Genotype concordance and polygenic risk score estimation across consumer genetic testing data.

The consumer genomics industry is steadily growing and delivering genetic information to over 10 million individuals. Yet, the implications of using data from different services remain unclear. We investigated the genotyped sites, concordance, and genetic risk estimation using data from three consumer services-two single nucleotide polymorphism (SNP)-array based and one sequencing based. In an N-of-one setting, we found the three services genotyped predominantly distinct sets of sites. While there was a high concordance between overlapping sites of the two SNP-array services (99.6%), there was a lower concordance between these services and a low-pass whole-genome service (73.0%). The discrepancy between the three sets of data resulted in different APOE genotypes and genetic risk scores of Alzheimer's disease. Our results demonstrate genotype results across consumer genomics platforms may lead to different genetic risk estimates, highlighting the need for careful quality control and interpretation.

Database of evidence for precision oncology portal.

Summary: A database of curated genomic variants with clinically supported drug therapies and other oncological annotations is described. The accompanying web portal provides a search engine with two modes: one that allows users to query gene, cancer type, variant type or position for druggable mutations, and another to search for and to visualize, on three-dimensional protein structures, putative druggable sites that cluster with known druggable mutations. Availability and implementation: http://dinglab.wustl.edu/depo.

Quantitative lung morphology: semi-automated measurement of mean linear intercept.

BACKGROUND: Quantifying morphologic changes is critical to our understanding of the pathophysiology of the lung. Mean linear intercept (MLI) measures are important in the assessment of clinically relevant pathology, such as emphysema. However, qualitative measures are prone to error and bias, while quantitative methods such as mean linear intercept (MLI) are manually time consuming. Furthermore, a fully automated, reliable method of assessment is nontrivial and resource-intensive. METHODS: We propose a semi-automated method to quantify MLI that does not require specialized computer knowledge and uses a free, open-source image-processor (Fiji). We tested the method with a computer-generated, idealized dataset, derived an MLI usage guide, and successfully applied this method to a murine model of particulate matter (PM) exposure. Fields of randomly placed, uniform-radius circles were analyzed. Optimal numbers of chords to assess based on MLI were found via receiver-operator-characteristic (ROC)-area under the curve (AUC) analysis. Intraclass correlation coefficient (ICC) measured reliability. RESULTS: We demonstrate high accuracy (AUCROC > 0.8 for MLIactual > 63.83 pixels) and excellent reliability (ICC = 0.9998, p < 0.0001). We provide a guide to optimize the number of chords to sample based on MLI. Processing time was 0.03 s/image. We showed elevated MLI in PM-exposed mice compared to PBS-exposed controls. We have also provided the macros that were used and have made an ImageJ plugin available free for academic research use at https://med.nyu.edu/nolanlab. CONCLUSIONS: Our semi-automated method is reliable, equally fast as fully automated methods, and uses free, open-source software. Additionally, we quantified the optimal number of chords that should be measured per lung field.

Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data.

High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.

Hair Loss in Lichen Planopilaris and Frontal Fibrosing Alopecia: Not Always Irreversible.

INTRODUCTION: We present 2 cases in which typically irreversible lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) showed signs of reversal. CASE PRESENTATION: A 27-year-old Caucasian man presented with hair loss and intense pruritus on the vertex scalp for 4 years with biopsy-proven LPP and having failed multiple pharmacologic modalities. Six months after adding oral tofacitinib and later dapsone, he demonstrated reduced scalp visibility, evidence of crown and vertex hair regrowth, and elimination of itch. A 45-year-old premenopausal Hispanic woman presented with eyebrow loss for 3.75 years and hair loss for 9 months with biopsy-proven FFA. After beginning oral finasteride and hydroxychloroquine, triamcinolone injections, and topical minoxidil, she initially worsened over 11 months but subsequently improved over 6 months, demonstrating hair and eyebrow regrowth, reduction in glabella-hairline distance, and new absence of frontal hair line hyperkeratosis and inflammation. DISCUSSION/CONCLUSION: Cicatricial alopecia involves inflammation with JAK-STAT upregulation. We report a positive clinical response in LPP to tofacitinib, a JAK1/3 inhibitor, and dapsone, an anti-neutrophilic agent. FFA is believed to involve autoimmune and/or hormonal processes. Here we report a positive clinical response to androgenic and immune modulators.

Genomic Stability in Syndromic Basal Cell Carcinoma.

Basal cell cancers (BCCs) are characterized by upregulation of Hedgehog pathway through loss of PTCH1 or activation of SMO, and SMO inhibitors, such as vismodegib, are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with basal cell nevus syndrome (BCNS) harbor germline defects in PTCH1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to SMO inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of UV mutagenesis, increased genomic stability, and harbor fewer functionally resistant SMO mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to SMO inhibitors. BCNS-BCCs appear to have reduced mutator phenotype compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.

Resting state functional connectivity magnetic resonance imaging integrated with intraoperative neuronavigation for functional mapping after aborted awake craniotomy.

BACKGROUND: Awake craniotomy is currently the gold standard for aggressive tumor resections in eloquent cortex. However, a significant subset of patients is unable to tolerate this procedure, particularly the very young or old or those with psychiatric comorbidities, cardiopulmonary comorbidities, or obesity, among other conditions. In these cases, typical alternative procedures include biopsy alone or subtotal resection, both of which are associated with diminished surgical outcomes. CASE DESCRIPTION: Here, we report the successful use of a preoperatively obtained resting state functional connectivity magnetic resonance imaging (MRI) integrated with intraoperative neuronavigation software in order to perform functional cortical mapping in the setting of an aborted awake craniotomy due to loss of airway. CONCLUSION: Resting state functional connectivity MRI integrated with intraoperative neuronavigation software can provide an alternative option for functional cortical mapping in the setting of an aborted awake craniotomy.

Protein-structure-guided discovery of functional mutations across 19 cancer types.

Local concentrations of mutations are well known in human cancers. However, their three-dimensional spatial relationships in the encoded protein have yet to be systematically explored. We developed a computational tool, HotSpot3D, to identify such spatial hotspots (clusters) and to interpret the potential function of variants within them. We applied HotSpot3D to >4,400 TCGA tumors across 19 cancer types, discovering >6,000 intra- and intermolecular clusters, some of which showed tumor and/or tissue specificity. In addition, we identified 369 rare mutations in genes including TP53, PTEN, VHL, EGFR, and FBXW7 and 99 medium-recurrence mutations in genes such as RUNX1, MTOR, CA3, PI3, and PTPN11, all mapping within clusters having potential functional implications. As a proof of concept, we validated our predictions in EGFR using high-throughput phosphorylation data and cell-line-based experimental evaluation. Finally, mutation-drug cluster and network analysis predicted over 800 promising candidates for druggable mutations, raising new possibilities for designing personalized treatments for patients carrying specific mutations.

Patterns and functional implications of rare germline variants across 12 cancer types.

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.