Driving mosaicism: somatic variants in reference population databases and effect on variant interpretation in rare genetic disease.

BACKGROUND: Genetic variation databases provide invaluable information on the presence and frequency of genetic variants in the 'untargeted' human population, aggregated with the primary goal to facilitate the interpretation of clinically important variants. The presence of somatic variants in such databases can affect variant assessment in undiagnosed rare disease (RD) patients. Previously, the impact of somatic mosaicism was only considered in relation to two Mendelian disease-associated genes. Here, we expand the analyses to identify additional mosaicism-prone genes in blood-derived reference population databases. RESULTS: To identify additional mosaicism-prone genes relevant to RDs, we focused on known/previously established ClinVar pathogenic and likely pathogenic single-nucleotide variants, residing in genes associated with early onset, severe autosomal dominant diseases. We asked whether any of these variants are present in a higher-than-expected frequency in the reference population databases and whether there is evidence of somatic origin (i.e., allelic imbalance) rather than germline heterozygosity (~ half of the reads supporting alternative allele). The mosaicism-prone genes identified were further categorized according to the processes they are involved in. Beyond the previously reported ASXL1 and DNMT3A, we identified 7 additional autosomal dominant RD-associated genes with known pathogenic single-nucleotide variants present in the reference population databases and good evidence of allelic imbalance: BRAF, CBL, FGFR3, IDH2, KRAS, PTPN11 and SETBP1. From this group of 9 genes, the majority (n = 7) was important for hematopoiesis. In addition, 4 of these genes were involved in cell proliferation. Further assessment of the known 156 hematopoietic genes led to identification of 48 genes (21 not yet associated with RDs) with at least some evidence of mosaicism detectable in reference population databases. CONCLUSIONS: These results stress the importance of considering genes involved in hematopoiesis and cell proliferation when interpreting the presence and frequency of genetic variants in blood-derived reference population databases, both public and private. This is especially important when considering new variants of uncertain significance in known hematopoietic/cell proliferation RD genes and future novel gene-disease associations involving this class of genes.

Risk of Total Hip Arthroplasty After Acetabular Fracture Fixation: The Importance of Age.

BACKGROUND: Geriatric patients are the most rapidly growing cohort of patients sustaining acetabular fractures (AFs). The purpose of this study was to examine the risk of a secondary total hip arthroplasty (THA) in older patients (>60 year old) with a prior AF open reduction internal fixation (ORIF) compared with younger patients (<60 year old) with an AF ORIF on a large population level. METHODS: Using administrative health care data from 1996 to 2010 inclusive of all 202 hospitals in Ontario, Canada, all adult patients with an AF ORIF and a minimum of two year follow-up were identified and included. The risk of THA was examined using a Cox proportional hazards model adjusting for patient risk factors. Secondary outcomes included surgical complications and all-cause mortality. RESULTS: A total of 1725 patients had an AF ORIF; 1452 (84.2%, mean age of 38.3 ± 12.1 years) aged <60 years ("younger") and 273 (15.8%, mean age of 69.9 ± 7.8 years) > 60 years ("older"). The mean (SD) follow-up time for all patients was 6.9 (4.2) years. In older patients, 19.4% (53 of 273) went on to receive a secondary THA with a median time to event of 3.9 years, compared with 12.9% (187 of 1452) in the younger patient cohort with a median time of 6.9 years (HR 1.7, 95% CI: 1.2-2.3). As expected, older patients had a higher 90-day mortality rate compared with younger patients (7.7% vs. 0.7%, respectively; HR 9.2, 95% CI: 4.3-19.9; P < .001). CONCLUSION: Older patients with an AF ORIF are at a significantly higher risk for a secondary THA than younger patients with an AF ORIF.

Pharmacoepidemiology.

At the time of their marketing authorization, the effects of drugs and especially their efficacy have been mostly studied in randomized controlled clinical trials (RCT), comparing them to placebo or to existing drugs. However, RCT are by nature limited in their extent, and the often stringent inclusion and exclusion criteria destined to provide for homogeneous study populations reduce the generalizability of RCT results.The post-authorization evaluation of drugs (pharmacoepidemiology or real-world evidence (RWE)) covers the description of drug utilization and population risks or benefits of these drugs after they have been marketed and provided to their target populations. Though field studies have existed for a long time, modern pharmacoepidemiology has been made possible essentially by the emergence of large population databases compiled from claims data or electronic health records. The methods can be exposure or disease-based cohorts or event-driven case-based studies, tailored to the specific questions to be answered. They rely on scrupulous analysis and execution of impeccable methodology, to ensure the most reliable results possible.Pharmacoepidemiology requires knowledge of the pharmacology of drugs, of the clinical aspects of diseases and disease management, and of the epidemiological methods that can apply.

Maternal Copy Number Imbalances in Non-Invasive Prenatal Testing: Do They Matter?

Non-invasive prenatal testing (NIPT) has become a routine practice in screening for common aneuploidies of chromosomes 21, 18, and 13 and gonosomes X and Y in fetuses worldwide since 2015 and has even expanded to include smaller subchromosomal events. In fact, the fetal fraction represents only a small proportion of cell-free DNA on a predominant background of maternal DNA. Unlike fetal findings that have to be confirmed using invasive testing, it has been well documented that NIPT provides information on maternal mosaicism, occult malignancies, and hidden health conditions due to copy number variations (CNVs) with diagnostic resolution. Although large duplications or deletions associated with certain medical conditions or syndromes are usually well recognized and easy to interpret, very little is known about small, relatively common copy number variations on the order of a few hundred kilobases and their potential impact on human health. We analyzed data from 6422 NIPT patient samples with a CNV detection resolution of 200 kb for the maternal genome and identified 942 distinct CNVs; 328 occurred repeatedly. We defined them as multiple occurring variants (MOVs). We scrutinized the most common ones, compared them with frequencies in the gnomAD SVs v2.1, dbVar, and DGV population databases, and analyzed them with an emphasis on genomic content and potential association with specific phenotypes.

Older rationales and other challenges in handling causes of death in historical individual-level databases: the case of Copenhagen, 1880-1881.

Large-scale historical databases featuring individual-level causes of death offer the potential for longitudinal studies of health and illnesses. There is, however, a risk that the transformation of the primary sources into 'data' may strip them of the very qualities required for proper medical historical analysis. Based on a pilot study of all 11,100 deaths registered in Copenhagen in 1880-1881, we identify, analyse and discuss the challenges of transcribing and coding cause of death sources into a database. The results will guide us in building Link-Lives, a database featuring close to all nine million Danish deaths from 1787 to 1968. The main challenge is how to accommodate different older medical rationales in one classification system. Our key finding is multi-coding with more than one version of the ICD system (e.g. ICD-1893 and ICD-10) can be used as a novel method to systematically handle historical causes of death over time.

Pharmacovigilance - The next chapter.

The discovery and quantification of adverse drug reactions has long relied on the careful analysis of spontaneously reported cases. Causality assessment (imputation) was a fundamental feature of individual case report analysis. This was complemented by analysis of aggregated cases, and of disproportionality analyses in spontaneous reports databases. In the absence of more specific information sources, these have resulted in the discovery of many new adverse reactions, altering drug information. It has led to the withdrawal from the market of many drugs, but its use for risk quantification remains fraught with uncertainty. The recent access to population-wide claims or electronic health records databases have confirmed for spontaneous reporting a predominant role in hypothesis generation for serious adverse drug reactions, notably those that result in hospital admission or death. In these cases, the events are identifiable at the population level, and can be quantified precisely using the tools of modern pharmacoepidemiology, to generate specific benefit-risk analyses. Spontaneous reporting remains irreplaceable in signal and alert generation in drug safety, despite its inherent limitations. For signal strengthening and assessment, more systematic and quantitative methods should be sought, such as claims databases for reactions resulting in hospital admissions.

The Y-Short Tandem Repeat Haplotype Reference Database (YHRD) and Male Population Stratification in Europe - Impact on Forensic Genetics.

The forensic application of patrilinearly transmitted Y-chromosomal markers requires knowledge of its substantial sensitivity to population substructuring. The establishment of carefully constructed, large, onlineavailable and worldwide population databases for Y-short tandem repeat-based haplotypes illustrates the magnitude and importance of male population subdivision, which is even recognizable in the otherwise nearly indistinguishable European populations. Thus, the choice of the suitable reference population is an absolute requirement for the interpretation of haplotype matches. Based on the specific haplotype distribution in a given population, an extrapolation method has been worked out that allows the frequency estimation of very rare haplotypes. This "haplotype surveying" approach is recommended as a conservative method to assess the match probabilities in cases with non-exclusion constellations. As exemplified further, the population-specific distribution of haplotypes can help to infer the population of origin of an unknown male DNA.