Clinical Validation of Genome Reference Consortium Human Build 38 in a Laboratory Utilizing Next-Generation Sequencing Technologies.

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DOI: 10.1093/clinchem/hvac113


BACKGROUND: Laboratories utilizing next-generation sequencing align sequence data to a standardized human reference genome (HRG). Several updated versions, or builds, have been released since the original HRG in 2001, including the Genome Reference Consortium Human Build 38 (GRCh38) in 2013. However, most clinical laboratories still use GRCh37, which was released in 2009. We report our laboratory's clinical validation of GRCh38.

METHODS: Migration to GRCh38 was validated by comparing the coordinates (lifting over) of 9443 internally curated variants from GRCh37 to GRCh38, globally comparing protein coding sequence variants aligned with GRCh37 vs GRCh38 from 917 exomes, assessing genes with known discrepancies, comparing coverage differences, and establishing the analytic sensitivity and specificity of variant detection using Genome in a Bottle data.

RESULTS: Eight discrepancies, due to strand swap or reference base, were observed. Three clinically relevant variants had the GRCh37 alternate allele as the reference allele in GRCh38. A comparison of 88 295 calls between builds identified 8 disease-associated genes with sequence differences: ABO, BNC2, KIZ, NEFL, NR2E3, PTPRQ, SHANK2, and SRD5A2. Discrepancies in coding regions in GRCh37 were resolved in GRCh38.

CONCLUSIONS: There were a small number of clinically significant changes between the 2 genome builds. GRCh38 provided improved detection of nucleotide changes due to the resolution of discrepancies present in GRCh37. Implementation of GRCh38 results in more accurate and consistent reporting.

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Clinical chemistry





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MeSH Keywords

3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Alleles; Cell Cycle Proteins; Exome; Genome, Human; High-Throughput Nucleotide Sequencing; Humans; Laboratories; Membrane Proteins; Receptor-Like Protein Tyrosine Phosphatases, Class 3


GRCh38; clinical laboratory genetics; human reference genome; next-generation sequencing

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