Emerging bone marrow failure syndromes- new pieces to an unsolved puzzle

Abstract

Inherited bone marrow failure (BMF) syndromes are genetically diverse - more than 100 genes have been associated with those syndromes and the list is rapidly expanding. Risk assessment and genetic counseling of patients with recently discovered BMF syndromes is inherently difficult as disease mechanisms, penetrance, genotype-phenotype associations, phenotypic heterogeneity, risk of hematologic malignancies and clonal markers of disease progression are unknown or unclear. This review aims to shed light on recently described BMF syndromes with sparse concise data and with an emphasis on those associated with germline variants in ADH5/ALDH2, DNAJC21, ERCC6L2 and MECOM. This will provide important data that may help to individualize and improve care for these patients.

Keywords: ADH5; ALDH2; DNAJC21; ERCC6L2; MECOM; bone marrow failure; early onset myeloid malignancies.

Figure 1

Schematic of the ERCC6L2 transcript (NM_020207.7) and its protein domains with the location of all reported germline variants. Circles represent females and squares represent males. Symbols on the same horizontal level are individuals from the same family. Letters within the symbols indicate individuals with compound heterozygous genotype, while symbols without letters indicate homozygosity for the variant. The color fill depicts different phenotypes, no color fill designates healthy individuals carrying homozygous/compound heterozygous causative variants. The dotted line shows the location of the sole described copy number variant. AML, acute myeloid leukemia; BMF, bone marrow failure; HEBO, helicase mutated in bone marrow failure; MDS, myelodysplastic syndrome.

Figure 2

Schematic of the MECOM transcript (NM_004991.4) and its protein domains with the location of all reported germline variants. Checkered domains with the numbers 1 to 10 stand for zinc fingers 1 to 10. Circles represent females, squares represent males and diamonds represent unknown gender. Symbols on the same horizontal level are individuals from the same family. The color fill depicts different phenotypes, no color fill indicates healthy individuals carrying a causative variant. A dot in the middle of the symbol designates the presence of RUS in these individuals. The dotted lines show the location of the described copy number variants, the arrow denotes that the copy number variant extends in this direction. AD, acidic domain; BMF, bone marrow failure; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; PR, PRDF1-RIZ domain; RD, repression domain; RUS, radioulnar synostosis.

Figure 3

Schematic of the DNAJC21 transcript (NM_001012339.3) and its protein domains with the location of all reported germline variants. Circles represent females and squares represent males. Symbols on the same horizontal level are individuals from the same family. Letters within the symbols indicate individuals with compound heterozygous genotype, while symbols without letters indicate homozygosity for the variant. The color fill depicts different phenotypes. The dotted line shows the location of the sole described copy number variant. AML, acute myeloid leukemia; BMF, bone marrow failure; ZF, zinc finger.

Figure 4

Schematic of the ADH5 transcript (NM_000671.4) and its protein domains with the location of all reported germline variants. Circles represent females and squares represent males. Symbols on the same horizontal level are individuals from the same family. Letters within the symbols indicate individuals with compound heterozygous genotype, while symbols without letters indicate homozygosity for the variant. The color fill depicts different phenotypes. ADH, alcohol dehydrogenase; AML, acute myeloid leukemia; BMF, bone marrow failure; MDS, myelodysplastic syndrome.