tumors. Immunohistochemistry for ATRX demonstrates a loss of protein expression in neoplastic cells that harbor inactivating mutations, whereas expression is retained in nonneoplastic cells within the sample, such as endothelial cells.