Commentary

Genomic sequencing is the broadest and most consequential clinical diagnostic innovation of the past decade. It is now routine to decode the genome or exome (comprising all protein coding exons) and rule in or out hundreds of genetic diseases in diseases of unknown etiology. Compared with proband singleton testing, parent–child trio testing—as here—enables determination of chromosome phase in suspected compound heterozygosity and facile detection of de novo variants, the leading mechanism of genetic disease in North America. Whole exome sequencing (WES)—as here—has attained broader use than whole genome sequencing (WGS) because of lower cost. However, WGS has superior technical performance than WES, largely because it does not include the biasing steps of enrichment by oligonucleotide hybridization or PCR (1). Both methods achieve accuracy by sequencing to high redundancy—typically 40-fold for WGS and at least 80-fold for WES. Statistically, one-half of autosomal sequencing reads should be derived each from the maternal and paternal chromosomes. Despite stochastic variability in the proportion of reads derived from each chromosome at each locus, deep sequencing can identify deviations in variant read frequency that denote copy number variation and loss of autosomal heterozygosity. In the current case, 8 unlinked variants were found incidentally with reduced read frequencies (about 20%) in the proband but were absent in parental WES, suggesting clonal somatic mutations. This case illustrates the need for multidisciplinary team-based interpretation of genomic sequencing tests with contributions both from molecular laboratory directors and physicians. In the absence of chart review that disclosed leukopenia, these putative incidental findings may not have met the threshold for reporting. True-positive somatic mutations are difficult to detect by WES because read depth varies widely and variants affect oligonucleotide hybridization. A genomic method to verify somatic variant occurrence is to compare allelic proportion in embryologically unrelated tissues. Herein, following reporting, targeted next-generation sequencing of bone marrow revealed about 50% variant read frequency, confirmed clonal somatic mutation, and diagnosed clonal cytopenia with high risk of myeloid malignancy. At present, most clinical WGS and WES are performed by regional reference laboratories. This case illustrates that patients are best served when genome interpretation is a continuum with the practice of medicine.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

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