The aims of this systematic review are to refine the catalogue of somatic variants in splenic marginal zone lymphoma (SMZL) and to provide a well-annotated, manually curated database of high-confidence somatic mutations to facilitate variant interpretation for further biological studies and future clinical implementation. Two independent reviewers systematically searched PubMed and Ovid in January 2019 and included studies that sequenced SMZL cases with confirmed diagnosis. The database included fourteen studies, comprising 2817 variants in over 1000 genes from 475 cases. We confirmed the high prevalence of NOTCH2, KLF2 and TP53 mutations and analysis of targeted genes further implicated TNFAIP3 , KMT2D , and TRAF3 as recurrent targets of somatic mutation based on their high incidence across studies. The major limitations we encountered were the low number of patients with whole-genome, unbiased analysis and the relative sensitivities of differing sequencing approaches. Overall, we showed that there is little concordance between whole exome sequencing studies of SMZL. We strongly support the continuing unbiased analysis of the SMZL genome for mutations in all protein-coding genes and provide a valuable database resource to facilitate this endeavour that will ultimately improve our understanding of SMZL pathobiology.
Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma comprising less than 2% of lymphoid neoplasms. Approximately 70% of patients have a progressive disease requiring treatment and up to 30% of patients relapse or transform to diffuse large B-cell lymphoma. Whilst research over the last decade has transformed our understanding of many B-cell tumours, it is only beginning to shed light on the molecular pathogenesis of SMZL. Expansive immunogenetic investigations have shown biases in the immunoglobulin gene repertoire with distinct patterns of somatic hypermutation, suggesting a pathogenic role for antigen selection. In parallel cytogenetic studies have found a number of recurrent chromosomal lesions, in particular a deletion of the long arm of chromosome 7, though causative genes have not been identified. Our understanding of the mutational landscape of SMZL is built on a limited number of index cases, but has highlighted recurrent mutations in KLF2, NOTCH2 and TP53, and a spectrum of genes that cluster within biological pathways of importance in B-cell differentiation. While preliminary DNA methylation profiling has shown epigenetically distinct patient sub-groups, including a group defined by elevated expression of polycomb repressor complex 2 components. This review will provide an overview of our current understanding of the molecular basis of SMZL, and how this information impacts patient outcomes. Furthermore, we will outline; (1) the knowledge gaps that still exist; (2) a potential future research direction; and (3) how a detailed molecular understanding of the disease will ultimately provide
Purpose: Identifying pathogenic non-coding variants in individuals with developmental disorders (DD) is challenging due to the large search space. It is common to find a single protein-altering variant in a recessive gene in DD patients, but the prevalence of pathogenic non-coding second hits in trans with these is unknown. Methods: In 4,073 genetically undiagnosed rare disease trio probands from the 100,000 Genomes project, we identified rare heterozygous loss-of-function (LoF) or ClinVar pathogenic variants in recessive DD-associated genes. Using stringent region-specific filtering, we identified rare non-coding variants on the other haplotype. Identified genes were clinically evaluated for phenotypic fit, and where possible, we performed functional testing using RNA-sequencing. Results: We found 2,430 probands with one or more rare heterozygous pLoF or ClinVar pathogenic variants in recessive DD-associated genes, for a total of 3,761 proband-variant pairs. For 1,366 (36.3%) of these pairs, we identified at least one rare non-coding variant in trans. After stringent bioinformatic filtering and clinical review, five were determined to be a good clinical fit (in ALMS1, NPHP3, LAMA2, IGHMBP2 and GAA). Conclusion: We developed a pipeline to systematically identify and annotate compound heterozygous coding/non-coding genotypes. Using this approach we uncovered new diagnoses and conclude that this mechanism is a rare cause of DDs.
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