Identification of Glucose Transport Modulators In Vitro and Method for Their Deep Learning Neural Network Behavioral Evaluation in Glucose Transporter 1-Deficient Mice.

Metabolic flux augmentation via glucose transport activation may be desirable in glucose transporter 1 (Glut1) deficiency syndrome (G1D) and dementia, whereas suppression might prove useful in cancer. Using lung adenocarcinoma cells that predominantly express Glut1 relative to other glucose transporters, we screened 9,646 compounds for effects on the accumulation of an extracellularly applied fluorescent glucose analog. Five drugs currently prescribed for unrelated indications or preclinically characterized robustly enhanced intracellular fluorescence. Additionally identified were 37 novel activating and nine inhibitory compounds lacking previous biologic characterization. Because few glucose-related mechanistic or pharmacological studies were available for these compounds, we developed a method to quantify G1D mouse behavior to infer potential therapeutic value. To this end, we designed a five-track apparatus to record and evaluate spontaneous locomotion videos. We applied this to a G1D mouse model that replicates the ataxia and other manifestations cardinal to the human disorder. Because the first two drugs that we examined in this manner (baclofen and acetazolamide) exerted various impacts on several gait aspects, we used deep learning neural networks to more comprehensively assess drug effects. Using this method, 49 locomotor parameters differentiated G1D from control mice. Thus, we used parameter modifiability to quantify efficacy on gait. We tested this by measuring the effects of saline as control and glucose as G1D therapy. The results indicate that this in vivo approach can estimate preclinical suitability from the perspective of G1D locomotion. This justifies the use of this method to evaluate our drugs or other interventions and sort candidates for further investigation. SIGNIFICANCE STATEMENT: There are few or no activators and few clinical inhibitors of glucose transport. Using Glut1-rich cells exposed to a glucose analog, we identified, in highthroughput fashion, a series of novel modulators. Some were drugs used to modify unrelated processes and some represented large but little studied chemical compound families. To facilitate their preclinical efficacy characterization regardless of potential mechanism of action, we developed a gait testing platform for deep learning neural network analysis of drug impact on Glut1-deficient mouse locomotion.

A concise study of acetazolamide in glucose transporter type 1 deficiency (G1D) epilepsy.

Epilepsy constitutes the most common paroxysmal manifestation of glucose transporter type 1 deficiency (G1D) and is generally considered medication-refractory. It can also prove therapeutic diet-resistant. We examined acetazolamide effects in G1D motivated by several longstanding and recent observations: First, the electrographic spike-waves characteristic of absence seizures often resemble those of G1D and, since the 1950s, they have occasionally been treated successfully with acetazolamide, well before G1D was segregated from absence epilepsy as a distinct syndrome. Second, synaptic inhibitory neuron failure characterizes G1D and, in other experimental models, this can be ameliorated by drugs that modify cellular chloride gradient such as acetazolamide. Third, acetazolamide potently stimulates model cell glucose transport in vitro. Seventeen antiepileptic drug or therapeutic diet-refractory individuals with G1D treated with acetazolamide were thus identified via medical record review complemented by worldwide individual survey. Acetazolamide was tolerated and decreased seizures in 76% of them, with 58% of all persons studied experiencing seizure reductions by more than one-half, including those who first manifested myoclonic-astatic epilepsy or infantile spams. Eighty-eight percent of individuals with G1D continued taking acetazolamide for over 6 months, indicating sustained tolerability and efficacy. The results provide a novel avenue for the treatment and mechanistic investigation of G1D.

Challenges in Inter-rater Agreement on Lamina Propria Fibrosis in Esophageal Biopsies.

BACKGROUND: Mucosal biopsies in eosinophilic esophagitis (EoE) can exhibit lamina propria (LP) fibrosis, which may portend stenotic complications; however, the histologic diagnosis of LP fibrosis is subjective. We sought to assess and improve the consistency of LP fibrosis diagnosis among our pathologist group. METHODS: At a large pediatric hospital, 25 esophageal biopsy slides from 19 patients (16 with EoE) exhibiting a wide spectrum of LP area, artifacts, and fibrosis severity were scanned into whole-slide images. Staff pediatric pathologists (n = 8) separate from the authors classified each biopsy by LP adequacy and fibrosis severity 1 month before and after completion of an educational tutorial. Consensus was defined as >70% agreement. RESULTS: At baseline, 16/25 (64%) cases reached consensus for no fibrosis (n = 3), fibrosis (n = 7), or inadequate LP (n = 6); agreement was fair (α = 0.34). Post-tutorial, 13/25 (52%) cases reached consensus for no fibrosis (n = 2), fibrosis (n = 7), or inadequate LP (n = 4); agreement was again fair (α = 0.33). There was moderate agreement in grading of fibrosis severity (α = 0.54). CONCLUSION: We document only fair-to-moderate agreement in the diagnosis of esophageal LP fibrosis and adequacy in a large pediatric pathologist group despite targeted education, highlighting a challenge in incorporating this feature into EoE research and clinical decision-making.

Hemoglobin ß-Globin Variants In Hispanic Patients: An Institutional Experience From Dallas, Texas.

Hemoglobinopathies are the most common single-gene disorders in humans. There are 1,424 variants of human hemoglobin described with 951 involving the ß-globin gene. Ancestry and geography play a significant role in the incidence and nature of hemoglobinopathies, with African, Asian, and Mediterranean populations and their descendants being amongst the most affected. Investigation of variants in individuals of Hispanic descent is needed to reflect the changing demographics of the United States. Hemoglobin ß-globin evaluation through gel electrophoresis, high-performance liquid chromatography, and HBB gene sequencing was performed on patients from Texas hospitals between 2010 and 2015 and demographic parameters (age, sex, ethnicity) was subsequently analyzed. A total of 846 patients underwent hemoglobinopathy evaluation. A ß chain variant was detected in 628 of the 846 total patients. Hispanic patients represented 37% (314/846 patients), which were equally distributed between females (50%; 156/314) and males (50%; 156/314). A ß-globin chain variant was found in 67% of Hispanic patients with a distribution across 10 variants seen in greater than 1% of patients. For hemoglobin variants, an understanding of the regional and ethnic prevalence will improve patient care through more effective screening and identification of the variant, early diagnosis, and appropriate treatment if necessary, and better genetic counseling.

Multiplex Fragment Analysis for Flexible Detection of All SARS-CoV-2 Variants of Concern.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge, and effective tracking requires rapid return of results. Surveillance of variants is typically performed by whole genome sequencing (WGS), which can be financially prohibitive and requires specialized equipment and bioinformatic expertise. Genotyping approaches are rapid methods for monitoring SARS-CoV-2 variants but require continuous adaptation. Fragment analysis may represent an approach for improved SARS-CoV-2 variant detection. METHODS: A multiplex fragment analysis approach (CoVarScan) was validated using PCR targeting variants by size and fluorescent color. Eight SARS-CoV-2 mutational hot spots in variants of concern (VOCs) were targeted. Three primer pairs (recurrently deleted region [RDR] 1, RDR2, and RDR3-4) flank RDRs in the S-gene. Three allele-specific primers target recurrent spike receptor binding domain mutants. Lastly, 2 primer pairs target recurrent deletions or insertions in ORF1A and ORF8. Fragments were resolved and analyzed by capillary electrophoresis (ABI 3730XL), and mutational signatures were compared to WGS results. RESULTS: We validated CoVarScan using 3544 clinical respiratory specimens. The assay exhibited 96% sensitivity and 99% specificity compared to WGS. The limit of detection for the core targets (RDR1, RDR2, and ORF1A) was 5 copies/reaction. Variants were identified in 95% of samples with cycle threshold (CT) <30 and 75% of samples with a CT 34 to 35. Assay design was frozen April 2021, but all subsequent VOCs have been detected including Delta (n = 2820), Mu, (n = 6), Lambda (n = 6), and Omicron (n = 309). Genotyping results are available in as little as 4 h. CONCLUSIONS: Multiplex fragment analysis is adaptable and rapid and has similar accuracy to WGS to classify SARS-CoV-2 variants.

Association of Pyuria with Uropathogens in Young Children.

OBJECTIVE: To examine the association between uropathogens and pyuria in children <24 months of age. STUDY DESIGN: A retrospective study of children <24 months of age evaluated in the emergency department for suspected urinary tract infection (UTI) with paired urinalysis and urine culture during a 6-year period. Bagged urine specimens or urine culture growing mixed/multiple urogenital organisms were excluded. Analysis was limited to children with positive urine culture as defined by the American Academy of Pediatrics clinical practice guideline culture thresholds. RESULTS: Of 30 462 children, 1916 had microscopic urinalysis and positive urine culture. Urine was obtained by transurethral in-and-out catheterization in 98.3% of cases. Pyuria (≥5 white blood cells per high-powered field) and positive leukocyte esterase (small or more) on the urine dipstick were present in 1690 (88.2%) and 1692 (88.3%) of the children respectively. Children with non-Escherichia coli species were less likely to exhibit microscopic pyuria than children with E coli (OR 0.24, 95% CI 0.17-0.34) with more pronounced effect on Enterococcus and Klebsiella (OR 0.08, 95% CI 0.03-0.18 and OR 0.18, 95% CI 0.11-0.27 respectively). Similarly, positive leukocyte esterase was less frequently seen in non-E coli uropathogens compared with E coli. CONCLUSIONS: Pyuria and leukocyte esterase are not sensitive markers to identify non-E coli UTI in young children. More sensitive screening biomarkers are needed to identify UTI with these uropathogens.

Chromosomal Microarray Reinterpretation: Applications to Pediatric Practice.

Chromosomal microarray analysis (CMA) frequently yields inconclusive results. We reexamined inconclusive CMA results from 33 previously tested patients and reached a definitive diagnosis in 3 (9.1%) and identified the need for additional testing in 4 (12.1%). Reinterpretation may resolve inconclusive CMA results.

Extrarenal Anaplastic Wilms Tumor: A Case Report With Genomic Analysis and Tumor Models.

Primary extrarenal Wilms tumors are rare neoplasms that are presumed to arise from metanephric or mesonephric remnants outside of the kidney. Their pathogenesis is debated but has not been studied, and there are no reports of genomic descriptions of extrarenal Wilms tumors. We describe a diffusely anaplastic extrarenal Wilms tumor that occurred in the lower abdomen and upper pelvis of a 10-year-old boy. In addition to the clinical, histopathologic, and radiologic features, we describe the cytogenetic changes and exomic profile of the tumor. The tumor showed loss of the tumor suppressor AMER1, loss of chromosome regions 1p, 16q, and 22q, gain of chromosome 8, and loss of function TP53 mutation-findings known to occur in renal Wilms tumors. This is the first description of the exomic profile of a primary extrarenal Wilms tumor. Our data indicate that primary extrarenal Wilms tumors may follow the same pathogenetic pathways that are seen in renal Wilms tumors. Finally, we describe the establishment of first ever tumor models (primary cell line and patient-derived xenograft) from an extrarenal Wilms tumor.

GAB1-ABL1 fusions in tumors that have histologic overlap with NTRK-rearranged spindle cell tumors.

Fibroblastic spindle cell tumors are a heterogeneous group of rare soft tissue tumors that are increasingly recognized as associated with a variety of kinase gene fusions. We report two cases of GAB1-ABL1 fusions in spindle cell tumors that histologically overlap with neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell tumors. The first case occurred in a 76-year-old female who had a large deep-seated spindle cell tumor composed of monotonous ovoid to spindle cells in a background of thick stromal collagen bands with prominent hyalinized vessels and inconspicuous mitoses (<1/10 HPF). Immunohistochemical stains showed co-expression of S100 and CD34. A GAB1-ABL1 fusion was detected by whole transcriptome RNA sequencing. The patient had a partial response to imatinib. The second case was previously described as a solitary fibrous tumor, occurring in a 9-year-old female with a cellular spindle cell tumor with patchy CD34 immunoexpression but no expression of S100. Upon clinicopathologic re-review, including anchored multiplex next-generation sequencing, a GAB1-ABL1 fusion was identified. In summary, we report the first two cases of spindle cell tumors with variable expression of CD34 and/or S100, driven by GAB1-ABL1 gene fusions with histologic overlap with NTRK-rearranged spindle cell tumors, suggesting that ABL-fusions may also be oncogenic drivers within this spectrum of tumors. These cases highlight the evolving understanding of fibroblastic spindle cell tumor biology and the utility of sequencing in identifying a targetable alteration.

Esophagitis Dissecans Superficialis in Children.

OBJECTIVES: Esophagitis dissecans superficialis (EDS) is a desquamative disorder of the superficial esophageal epithelium with variable clinical characteristics. Endoscopically, there is an appearance of superficial peeling of sheets of epithelium. Histologically there is 2-toned epithelium with coagulative necrosis of the superficial epithelium. Currently, there is paucity of data regarding this condition in children. METHODS: A 10-year retrospective search of the pathology information system was performed for cases with a pathologic diagnosis of EDS in a tertiary care pediatric center. Demographic data, clinical history, endoscopic findings, and histopathologic reports were reviewed. RESULTS: Thirteen patients (9 girls; ages 3-18 years), were identified with histologic findings of EDS. Esophageal food impaction, dysphagia, vomiting, and abdominal pain were the most common presenting symptoms. Sixty-nine percentage of the patients had underlying comorbidities and 76% were on at least 1 medication chronically. Eosinophilic esophagitis (23%), inflammatory bowel disease (23%), and gastroesophageal reflux disease (GERD) (15%) were the most common associated diagnoses. Of the 13 patients, 5 had repeat endoscopies showing complete resolution of EDS with no complications. CONCLUSIONS: EDS is an under-recognized entity that endoscopists should be familiar with. In our series, the most prevalent associations were with food impaction and eosinophilic esophagitis (EoE). Contact injury and/or inflammation may precede the development of EDS. Pediatric EDS appears to be an incidental finding without significant morbidity or mortality.

Esophageal Fibrosis in Eosinophilic Gastrointestinal Diseases.

OBJECTIVES: Eosinophilic esophagitis (EoE), the most common eosinophilic gastrointestinal disease (EGID), is associated with lamina propria (LP) fibrosis. The relationship of EoE to other EGIDs is still unclear. We frequently observe cases of concurrent esophageal eosinophilia and extra-esophageal mucosal eosinophilia. The purpose of this study was to compare clinical, endoscopic, and histologic features, as well as the prevalence of esophageal LP fibrosis in children with EGID and concurrent esophageal eosinophilia to children with EoE. We also examine the current practices of pathologists in evaluating fibrosis. METHODS: We reviewed esophageal biopsies from index cases of EoE (N = 38), EGID with significant esophageal eosinophilia (≥15 eos/hpf) (EGID-SEE, N = 38), EGID with mild esophageal eosinophilia (1-14 eos/hpf) (EGID-MEE, N = 12), and EGID with no esophageal eosinophilia (EGID-NEE, N = 12) for LP presence, adequacy, and fibrosis. RESULTS: EoE and EGID-SEE cases share similar demographics, esophageal endoscopic features, and symptoms. A majority of EGID-SEE cases (71%) had adequate LP for the evaluation of fibrosis, similar to EoE cases (87%). The prevalence of esophageal fibrosis in EoE (79%) and EGID-SEE (55%) cases were similar, whereas no fibrosis was detected in the EGID-MEE and EGID-NEE cases. The fibrosis was patchy and often detected in the distal esophagus. Fourteen cases were reclassified from their original clinical diagnosis as having fibrosis by the study pathologists. CONCLUSIONS: Cases of EGID-SEE have overlapping features with EoE, suggesting that all EGIDs are part of a disease continuum. A consensus for the evaluation of LP fibrosis is needed.

GEAMP, a novel gastroesophageal junction carcinoma cell line derived from a malignant pleural effusion.

Gastroesophageal junction (GEJ) cancer remains a clinically significant disease in Western countries due to its increasing incidence, which mirrors that of esophageal cancer, and poor prognosis. To develop novel and effective approaches for prevention, early detection, and treatment of patients with GEJ cancer, a better understanding of the mechanisms driving pathogenesis and malignant progression of this disease is required. These efforts have been limited by the small number of available cell lines and appropriate preclinical animal models for in vitro and in vivo studies. We have established and characterized a novel GEJ cancer cell line, GEAMP, derived from the malignant pleural effusion of a previously treated GEJ cancer patient. Comprehensive genetic analyses confirmed a clonal relationship between GEAMP cells and the primary tumor. Targeted next-generation sequencing identified 56 nonsynonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer. In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B. Histological examination of subcutaneous flank xenografts in nude and NOD-SCID mice showed a carcinoma with mixed squamous and glandular differentiation, suggesting GEAMP cells contain a subpopulation with multipotent potential. Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro. Thus, GEAMP represents a valuable addition to the limited number of bona fide GEJ cancer cell lines.

Lack of Association Between Radiographic Tumor Burden and Efficacy of Immune Checkpoint Inhibitors in Advanced Lung Cancer.

BACKGROUND: Historically, tumor burden has been considered an impediment to efficacy of immunotherapeutic agents, including vaccines, stem cell transplant, cytokine therapy, and intravesical bacillus Calmette-Guérin. This effect has been attributed to hypoxic zones in the tumor core contributing to poor T-cell infiltration, formation of immunosuppressive stromal cells, and development of therapy-resistant cell populations. However, the association between tumor burden and efficacy of immune checkpoint inhibitors is unknown. We sought to determine the association between radiographic tumor burden parameters and efficacy of immune checkpoint inhibitors in advanced lung cancer. MATERIALS AND METHODS: We performed a retrospective analysis of patients with advanced lung cancer treated with immune checkpoint inhibitors. Demographic, disease, and treatment data were collected. Serial tumor dimensions were recorded according to RECIST version 1.1. Associations between radiographic tumor burden (baseline sum of longest diameters, longest single diameter) and clinical outcomes (radiographic response, progression-free survival, and overall survival) were determined using log-rank tests, Cox proportional-hazard regression, and logistic regression. RESULTS: Among 105 patients, the median baseline sum of longest diameters (BSLD) was 6.4 cm; median longest single diameter was 3.6 cm. BSLD was not associated with best radiographic, progression-free survival, or overall survival. In univariate and multivariate analyses, no significant associations were observed for the other radiographic parameters and outcomes when considered as categorical or continuous variables. CONCLUSION: Although tumor burden has been considered a mediator of efficacy of earlier immunotherapies, in advanced lung cancer it does not appear to affect outcomes from immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: Historically, tumor burden has been considered an impediment to the efficacy of various immunotherapies, including vaccines, cytokines, allogeneic stem cell transplant, and intravesical bacillus Calmette-Guérin. However, in the present study, no association was found between tumor burden and efficacy (response rate, progression-free survival, overall survival) of immune checkpoint inhibitors in advanced lung cancer. These findings suggest that immune checkpoint inhibitors may provide benefit across a range of disease burden, including bulky tumors considered resistant to other categories of immunotherapy.

Statin Intolerance, Anti-HMGCR Antibodies, and Immune Checkpoint Inhibitor-Associated Myositis: A "Two-Hit" Autoimmune Toxicity or Clinical Predisposition?

Immune-related adverse events induced by immune checkpoint inhibitor (ICI) therapy may affect diverse organ systems, including skeletal and cardiac muscle. ICI-associated myositis may result in substantial morbidity and occasional mortality. We present a case of a patient with advanced non-small cell lung cancer who developed grade 4 myositis with concurrent myocarditis early after initiation of anti-programmed death ligand 1 therapy (durvalumab). Autoantibody analysis revealed marked increases in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody levels that preceded clinical toxicity, and further increased during toxicity. Notably, the patient had a history of intolerable statin myopathy, which had resolved clinically after statin discontinuation and prior to ICI initiation. This case demonstrates a potential association between statin exposure, autoantibodies, and ICI-associated myositis.

Late-Onset Immunotherapy Toxicity and Delayed Autoantibody Changes: Checkpoint Inhibitor-Induced Raynaud's-Like Phenomenon.

Immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs) may affect almost any organ system and occur at any point during therapy. Autoantibody analysis may provide insight into the mechanism, nature, and timing of these events. We report a case of ICI-induced late-onset Raynaud's-like phenomenon in a patient receiving combination immunotherapy. A 53-year-old woman with advanced non-small lung cancer received combination anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed death 1 ICI therapy. She developed early (hypophysitis at 4 months) and late (Raynaud's at >20 months) irAEs. Longitudinal assessment of 124 autoantibodies was correlated with toxicity. Although autoantibody levels were generally stable for the first 18 months of therapy, shortly before the development of Raynaud's, a marked increase in multiple autoantibodies was observed. This case highlights the potential for delayed autoimmune toxicities and provides potential biologic insights into the dynamic nature of these events. KEY POINTS: A patient treated with dual anti-PD1 and anti-CTLA4 therapy developed Raynaud's-like signs and symptoms more than 18 months after starting therapy. In this case, autoantibody changes became apparent shortly before onset of clinical toxicity. This case highlights the potential for late-onset immune-related adverse events checkpoint inhibitors, requiring continuous clinical vigilance. The optimal duration of checkpoint inhibitor therapy in patients with profound and prolonged responses remains unclear.

Clinical Exome Studies Have Inconsistent Coverage.

BACKGROUND: Exome sequencing has become a commonly used clinical diagnostic test. Multiple studies have examined the diagnostic utility and individual laboratory performance of exome testing; however, no previous study has surveyed and compared the data quality from multiple clinical laboratories. METHODS: We examined sequencing data from 36 clinical exome tests from 3 clinical laboratories. Exome data were compared in terms of overall characteristics and coverage of specific genes and nucleotide positions. The sets of genes examined included genes in Consensus Coding Sequence (CCDS) (n = 17723), a subset of genes clinically relevant to epilepsy (n = 108), and genes that are recommended for reporting of secondary findings (n = 57; excludes X-linked genes). RESULTS: The average exome nucleotide coverage (≥20×) of each laboratory varied at 96.49% (CV = 3%), 96.54% (CV = 1%), and 91.68% (CV = 4%), for laboratories A, B, and C, respectively. For CCDS genes, the average number of completely covered genes varied at 12184 (CV = 29%), 11687 (CV = 13%), and 5989 (CV = 37%), for laboratories A, B, and C, respectively. With smaller subsets of genes related to epilepsy and secondary findings, the CV revealed low consistency, with a maximum CV seen in laboratory C for both epilepsy genes (CV = 60%) and secondary findings genes (CV = 71%). CONCLUSIONS: Poor consistency in complete gene coverage was seen in the clinical exome laboratories surveyed. The degree of consistency varied widely between the laboratories.

Reinterpretation of Chromosomal Microarrays with Detailed Medical History.

OBJECTIVE: To investigate the utility of a detailed medical history in the interpretation of chromosomal microarray results for pediatric patients with a constitutional disease. STUDY DESIGN: A retrospective review and reinterpretation of test results from chromosomal microarrays performed from 2011 to 2013. Previously reported genetic variants were reanalyzed after review of the patient's complete electronic medical record (cEMR). A 3-tier system was used for reclassification of variants: pathogenic or likely pathogenic (P/LP); variant of uncertain significance (VUS); or benign or likely benign (B/LB). RESULTS: Over an 18-month period, 998 patients with chromosomal microarray results were identified. The most common reasons for chromosomal microarray testing were developmental delay (n = 336), autism spectrum disorder (n = 241), and seizures (n = 143). Chromosomal microarray testing identified 1 or more variants in 48% (482 of 998) of patients; 516 patients had a negative report. For the 482 patients with variants, the original interpretations were composed of 19.3% P/LP (93 of 482), 44.8% VUS (216 of 482), and 35.9% B/LB (173 of 482) variants. After review of the cEMR, 34% of patient results (164 of 482) were changed in interpretation. One case changed from B/LB to VUS, 7 VUS were upgraded to P/LP, and 156 VUS were downgraded to B/LB. No P/LP variants had a change in interpretation. CONCLUSIONS: Overall, 16.4% (164 of 998) of patients with chromosomal microarray testing had a change in interpretation. Access to the patient's cEMR improves the interpretation of chromosomal microarrays by decreasing the number of uncertain (VUS) interpretations.

Hb Alcorn County: A ß-Globin Variant [ß40(C6)Arg→Thr; HBB: c.122G>C (p.Arg41Thr)] with Increased Oxygen Affinity.

We describe Hb Alcorn County, a heterozygous hemoglobin (Hb) variant, in a 6-month-old Hispanic male and his mother. DNA sequencing demonstrated a mutation on the HBB gene [ß40(C6)Arg→Thr; HBB: c.122G>C (p.Arg41Thr)], predictive of a substitution of arginine to threonine at position 40 of the ß-globin protein. This amino acid substitution involves the α1ß2 contact and occurs at the same position as Hb Austin [ß40(C6)Arg→Ser; HBB: c.[123G>C or 123G>T] (p.Arg41Ser)] and Hb Athens-GA [ß40(C6)Arg→Lys; HBB: c.122G>A (p.Arg41Lys)], both of which show increased oxygen affinity.

Genomic Privacy.

BACKGROUND: Genetic information is unique among all laboratory data because it not only informs the current health of the specific person tested but may also be predictive of the future health of the individual and, to varying degrees, all biological relatives. CONTENT: As DNA sequencing has become ubiquitous with decreasing cost, large repositories of genomic data have emerged from the domains of research, healthcare, law enforcement, international security, and recreational consumer interest (i.e., genealogy). Broadly shared genomic data are believed to be a key element for future discoveries in human disease. For example, the National Cancer Institute's Genomic Data Commons is designed to promote cancer research discoveries by providing free access to the genome data sets of 12000 cancer patients. However, in parallel with the promise of curing diseases, genomic data also have the potential for harm. Genomic data that are deidentified by standard healthcare practices (e.g., removal of name, date of birth) can be reidentified by methods that combine genomic software with publicly available demographic databases (e.g., phone book). Recent law enforcement cases (i.e., Bear Brook Murders, Golden State Killer) in the US have demonstrated the power of combining DNA profiles with genealogy databases. SUMMARY: We examine the current environment of genomic privacy and confidentiality in the US and describe current and future risks to genomic privacy. Reidentification and inference of genetic information of biological relatives will become more important as larger databases of clinical, criminal, and recreational genomic information are developed over the next decade.