Driven by technological innovations, newborn screening (NBS) panels have been expanded and the development of genomic NBS pilot programs is rapidly progressing. Decisions on disease selection for NBS are still based on the Wilson and Jungner (WJ) criteria published in 1968. Despite this uniform reference, interpretation of the WJ criteria and actual disease selection for NBS programs are highly variable. A systematic literature search [PubMED search “Wilson” AND “Jungner”; last search 16.07.22] was performed to evaluate the applicability of the WJ criteria for current and future NBS programs and the need for adaptation. By at least two reviewers, 105 publications (systematic literature search, N = 77; manual search, N = 28) were screened for relevant content and, finally, 38 publications were evaluated. Limited by the study design of qualitative text analysis, no statistical evaluation was performed, but a structured collection of reported aspects of criticism and proposed improvements was instead collated. This revealed a set of general limitations of the WJ criteria, such as imprecise terminology, lack of measurability and objectivity, missing pediatric focus, and absent guidance on program management. Furthermore, it unraveled specific aspects of criticism on clinical, diagnostic, therapeutic, and economical aspects. A major obstacle was found to be the incompletely understood natural history and phenotypic diversity of rare diseases prior to NBS implementation, resulting in uncertainty about case definition, risk stratification, and indications for treatment. This gap could be closed through the systematic collection and evaluation of real-world evidence on the quality, safety, and (cost-)effectiveness of NBS, as well as the long-term benefits experienced by screened individuals. An integrated NBS public health program that is designed to continuously learn would fulfil these requirements, and a multi-dimensional framework for future NBS programs integrating medical, ethical, legal, and societal perspectives is overdue.

Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B₁₂ deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study “NGS2025” from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B₁₂ deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B₁₂ deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B₁₂, vitamin B₆ respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.

Newborn screening (NBS) is one of the most effective measures of secondary prevention. While the benefit of NBS on the clinical long‐term outcomes of children with inherited metabolic diseases (IMD) has been demonstrated, the potential burden of families living with an early diagnosed and treated child with an IMD has not been thoroughly investigated. The aim of this longitudinal questionnaire‐based study on 369 families living with a child with an IMD was to investigate the psychosocial and financial burden following a true‐positive NBS. The reported psychosocial burden differed between children and their parents, and was associated with the child's age, diagnosis, and treatment. At younger ages, parent‐reported burden was higher for the parents than for the individual child, while it increased for children and decreased for parents as the child grew older. Furthermore, psychosocial burden increased if the child required a strict dietary treatment and was at risk of metabolic decompensation. Regardless of diagnosis and treatment, the developmental delay of their child independently increased the parental psychosocial burden. Financial burden was reported by 24% of all families, and was higher in low‐income families and in families whose children required dietary treatment. In conclusion, a substantial psychosocial and financial burden was revealed for children and their families after true‐positive NBS. Since this burden is likely to have a negative impact on the long‐term individual health benefits of NBS, this study underlines the importance of regularly assessing the psychosocial and financial needs of these families.

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222; miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients (n = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials.

Newborn screening (NBS) is a successful program of secondary prevention for rare diseases, such as neuro-metabolic diseases, enabling early identification of affected individuals and pre-symptomatic treatment. Driven by innovations in high-throughput sequencing technologies, NBS panels have continued to grow and will probably be extended further in the future. However, implementing NBS for a disease is subject to various preconditions to maximize the benefit for the affected children, while avoiding harm to the screened healthy cohort, their families and the society. Ideally, data on clinical long-term benefit of NBS and early treatment is collected prior to NBS implementation through long-term observational studies and registries. In addition, NBS should be implemented as an iteratively evaluated public health program and the data collection should be accompanied by intra-operable long-term observational studies, ideally extended in international cooperations. In this review, the current expertise in NBS, the screening strategies and possible long-term clinical benefits are presented and discussed for several neuro-metabolic diseases, including propionic acidemia and isolated methylmalonic acidemias, homocystinurias, remethylation defects, acquired cobalamin (vitamin B₁₂) deficiency, urea cycle disorders, tetrahydrobiopterin (BH₄) and primary neurotransmitter disorders, as well as lysosomal storage disorders. Given these prerequisites, several of the neuro-metabolic diseases discussed here might be part of future NBS programs worldwide.

Newborn screening (NBS) is an effective measure of secondary prevention. The application of genomic sequencing in population-based screening would enable further expansions of the NBS disease panel and a genomic NBS (gNBS). The selection of NBS target diseases is still based on the Wilson and Jungner screening principles from 1968, which are considered incomplete, particularly for an extension towards gNBS. The present work aims to establish a multi-dimensional framework for future gNBS programs. An interdisciplinary expert panel comprising researchers from pediatric and adolescent medicine, human genetics, ethics, medical psychology, law, and patient representatives used a nominal group technique-like multi-stage consensus process to define criteria for gNBS, considering ethical, legal, and social implications, medical aspects, and patient perspectives. Overall, 18 criteria were developed, clustered into four subcategories: I. Clinical criteria (characteristics of the target disease); II. Diagnostic criteria (requirements of the test); III. Therapeutic-interventional criteria (prerequisites of the intervention); IV. Program management criteria (requirements of the program). Subcategories I–III define selection criteria for target diseases, subcategory IV defines criteria for how to establish and manage the program. In conclusion, this multi-dimensional framework serves as a well-balanced basis for developing thoroughly revised and internationally accepted consensus screening criteria.