aRgus: Multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment.

The widespread use of high-throughput sequencing techniques is leading to a rapidly increasing number of disease-associated variants of unknown significance and candidate genes. Integration of knowledge concerning their genetic, protein as well as functional and conservational aspects is necessary for an exhaustive assessment of their relevance and for prioritization of further clinical and functional studies investigating their role in human disease. To collect the necessary information, a multitude of different databases has to be accessed and data extraction from the original sources commonly is not user-friendly and requires advanced bioinformatics skills. This leads to a decreased data accessibility for a relevant number of potential users such as clinicians, geneticist, and clinical researchers. Here, we present aRgus (https://argus.urz.uni-heidelberg.de/), a standalone webtool for simple extraction and intuitive visualization of multi-layered gene, protein, variant, and variant effect prediction data. aRgus provides interactive exploitation of these data within seconds for any known gene of the human genome. In contrast to existing online platforms for compilation of variant data, aRgus complements visualization of chromosomal exon-intron structure and protein domain annotation with ClinVar and gnomAD variant distributions as well as position-specific variant effect prediction score modeling. aRgus thereby enables timely assessment of protein regions vulnerable to variation with single amino acid resolution and provides numerous applications in variant and protein domain interpretation as well as in the design of in vitro experiments.

Towards Achieving Equity and Innovation in Newborn Screening across Europe.

Although individual rare disorders are uncommon, it is estimated that, together, 6000+ known rare diseases affect more than 30 million people in Europe, and present a substantial public health burden. Together with the psychosocial burden on affected families, rare disorders frequently, if untreated, result in a low quality of life, disability and even premature death. Newborn screening (NBS) has the potential to detect a number of rare conditions in asymptomatic children, providing the possibility of early treatment and a significantly improved long-term outcome. Despite these clear benefits, the availability and conduct of NBS programmes varies considerably across Europe and, with the increasing potential of genomic testing, it is likely that these differences may become even more pronounced. To help improve the equity of provision of NBS and ensure that all children can be offered high-quality screening regardless of race, nationality and socio-economic status, a technical meeting, endorsed by the Slovenian Presidency of the Council of the European Union, was held in October 2021. In this article, we present experiences from individual EU countries, stakeholder initiatives and the meeting's final conclusions, which can help countries attempting to establish new NBS programmes or expand existing provision.

How longitudinal observational studies can guide screening strategy for rare diseases.

Newborn screening (NBS) is an important secondary prevention program, aiming to shift the paradigm of medicine to the pre-clinical stage of a disease. Starting more than 50 years ago, technical advances, such as tandem mass spectrometry (MS/MS), paved the way to a continuous extension of NBS programs. However, formal evidence of the long-term clinical benefits in large cohorts and cost-effectiveness of extended NBS programs is still scarce. Although published studies confirmed important benefits of NBS programs, it also unraveled a significant number of limitations. These include an incompletely understood natural history and phenotypic diversity of some screened diseases, unreliable early and precise prediction of individual disease severity, uncertainty about case definition, risk stratification, and indication to treat, resulting in a diagnostic and treatment dilemma in individuals with ambiguous screening and confirmatory test results. Interoperable patient registries are multi-purpose tools that could help to close the current knowledge gaps and to inform further optimization of NBS strategy. Standing at the edge of introducing high throughput genetic technologies to NBS programs with the opportunity to massively extend NBS programs and with the risk of aggravating current limitations of NBS programs, it seems overdue to include mandatory long-term follow-up of NBS cohorts into the list of screening principles and to build an international collaborative framework that enables data collection and exchange in a protected environment, integrating the perspectives of patients, families, and the society.

Newborn screening by tandem mass spectrometry for glutaric aciduria type 1: a cost-effectiveness analysis.

BACKGROUND: Glutaric aciduria type I (GA-I) is a rare metabolic disorder caused by inherited deficiency of glutaryl-CoA dehydrogenase. Despite high prognostic relevance of early diagnosis and start of metabolic treatment as well as an additional cost saving potential later in life, only a limited number of countries recommend newborn screening for GA-I. So far only limited data is available enabling health care decision makers to evaluate whether investing into GA-I screening represents value for money. The aim of our study was therefore to assess the cost-effectiveness of newborn screening for GA-I by tandem mass spectrometry (MS/MS) compared to a scenario where GA-I is not included in the MS/MS screening panel. METHODS: We assessed the cost-effectiveness of newborn screening for GA-I against the alternative of not including GA-I in MS/MS screening. A Markov model was developed simulating the clinical course of screened and unscreened newborns within different time horizons of 20 and 70 years. Monte Carlo simulation based probabilistic sensitivity analysis was used to determine the probability of GA-I screening representing a cost-effective therapeutic strategy. RESULTS: Within a 20 year time horizon, GA-I screening averts approximately 3.7 DALYs (95% CI 2.9 - 4.5) and about one life year is gained (95% CI 0.7 - 1.4) per 100,000 neonates screened initially . Moreover, the screening programme saves a total of around 30,682 Euro (95% CI 14,343 to 49,176 Euro) per 100,000 screened neonates over a 20 year time horizon. CONCLUSION: Within the limitations of the present study, extending pre-existing MS/MS newborn screening programmes by GA-I represents a highly cost-effective diagnostic strategy when assessed under conditions comparable to the German health care system.