Partial trisomy of the short arm of chromosome 6 is a rare and clinically distinct syndrome. The breakpoints have been found to be variable ranging from bands 6p11 to 6p25. This study reports partial trisomy for 6p22.3→pter in a 2-year-old boy referred with a complaint of developmental delay and facial dysmorphism. Conventional cytogenetic analysis showed the presence of an abnormal chromosome 5 resulting from an unbalanced translocation in the proband. Array comparative genomic hybridization revealed trisomy of distal 6p which was confirmed by fluorescence in situ hybridization using subtelomeric probes for chromosomes 5 and 6. A comparison of the phenotypic features in similar cases of trisomy for different segments of 6p will facilitate an accurate karyotype-phenotype correlation and, subsequently, in the identification of the candidate genes through molecular characterization of the potential genes mapped to these loci.
The genetic analysis of monogenic disorders has over the past 3 decades resulted in the identification of thousands of genes which either cause or impact these conditions; most of these disorders have no therapies. The modulation of the transcripts and proteins encoded by these genes might be anticipated to have therapeutic utility, either by their upregulation (e.g. of mutated recessive disease genes encoding proteins with residual enzymatic activity, of genes that are sequentially similar to, and that functionally recapitulate, mutated recessive disease genes or of genes that cause disease when haploinsufficient) or downregulation (e.g. of mutated dominant genes which confer a gain of pathologic function or of genes which, when present in increased number, cause disease). Moreover, it is known that small molecules including clinically approved drugs can affect the human transcriptome. Given the number of genes that cause or effect inherited human conditions and the substantial subset of the transcriptome that is impacted by drugs, we believe that there are likely genes which are both modifiers of rare disease and responsive to pharmacologic modulation. The enhanced CARE for RARE project in Canada is therefore exploring whether previously unknown off-target effects of clinically approved drugs may lead to new therapies. We have screened ∼ 80 rare conditions, (haploinsufficient, rescuing paralogous genes and hypomorphic mutation with residual function) using this approach. There are currently 5 conditions which show some induction (GLUT1, SMAD3, DDHD2, NEU1, HPRT) ; the most promising results and lessons learned from this approach shall be presented.
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