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Measure Intolerance to Mutation in Children with a Pediatric Condition

Zhu, K., MS, CHOP Haag, S. M., PhD, CHOP Feldman, N. A., MS, CHOP Pakstis, J., MS, CHOP Olsen, A. R., MS, CHOP Helbig, I., MD, CHOP

Poster # 69

Background: The emergence of big genomics platforms such as AWS HealthOmics has revolutionized the field of human genetics. Advances in massively parallel computing make it possible to examine the landscape of intolerant genetic variants at a genome-wide scale. Petrovski et al in 2013 hypothesized that the variation in intolerance among genes causes different classes of genetic disease. With that principle in mind, we collected whole exome sequencing data from 1217 children who were diagnosed with neurodevelopmental disorders at CHOP. We then studied the intolerance to functional variants and the functional impact of individual mutations in children with or without a disease condition. Methods: DNA from 1217 children was captured using the Agilent SureSelect Clinical Research Exome and sequenced on Illumina HiSeq 2500. Exomes were harmonized to the build Hg38 reference genome and recalibrated to remove sequencing artifacts before haplotyping for short germline variant discovery. Variant quality score calibration was applied to eliminate false positives introduced by the bias of PCR amplification. Variant consequences were annotated using the Ensembl Variant Effect Predictor. Results: 182 pathogenic or likely pathogenic variants spanning the 13 most implicated genes common in this cohort were found in 469 Epilepsy cases (38.81%). 67 of those variants were seen in 274 Hearing Loss cases (24.45%), and 11 of those variants were seen in 60 Inflammatory Bowel Disease cases (18.33%). 1 STXBP1 high impact rare splice donor variant (c.663+1G>C) was only found in 3 Epilepsy cases. 13 SCN1A moderate impact missense variants were seen in 25 Epilepsy cases. Conclusion: Pathogenic variations were higher in children with Epilepsy than with the other two disease conditions. This suggests that genes that are intolerant to genetic variation in the human population are more likely to cause genetic disorders in children.

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