Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011-August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34-0.48, I2 = 44%) and WES (0.36, 95% CI 0.33-0.40, I2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08-0.12, I2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I2 = 13% and I2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I2 = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62-2.56, I2 = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38-0.45, I2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27-0.31, I2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I2 = 22% and I2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17-0.40, I2 = 54%) and WES (0.17, 95% CI 0.12-0.24, I2 = 76%) were higher than CMA (0.06, 95% CI 0.05-0.07, I2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases

Napyradiomycin derivatives, produced by a marine-derived actinomycete, illustrate cytotoxicity by induction of apoptosis.

The microbial production, isolation, and structure elucidation of four new napyradiomycin congeners (1-4) is reported. The structures of these compounds, which are new additions to the marine-derived meroterpenoids, were defined by comprehensive spectroscopic analysis and by X-ray crystallography. Using fluorescence-activated cell sorting (FACS) analysis, napyradiomycins 1-4 were observed to induce apoptosis in the colon adenocarcinoma cell line HCT-116, indicating the possibility of a specific biochemical target for this class of cytotoxins

Napyradiomycin Derivatives, Produced by a Marine-Derived Actinomycete, Illustrate Cytotoxicity by Induction of Apoptosis

The microbial production, isolation, and structure elucidation of four new napyradiomycin congeners (<b>1</b>–<b>4</b>) is reported. The structures of these compounds, which are new additions to the marine-derived meroterpenoids, were defined by comprehensive spectroscopic analysis and by X-ray crystallography. Using fluorescence-activated cell sorting (FACS) analysis, napyradiomycins <b>1</b>–<b>4</b> were observed to induce apoptosis in the colon adenocarcinoma cell line HCT-116, indicating the possibility of a specific biochemical target for this class of cytotoxins

Biallelic loss of GNAS in a patient with pediatric medulloblastoma.

Genome sequencing was performed on matched normal and tumor tissue from a 6.5-yr-old boy with a diagnosis of recurrent medulloblastoma. A pathogenic heterozygous c.432+1G&gt;A canonical splice donor site variant in GNAS was detected on analysis of blood DNA. Analysis of tumor DNA showed the same splice variant along with copy-neutral loss of heterozygosity on Chromosome 20 encompassing GNAS, consistent with predicted biallelic loss of GNAS in the tumor specimen. This case strengthens the evidence implicating GNAS as a tumor-suppressor gene in medulloblastoma and highlights a scenario in which therapeutics targeting the cAMP pathway may be of great utility

Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome

ABSTRACT Background Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross‐complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS. Methods A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole‐exome sequencing, was screened for causal variants with whole‐genome sequencing (WGS). Results WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV‐irradiation. Conclusion The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing