Xp11.23

ERYF1,GF1,NFE1

Myeloid proliferation associated with Down syndrome, including transient abnormal myelopoiesis associated with Down Syndrome and myeloid leukemia associated with Down syndrome

Acquired somatic mutations resulting in the exclusive production of the short-form GATA1 protein (GATA1s) are pathognomonic in myeloid proliferation associated with Down syndrome (MP-DS) (Ahmed M et al, 2004; Groet J et al, 2003; Rainis L et al, 2003; Wechsler J et al, 2002). These mutations are often in the forms of nonsense or frame-shift mutations that result in premature stop codons in exon 2 or 3, while sparing the alternative start codon further downstream in the exon 3. GATA1 mutations can be detected in umbilical cord blood of DS patients and in fetal liver of aborted DS embryos; therefore, these mutations are thought to occur in-utero, likely during fetal liver hematopoiesis (Ahmed M et al, 2004; Taub JW et al, 2004). The presence of GATA1s in the absence of full length GATA1 is thought to block megakaryocytic differentiation and promote the proliferation of megakaryoblasts (Vyas P et al, 1999; Li Z et al, 2005; Lee WY et al, 2018). This disease entity only occurs in DS patients; however, the genes on chromosome 21 that enables the development of this disease are not known. MP-DS mostly occurs in children with DS younger than 5 years of age and manifests initially as transient abnormal myelopoiesis (TAM) within 7 days of birth. TAM is characterized by increased circulating megakaryocytic blasts, thrombocytopenia, and leukocytosis. The majority of cases of TAM undergo clonal extinction and spontaneously remit. However, about a third of the cases eventually recur within 3 years as myeloid leukemia associated with Down syndrome (ML-DS), which phenotypically resembles acute megakaryocytic leukemia and requires therapy. Next generation sequencing studies comparing the genomic landscape of TAM and ML-DS have established the GATA1 mutations as the first-hit mutations that presents phenotypically as TAM, and the subsequent gain of additional hits leads to the progression as ML-DS (Nikolaev SI et al, 2013; Yoshida K et al, 2013).

Diamond-Blackfan anemia (DBA) is a congenital condition characterized by isolated erythroid hypoplasia. Approximately half of the DBA cases are associated with germline mutations that result in haploinsufficiency of ribosomal proteins. A smaller subset of DBA cases, all of which are X-linked, is associated with germline GATA1 mutations, including substitution or splice site mutations involving exon 2 or 3 (Ludwig LS et al, 2014; Parrella S et al, 2014; Klar J et al, 2014; Sankaran VG, 2012). These mutations, similar to those seen in MP-DS (see above), create missense or nonsense mutations at the first start codon or premature stop codons before the second alternative start codon, thereby precluding the production of the full length GATA1 and leading to the exclusive production of the short form of GATA1 (GATA1s). Interestingly, several studies have suggested that in DBA with ribosomal protein haploinsufficiency exhibits altered translation of GATA1 mRNA, providing a possible converging mechanism of DBA (Ludwig LS et al, 2014; Khajuria RK et al, 2018).

Dyserythropoietic anemia

Dyserythropoietic anemia (DA), is a rare congenital red blood cell disorder characterized by anemia with erythrodysplasia (often abnormal forms with multinucleated nuclei) and varying degrees of macrothrombocytopenia with dysplastic megakaryocytes. There are several isolated case reports describing the roles of GATA1 mutations in a subset of DA, which often presents as severe fetal anemia requiring intrauterine transfusion (Zucker J et al , 2016; Abdulhay NJ et al, 2019; Kratz CP et al, 2008; Freson K et al, 2002; Nichols KE et al, 2000; Del Vecchio GC et al, 2005). Based on the limited case reports, there appears to be two different classes of GATA1 mutations that can cause DA. The first class of mutations (such as, V205M, G208R, and D218Y/G) appears to affect interaction with FOG-1 (Friends of GATA1), a transcriptional co-factor required for normal erythroid and megakaryocytic differentiation. The second class of mutations appears to affect the splicing of GATA1 transcripts that result in the preferential production of the short form of GATA1 protein, in a similar manner seen in DBA (see above). Mutations altering the pattern of splicing were described to involve the 5 untranslated region and in the fifth intron. Of note, these cases are distinctly different from congenital dyserythropoietic anemia type I, II, and III. Some have proposed to include the GATA1 mutated DA cases as congenital dyserythropoietic anemia variants.