Analytic validation of NeXT Dx™, a comprehensive genomic profiling assay.

We describe the analytic validation of NeXT Dx, a comprehensive genomic profiling assay to aid therapy and clinical trial selection for patients diagnosed with solid tumor cancers. Proprietary methods were utilized to perform whole exome and whole transcriptome sequencing for detection of single nucleotide variants (SNVs), insertions/deletions (indels), copy number alterations (CNAs), and gene fusions, and determination of tumor mutation burden and microsatellite instability. Variant calling is enhanced by sequencing a patient-specific normal sample from, for example, a blood specimen. This provides highly accurate somatic variant calls as well as the incidental reporting of pathogenic and likely pathogenic germline alterations. Fusion detection via RNA sequencing provides more extensive and accurate fusion calling compared to DNA-based tests. NeXT Dx features the proprietary Accuracy and Content Enhanced technology, developed to optimize sequencing and provide more uniform coverage across the exome. The exome was validated at a median sequencing depth of >500x. While variants from 401 cancer-associated genes are currently reported from the assay, the exome/transcriptome assay is broadly validated to enable reporting of additional variants as they become clinically relevant. NeXT Dx demonstrated analytic sensitivities as follows: SNVs (99.4%), indels (98.2%), CNAs (98.0%), and fusions (95.8%). The overall analytic specificity was >99.0%.

Traumatic Bone Cyst of the Anterior Mandibular Region: A Case Report.

A traumatic bone cyst (TBC) is an unusual non-neoplastic pseudocystic cavity in the bone that is often asymptomatic and slow-growing. It is unexpectedly detected by regular radiography imaging. These lesions are more common in the mandible than they are in the maxilla, and they are often seen in patients older than 40 years of age. A radiolucent unilocular lesion with scalloped margins is the most common radiographic appearance. If the hollow is found to contain blood or straw-colored fluid, surgical exploration is the only way to make a conclusive diagnosis of this uncommon condition. We present a case of an asymptomatic, incidentally diagnosed (on radiograph) traumatic bone cyst in a young patient involving the mandibular anterior region with periapical radiolucency. The case was diagnosed by radiographs and histopathological evaluation.

Paternally inherited cis-regulatory structural variants are associated with autism.

The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.