Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are usually sporadic diseases, however, rare familial cases have helped to identify human disease genes and provide crucial insight into hematopoiesis. Multiple predisposition genes have been identified, including RUNX1, CEBPA, GATA2, ETV6 and DDX41. 1 These syndromes are characterized by autosomal dominant inheritance and heterozygous germline mutations. Latency periods preceding the onset of MDS or other hematologic malignancies are widely variable, and appearance of the malignant phenotype is thought to require additional somatic mutations. In addition to improving diagnosis and treatment of hematologic malignancies, identification of disease-predisposing mutations has broadened our understanding of the role of these genes in normal hematopoiesis. Nevertheless, a large portion of familial MDS/AML cases remain unexplained. One potentially distinct form is MDS/AML with erythroid hyperplasia (OMIM 133180). Patients typically present in the erythroleukemic phase with multilineage dysplasia and complex cytogenetics; the prognosis is poor, with an overall survival of 3-9 months. 2 There are at least five families reported in the literature, all with an autosomal dominant mode of inheritance and an unexplained genetic basis. We investigated one of these families, first reported in 1982 and again in 1987. 3, 4

The proband was diagnosed with evolving erythroleukemia following a bone marrow biopsy that revealed a hypercellular marrow with multilineage dysplasia, marked erythroid hyperplasia, excess blasts and complex cytogenetics (Supplementary Figure S1A). An updated pedigree was established (Figure 1a), exhibiting an inheritance pattern consistent with autosomal dominance with a variable latency period (age range: 27-73 years, median 54). Family members and published reports confirmed that all affected individuals in this family were diagnosed with erythroleukemia or erythroid MDS. Further, multiple affected family members displayed normal hematopoiesis during evaluations before disease onset, indicating that overt hematologic abnormalities were absent during the latency period (Supplementary Table S1). An initial screen of 12 known predisposition genes failed to detect a pathogenic variant in the proband. 5 This, along with the consistent erythroid phenotype suggested that the germline variant predisposing to disease in this family was distinct from those currently known. Whole-exome sequencing of the proband identified a potential pathologic c. 4009G> A; p. A1337T variant in the erb-b2 receptor tyrosine kinase 3 (ERBB3) gene (see Supplementary Methods). This variant is not found in the Exome Variant Server (NHLBI Exome Sequencing Project (EVS) 6) or the Catalogue Of Somatic Mutations In Cancer (COSMIC). 7 The Exome Aggregation Consortium (ExAC) identifies the p. A1337T variant in 7/119 654 alleles, indicating it is rare. 8 Further analysis revealed the presence of the variant in another affected individual (II-03) and in a female who died at the age of 47 of metastatic breast cancer with bone marrow infiltration (IV-03). She inherited the variant from affected individual III-12. One currently unaffected family member, age 63, is heterozygous for the p. A1337T variant (III-14). In total, our analysis confirmed the presence of the ERBB3 p. A1337T variant in two affected individuals and identified two affected individuals as obligate carriers, as well as one asymptomatic carrier. In addition, it confirmed the absence of the variant in eight unaffected individuals (Figure 1a;