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Due to their rarity, heterogeneity and overlapping clinical and hematologic phenotypes, the diagnosis of rare types of anemia including inherited bone marrow failure syndromes is not straight forward, although this challenge has been helped by high-throughput technologies such as whole exome sequencing (WES) in recent years. In this study, we used WES to identify the cause of congenital severe anemia in the affected member/members of four unrelated Iranian families (families I-IV) (Figure 1) with an inconclusive diagnosis. The affected members were suspected to have red blood cell (RBC) disorders, including bone marrow failure syndromes, based on their clinical and hematologic information (Online Supplementary Table S1, Figure 2). All probands were dependent on RBC or platelet transfusion on a regular or irregular basis and had unaffected parents with no family history of severe anemia in previous generations. WES was performed in the probands and tertiary analysis was focused on 281 genes related to RBC disorders and bone marrow failure syndromes (Online Supplementary File). The pathogenicity of the candidate variants was predicted using the American College of Medical Genetics (ACMG) guidelines. Sanger sequencing was used to confirm the WES data and family studies (Online Supplementary Figures S1-S5). Five variants in RPL5, RUNX1, RPS26, ADA2 and CDAN1 genes, associated with different types of inherited bone marrow failure syndromes were identified, three of which were new (Table 1, Figure 1). The first proband (P-I) was a 6-year old boy with a congenital thumb abnormality (Figure 2A) and severe anemia. After presenting with a low hemoglobin concentration (<8.5 g/dL) and later frequent bruising and nose bleeding associated with severe thrombocytopenia in the first year of his life, he started to receive initially RBC and later platelet transfusions at irregular intervals (every 15 days to 2 months). Fanconi anemia was ruled out by chromosomal breakage analysis. Hypocellular marrow (Figure 2B), with 60-65% cellularity and usual composition of hematopoietic elements, was reported in his bone marrow examination. After performing WES, we identified a known mutation in a ribosomal protein (RP)-encoding gene RPL5, together with a new variant in the RUNX1 gene, both in a heterozygous state. These variants were absent in the proband’s unaffected family members, including his parents and siblings, suggesting that they were de novo variants (Table 1, Figure 1). Thumb abnormality has been reported in 38% of cases of Diamond Blackfan anemia (DBA), including those with RPL5 mutations. The RPL5 variant observed here has been previously reported in a de novo or sporadic status, with a range of other physical abnormalities, including myelomeningocele, cleft palate, facial dysmorphism, flat thenar eminence, grouped carpal bones, short stature and partial anomalous pulmonary venous return. Mutations in RUNX1 are associated with familial platelet disorder with a predisposition to myelodysplasia and/or acute myeloid leukemia. RUNX1-

Novel variants in Iranian individuals suspected to have inherited red blood cell disorders, including bone marrow failure syndromes