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- Hasle, Henrik, et al.
(författare)
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Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
- 2022
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 139:21, s. 3159-3165
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.
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| 2. |
- Verweij, Niek, et al.
(författare)
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Germline Mutations in CIDEB and Protection against Liver Disease
- 2022
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 387:4, s. 332-344
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P=4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P=9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS Rare germline mutations in CIDEB conferred substantial protection from liver disease.
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