Clinical utility of the low-density Infinium QC genotyping Array in a genomics-based diagnostics laboratory

• Main Authors: Petr Ponomarenko (Author), Alex Ryutov (Author), Dennis T. Maglinte (Author), Ancha Baranova (Author), Tatiana V. Tatarinova (Author), Xiaowu Gai (Author)
• Format: Book
• Published: BMC, 2017-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1186/s12920-017-0297-7; 1755-8794
• Keywords: Quality control; Infinium QC Array-24; Ethnicity; Sample identity; Kinship; Clinical exome sequencing; Internal medicine; RC31-1245; Genetics; QH426-470
• Source: BMC Medical Genomics, Vol 10, Iss 1, Pp 1-11 (2017)

Abstract Background With 15,949 markers, the low-density Infinium QC Array-24 BeadChip enables linkage analysis, HLA haplotyping, fingerprinting, ethnicity determination, mitochondrial genome variations, blood groups and pharmacogenomics. It represents an attractive independent QC option for NGS-based diagnostic laboratories, and provides cost-efficient means for determining gender, ethnic ancestry, and sample kinships, that are important for data interpretation of NGS-based genetic tests. Methods We evaluated accuracy and reproducibility of Infinium QC genotyping calls by comparing them with genotyping data of the same samples from other genotyping platforms, whole genome/exome sequencing. Accuracy and robustness of determining gender, provenance, and kinships were assessed. Results Concordance of genotype calls between Infinium QC and other platforms was above 99%. Here we show that the chip's ancestry informative markers are sufficient for ethnicity determination at continental and sometimes subcontinental levels, with assignment accuracy varying with the coverage for a particular region and ethnic groups. Mean accuracies of provenance prediction at a regional level were varied from 81% for Asia, to 89% for Americas, 86% for Africa, 97% for Oceania, 98% for Europe, and 100% for India. Mean accuracy of ethnicity assignment predictions was 63%. Pairwise concordances of AFR samples with the samples from any other super populations were the lowest (0.39-0.43), while the concordances within the same population were relatively high (0.55-0.61). For all populations except African, cross-population comparisons were similar in their concordance ranges to the range of within-population concordances (0.54-0.57). Gender determination was correct in all tested cases. Conclusions Our results indicate that the Infinium QC Array-24 chip is suitable for cost-efficient, independent QC assaying in the settings of an NGS-based molecular diagnostic laboratory; hence, we recommend its integration into the standard laboratory workflow. Low-density chips can provide sample-specific measures for variant call accuracy, prevent sample mix-ups, validate self-reported ethnicities, and detect consanguineous cases. Integration of low-density chips into QC procedures aids proper interpretation of candidate sequence variants. To enhance utility of this low-density chip, we recommend expansion of ADME and mitochondrial markers. Inexpensive Infinium-like low-density human chips have a potential to become a "Swiss army knife" among genotyping assays suitable for many applications requiring high-throughput assays.