Detection of distant relatedness in biobanks for identification of undiagnosed carriers of a Mendelian disease variant: application to Long QT Syndrome.

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we developed a generalizable method of genotype inference based on distant relatedness and deployed this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identified 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncovered recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identified 22 additional subjects sharing this haplotype, subsequently confirmed to carry p.Asp76Asn. Referral and non-referral carriers had prolonged QTc compared to controls, and, among carriers, QTc polygenic score additively associated with QTc prolongation. Thus, our novel analysis of shared chromosomal segments identified undiagnosed cases of genetic disease and refined the understanding of LQT5 penetrance and phenotype.

Detection of distant familial relatedness in biobanks for identification of undiagnosed carriers of a Mendelian disease variant: application to Long QT syndrome.

Importance: The diagnosis and study of rare genetic disease is often limited to referral populations, leading to underdiagnosis and a biased assessment of penetrance and phenotype. Objective: To develop a generalizable method of genotype inference based on distant relatedness and to deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. Participants: We identified 9 LQT5 probands and 3 first-degree relatives referred to a single Genetic Arrhythmia clinic, each carrying D76N (p.Asp76Asn), the most common variant implicated in LQT5. The non-referral population consisted of 69,879 ancestry-matched subjects in BioVU, a large biobank that links electronic health records to dense array data. Participants were enrolled from 2007-2022. Data analysis was performed in 2022. Exposures: We developed and applied a novel approach to genotype inference (Distant Relatedness for Identification and Variant Evaluation, or DRIVE) to identify shared, identical-by-descent (IBD) large chromosomal segments in array data. Main Outcomes and Measures: We sought to establish genetic relatedness among the probands and to use genomic segments underlying D76N to identify other potential carriers in BioVU. We then further studied the role of D76N in LQT5 pathogenesis. Results: Genetic reconstruction of pedigrees and distant relatedness detection among clinic probands using DRIVE revealed shared recent common ancestry and identified a single long shared haplotype. Interrogation of the non-referral population in BioVU identified a further 23 subjects sharing this haplotype, and sequencing confirmed D76N carrier status in 22, all previously undiagnosed with LQT5. The QTc was prolonged in D76N carriers compared to BioVU controls, with 40% penetrance of QTc ≥ 480 msec. Among D76N carriers, a QTc polygenic score was additively associated with QTc prolongation. Conclusions and Relevance: Detection of IBD shared chromosomal segments around D76N enabled identification of distantly related and previously undiagnosed rare-variant carriers, demonstrated the contribution of polygenic risk to monogenic disease penetrance, and further established LQT5 as a primary arrhythmia disorder. Analysis of shared chromosomal regions spanning disease-causing mutations can identify undiagnosed cases of genetic diseases.

2-Aminobenzimidazoles as antibiofilm agents against Salmonella enterica serovar Typhimurium.

Serovars within the species Salmonella enterica are some of the most common food and water-borne pathogens worldwide. Some S. enterica serovars have shown a remarkable ability to persist both inside and outside the human body. Salmonella enterica serovar Typhi can cause chronic, asymptomatic infection of the human gallbladder. This organism's ability to survive inside the gallbladder centers around its ability to form biofilms on gallstone surfaces. Currently, chronic carriage of S. Typhi is treated by invasive methods, which are not well suited to areas where Salmonella carriage is prevalent. Herein, we report 2-aminobenzimidazoles that inhibit S. enterica serovar Typhimurium (a surrogate for S. Typhi) biofilm formation in low micromolar concentrations. Modifications to the head, tail, and linker regions of the original hit compound elucidated new, more effective analogues that inhibit S. Typhimurium biofilm formation while being non-toxic to planktonic bacterial growth.

Meridianin D Analogues Display Antibiofilm Activity against MRSA and Increase Colistin Efficacy in Gram-Negative Bacteria.

In the last 30 years, development of new classes of antibiotics has slowed, increasing the necessity for new options to treat multidrug resistant bacterial infections. Development of antibiotic adjuvants that increase the effectiveness of currently available antibiotics is a promising alternative approach to classical antibiotic development. Reports of the ability of the natural product meridianin D to modulate bacterial behavior have been rare. Herein, we describe the ability of meridianin D to inhibit biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA) and to increase the potency of colistin against colistin-resistant and sensitive Gram-negative bacteria. Analogues were identified that are capable of inhibiting and dispersing MRSA biofilms and lowering the colistin MIC to below the CLSI breakpoint against Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli.

A rational approach to pulmonary screening in newly diagnosed head and neck cancer.

BACKGROUND: The purpose of this study was to determine the detection rate of lung metastasis or a synchronous lung primary tumor in patients with newly diagnosed head and neck mucosal squamous cell carcinoma (SCC) and to determine factors that are associated with positive findings. METHODS: This was a prospective cohort study of 102 patients with head and neck mucosal SCC diagnosed in a tertiary cancer center. Chest x-rays and a CT scan of the thorax were performed. An indeterminate nodule on CT scan was followed with either a repeat scan to assess progression or a CT-guided needle biopsy. Metastasis or synchronous lung primary tumor were determined by CT scan. The findings were correlated with age, sex, duration of symptoms, site of primary tumor, grade of tumor, T classification, and N classification. RESULTS: A CT scan of the thorax showed abnormalities or suspicious nodules in 20 patients (19.6%). With either follow-up scans or CT-guided biopsy, 10 patients were eventually proven to have pulmonary metastasis and one a synchronous lung primary tumor. Of those eleven patients (10.8%), seven had normal chest x-ray. Eight (72.7%) of 11 patients with a positive CT scan had N2 or N3 disease in contrast to 32 (35.2%) of 91 patients with a normal CT scan (p = .02). Seven patients (63.6%) with a positive CT scan had T4 disease, whereas 34 (37.4%) with a normal CT scan had T4 disease (p = .08). Primary tumors arising in the oropharynx, hypopharynx, and supraglottis had a greater risk of a positive CT scan than tumors arising in the oral cavity, glottis, or unknown sites (OR = 5.4; 95% CI, 1.3-21.9). Age, sex, duration of symptoms, and grade of disease did not predict a positive CT scan. CONCLUSIONS: The detection rate of lung metastasis or a synchronous lung primary tumor by CT scan is 10.8%. We recommend the use of CT scans of the thorax in screening the lungs of newly diagnosed patients with T4 and/or N2 or N3 oropharyngeal, hypopharyngeal, and supraglottic SCC.