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Summary: In myelodysplastic syndromes (MDS), the 20q deletion [del(20q)] may cause deletion of the ASXL1 gene. We studied 153 patients with MDS and del(20q) to assess the incidence, prognostic value and impact on response to azacitidine (AZA) of ASXL1 chromosomal alterations and genetic mutations. Additionally, in vitro assay of the response to AZA in HAP1 (HAP1WT) and HAP1 ASXL1 knockout (HAP1KN) cells was performed. ASXL1 chromosomal alterations were detected in 44 patients (28·5%): 34 patients (22%) with a gene deletion (ASXL1DEL) and 10 patients (6·5%) with additional gene copies. ASXL1DEL was associated with a lower platelet count. The most frequently mutated genes were U2AF1 (16%), ASXL1 (14%), SF3B1 (11%), TP53 (7%) and SRSF2 (6%). ASXL1 alteration due to chromosomal deletion or genetic mutation (ASXL1DEL/ASXL1MUT) was linked by multivariable analysis with shorter overall survival [hazard ratio, (HR) 1·84; 95% confidence interval, (CI): 1·11–3·04; P = 0·018] and a higher rate for acute myeloid leukaemia progression (HR 2·47; 95% CI: 1·07–5·70, P = 0·034). ASXL1DEL/ASXL1MUT patients were correlated by univariable analysis with a worse response to AZA. HAP1KN cells showed more resistance to AZA compared to HAP1WT cells. In conclusion, ASXL1 alteration exerts a negative impact on MDS with del(20q) and could become useful for prognostic risk stratification and treatment decisions. [ABSTRACT FROM AUTHOR]

The article presents the study conducted by Vera Adema et al. which is published in the "British Journal of Haematology'. It mentions that the researchers studied the mutational status of TP53 and SETBP1 in 27 myelodysplastic syndromes (MDS) patients of the Spanish MDS group. It highlights that five and eleven of 27 patients had point mutations of the genes TP53 and SETBP1 respectively. It states that correlation was observed between the mutation groups and karyotype classification.

The article reports on research which was conducted to investigate gene mutations involved in DNA methylation in patients with acute myeloid leukemia (AML) and myeldysplastic syndrome (MDS). Researchers evaluated two patients with AML and one with MDS. They found that myeloid leukemias with genetic mutations do not have an associated fusion gene and that patients with this type of disease and mutation also have mutations in their epigenetic modifiers.

Lenalidomide is an effective drug in low-risk myelodysplastic syndromes ( MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics ( CC), single nucleotide polymorphism array ( SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 109/l) were associated with the achievement of haematological response ( P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response ( P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 109/l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide. [ABSTRACT FROM AUTHOR]

Mutations in the ANO3 gene have been associated with autosomal dominant craniocervical dystonia. However, little else is known about the genotype-phenotype characteristics of this disorder. Here we describe a 3 years-old girl with distal myoclonic dystonia. Whole exome sequencing in trio revealed a de novo missense ANO3 variant not previously described in international databases. A global psychomotor regression was observed once dystonia was present. Brain MRI changes paralleled these findings: whereas MRI at the age of 18 months was normal, mild brain and cerebellar atrophy was observed 18 months later. These results suggest that missense mutations in ANO3 may underlie complex disorders particularly characterized by early psychomotor regression and dystonia. [ABSTRACT FROM AUTHOR]