期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 29, 期 4, 页码 637-648出版社
SPRINGERNATURE
DOI: 10.1038/s41431-020-00770-0
关键词
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资金
- Dutch Research Council [Aspasia 015.014.066]
- ZonMW [846002003, 917-17-353]
- European Union [779257]
- NWO [184.034.019]
- Solve-RD project
Long-read sequencing has the potential to comprehensively identify medically relevant genome variation, including those missed by short-read sequencing. Systematic assessment of long-read sequencing coverage in individuals with intellectual disability revealed a high concordance of structural variants and single nucleotide substitutions, suggesting its added value in identifying clinically relevant genome variation.
Long-read sequencing (LRS) has the potential to comprehensively identify all medically relevant genome variation, including variation commonly missed by short-read sequencing (SRS) approaches. To determine this potential, we performed LRS around 15x-40x genome coverage using the Pacific Biosciences Sequel I System for five trios. The respective probands were diagnosed with intellectual disability (ID) whose etiology remained unresolved after SRS exomes and genomes. Systematic assessment of LRS coverage showed that similar to 35 Mb of the human reference genome was only accessible by LRS and not SRS. Genome-wide structural variant (SV) calling yielded on average 28,292 SV calls per individual, totaling 12.9 Mb of sequence. Trio-based analyses which allowed to study segregation, showed concordance for up to 95% of these SV calls across the genome, and 80% of the LRS SV calls were not identified by SRS. De novo mutation analysis did not identify any de novo SVs, confirming that these are rare events. Because of high sequence coverage, we were also able to call single nucleotide substitutions. On average, we identified 3 million substitutions per genome, with a Mendelian inheritance concordance of up to 97%. Of these, similar to 100,000 were located in the similar to 35 Mb of the genome that was only captured by LRS. Moreover, these variants affected the coding sequence of 64 genes, including 32 known Mendelian disease genes. Our data show the potential added value of LRS compared to SRS for identifying medically relevant genome variation.
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