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Background: Alterations of FLT3 are among the most common driver events in acute leukaemia with important clinical implications, since it allows patient classification into prognostic groups and the possibility of personalising therapy thanks to the availability of FLT3 inhibitors. Most of the knowledge on FLT3 implications comes from the study of acute myeloid leukaemia and so far, few studies have been performed in other leukaemias. Methods: A comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed. Mutations were functionally characterised by in vitro experiments. Results: Point mutations (PM) and internal tandem duplications (ITD) were detected in 4.3% and 2.7% of the patients, respectively. A new activating mutation of the TKD, G846D, conferred oncogenic properties and sorafenib resistance. Moreover, a novel alteration involving the circularisation of read-through transcripts (rt-circRNAs) was observed in 10% of the cases. Patients presenting FLT3 alterations exhibited higher levels of the receptor. In addition, patients with ZNF384- and MLL/KMT2A-rearranged ALL, as well as hyperdiploid subtype, overexpressed FLT3. Discussion: Our results suggest that specific ALL subgroups may also benefit from a deeper understanding of the biology of FLT3 alterations and their clinical implications. [ABSTRACT FROM AUTHOR]

Intellectual disability affects about 3% of individuals globally, with∼50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copy-number variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis. [ABSTRACT FROM AUTHOR]

Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism. [ABSTRACT FROM AUTHOR]

Two distinct phenotypes of triploid fetuses have been previously described and a correlation with parental origin of the triploidy has been suggested. We have studied the parental origin of the extra haploid set of chromosomes in nine triploid fetuses using analysis of DNA polymorphisms at a variety of loci. Maternal origin of the triploidy (digyny) was demonstrated in six fetuses with type II phenotype, paternal origin (diandry) in two cases with type I phenotype, and nonpaternity in one case. The predominance of digynic triploids in our study contrasts with the results reported in previous studies in which, through analysis of cytogenetic polymorphisms, paternal origin was found to account for the majority of triploid conceptuses. This difference may be accounted for by a combination of factors - the different methods of parental assignment used and analysis of a different subset of triploid conceptuses. The correlation between the observed phenotypes and the parental origin of triploidy may represent another example of imprinting in human development. [ABSTRACT FROM AUTHOR]

Setting: Congenital anomalies (CAs) can cause lifelong morbidity and accounted for 23.2% of infant deaths from 2003 to 2007. In British Columbia (BC), surveillance of CAs has been irregular since the early 2000s. To enhance CAs surveillance in BC, the Public Health Agency of Canada has provided funding for the implementation of the BC Congenital Anomalies Surveillance System (BCCASS)., Intervention: BCCASS is a population-based surveillance system. The system leverages existing administrative data sources that capture information regarding vital events, disease status, drug prescription, and healthcare utilization. The system uses a series of algorithms to capture specific CAs diagnoses, some of which are further validated with the support of the Provincial Advisory Committee. This Advisory Committee is a multi-stakeholder coalition that includes the BC Office of the Provincial Health Officer, subject matter experts, data partners, users, and academia, and acts to provide support, expertise, and strategic guidance to BCCASS., Outcomes: Through BCCASS, prevalence and historical trends for 35 CAs in BC are available. Information pertaining to maternal place of residence, risk, and protective factors can be used for association studies such as links to environmental hazards and cluster analysis., Implications: BCCASS is a cost-effective and sustainable system that leverages existing data sources necessary to understand the overall burden of CAs across the BC population. This is fundamental to support data-driven decisions around policy development, program planning, and evaluation of preventive measures. Strong coalitions with stakeholders are instrumental to ensure successful implementation and expansion in the future., (© 2022. The Author(s) under exclusive license to The Canadian Public Health Association.)