Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved

Antibody Response to SARS-CoV-2: A Cohort Study in Qatar's Primary Care Settings.

Globally, countries are rolling out Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) quarantine policies and vaccination programs. Research studies are needed in helping understand the likelihood of acquired immunity to reinfection and identify priority groups for vaccination to inform them. This study aimed to assess period prevalence and longitudinal changes in antibody levels after SARS-CoV-2 infection in Qatari primary care settings. A cohort study design with 2 data collection phases was undertaken-Phase 1 (conducted in July 2020) and Phase 2 (conducted in October 2020). A stratified random sampling technique by age, gender and nationality was utilized to identify the study sample. The total sample size required for the study was estimated to be 2102. Participants were invited to an appointment where they were administered a questionnaire and provided samples for polymerase chain reaction and Immunoglobulin G immunoassay tests. A total of 943 individuals participated in both Phase 1 and Phase 2. In this cohort, seroprevalence of SARS-CoV-2 was found to be 12% (N = 113) in Phase 1 and 17.2% (N = 162) in Phase 2. Of the 113 participants who were seropositive in Phase 1, 38.1% (CI 29.5-47.2%, N = 43) had a reduction, 54.9% (CI 45.7-63.8%, N = 62) had no change, and 7.1% (CI 3.4-12.9%, N = 8) had an increase in IgG titer in Phase 2. All (N = 18) participants aged 10 to 17 years retained their antibodies. The proportion of men who retained their antibodies was slightly higher compared to women-92.5% (N = 74) and 87.9% (N = 29) respectively. Similarly, symptomatic individuals (97.8%; N = 45) had a higher antibody retention compared with asymptomatic individuals (86.4%; N = 57). This study provides preliminary information on the longitudinal changes in antibody levels after SARS-CoV-2 infection. These findings will help inform quarantine policies and vaccination programs.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by PHCC (PHCCDCR202005047).The funders had no role in the design, analysis, interpretation, or writing