Reinterpretation of Chromosomal Microarrays with Detailed Medical History.

OBJECTIVE: To investigate the utility of a detailed medical history in the interpretation of chromosomal microarray results for pediatric patients with a constitutional disease. STUDY DESIGN: A retrospective review and reinterpretation of test results from chromosomal microarrays performed from 2011 to 2013. Previously reported genetic variants were reanalyzed after review of the patient's complete electronic medical record (cEMR). A 3-tier system was used for reclassification of variants: pathogenic or likely pathogenic (P/LP); variant of uncertain significance (VUS); or benign or likely benign (B/LB). RESULTS: Over an 18-month period, 998 patients with chromosomal microarray results were identified. The most common reasons for chromosomal microarray testing were developmental delay (n = 336), autism spectrum disorder (n = 241), and seizures (n = 143). Chromosomal microarray testing identified 1 or more variants in 48% (482 of 998) of patients; 516 patients had a negative report. For the 482 patients with variants, the original interpretations were composed of 19.3% P/LP (93 of 482), 44.8% VUS (216 of 482), and 35.9% B/LB (173 of 482) variants. After review of the cEMR, 34% of patient results (164 of 482) were changed in interpretation. One case changed from B/LB to VUS, 7 VUS were upgraded to P/LP, and 156 VUS were downgraded to B/LB. No P/LP variants had a change in interpretation. CONCLUSIONS: Overall, 16.4% (164 of 998) of patients with chromosomal microarray testing had a change in interpretation. Access to the patient's cEMR improves the interpretation of chromosomal microarrays by decreasing the number of uncertain (VUS) interpretations.

Prp22 and spliceosome components regulate chromatin dynamics in germ-line polyploid cells.

During Drosophila oogenesis, the endopolyploid nuclei of germ-line nurse cells undergo a dramatic shift in morphology as oogenesis progresses; the easily-visible chromosomes are initially polytenic during the early stages of oogenesis before they transiently condense into a distinct '5-blob' configuration, with subsequent dispersal into a diffuse state. Mutations in many genes, with diverse cellular functions, can affect the ability of nurse cells to fully decondense their chromatin, resulting in a '5-blob arrest' phenotype that is maintained throughout the later stages of oogenesis. However, the mechanisms and significance of nurse-cell (NC) chromatin dispersal remain poorly understood. Here, we report that a screen for modifiers of the 5-blob phenotype in the germ line isolated the spliceosomal gene peanuts, the Drosophila Prp22. We demonstrate that reduction of spliceosomal activity through loss of peanuts promotes decondensation defects in NC nuclei during mid-oogenesis. We also show that the Prp38 spliceosomal protein accumulates in the nucleoplasm of nurse cells with impaired peanuts function, suggesting that spliceosomal recycling is impaired. Finally, we reveal that loss of additional spliceosomal proteins impairs the full decondensation of NC chromatin during later stages of oogenesis, suggesting that individual spliceosomal subcomplexes modulate expression of the distinct subset of genes that are required for correct morphology in endopolyploid nurse cells.