Biochemical Newborn Screening Research Articles

Newborn screening in South Africa: the past, present, and plans for the future

Worldwide, comprehensive newborn screening (NBS) now includes a clinical examination at birth, hearing screening, pulse oximetry measurement for congenital heart defects, and biochemical screening to identify congenital disorders early in life, preventing irreversible damage, early mortality and enhancing overall health outcomes. This article provides a comprehensive overview of biochemical NBS in South Africa, outlining the history, current status, and future plans for NBS expansion. In South Africa, NBS is fragmented, with some investigations included in neonatal health assessments. Historically, biochemical NBS pilot projects in the country in the 1960s and 1980s focused on phenylketonuria and congenital hypothyroidism (CH). Despite showing initial promise, these programmes were discontinued, largely due to competing health priorities. The current status of biochemical NBS in South Africa is discussed, both for the state and private healthcare sectors, which collectively screen approximately 0.5% of births annually. While recent clinical guidelines provide for a national biochemical NBS programme, implementation has been limited, and guideline adherence remains a challenge. A brief report of a two-day meeting held in Cape Town in February 2023 focusing on biochemical NBS for South Africa is provided. The meeting addressed the importance of NBS, technology requirements, and the need for a comprehensive demonstration project for biochemical CH NBS. Key challenges identified included early newborn post-delivery discharge, technical, logistical, and infrastructure issues, as well as limited financial and human resources. Meeting recommendations included the establishment of a National Advisory Panel for Biochemical NBS, and the development and implementation of a demonstration project for CH biochemical NBS in two provinces.

Targeted next generation sequencing for newborn screening of Menkes disease

PurposePopulation-based newborn screening (NBS) allows early detection and treatment of inherited disorders. For certain medically-actionable conditions, however, NBS is limited by the absence of reliable biochemical signatures amenable to detection by current platforms. We sought to assess the analytic validity of an ATP7A targeted next generation DNA sequencing assay as a potential newborn screen for one such disorder, Menkes disease. MethodsDried blood spots from control or Menkes disease subjects (n = 22) were blindly analyzed for pathogenic variants in the copper transport gene, ATP7A. The analytical method was optimized to minimize cost and provide rapid turnaround time. ResultsThe algorithm correctly identified pathogenic ATP7A variants, including missense, nonsense, small insertions/deletions, and large copy number variants, in 21/22 (95.5%) of subjects, one of whom had inconclusive diagnostic sequencing previously. For one false negative that also had not been detected by commercial molecular laboratories, we identified a deep intronic variant that impaired ATP7A mRNA splicing. ConclusionsOur results support proof-of-concept that primary DNA-based NBS would accurately detect Menkes disease, a disorder that fulfills Wilson and Jungner screening criteria and for which biochemical NBS is unavailable. Targeted next generation sequencing for NBS would enable improved Menkes disease clinical outcomes, establish a platform for early identification of other unscreened disorders, and complement current NBS by providing immediate data for molecular confirmation of numerous biochemically screened conditions.

Population spectrum ofACADMgenotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most frequent inherited defect of fatty acid oxidation, with a significant morbidity and mortality in undiagnosed patients. Adverse outcomes can effectively be prevented by avoiding metabolic stress and following simple dietary measures. Therefore, prospective newborn screening (NBS) is being proposed for this condition. However, technical validation of MCADD population screening and assessment of its overall benefit require broadening of the as-yet-scarce knowledge of the MCADD genetic heterogeneity unraveled by NBS and its phenotypic consequences. Here, we describe the entire spectrum of sequence variations occurring in newborns with MCADD in the population of Bavaria, Germany, in relation to the biochemical phenotype. Among 524,287 newborns, we identified 62 cases of MCADD, indicating a birth incidence of 1 in 8,456. In all of the 57 newborns available for analysis, two alterations within the MCADD gene (ACADM) were identified. The most prevalent alteration c.985A>G (Lys329Glu) occurred in 27 (47%) newborns in the homozygous and in 18 (32%) in the heterozygous state (63% of defective alleles). The mild folding variant c.199T>C (Tyr67His) was identified in nine individuals, six of them being compound heterozygous with c.985A>G (Lys329Glu). Neither of the prevalent alterations were found in the remaining nine newborns. A total of 18 sequence variations were identified; 13 of them were novel: eight missense mutations, one nonsense mutation, two splice variants, and two small deletions. The remaining five were previously reported in MCADD patients. The ACADM heterogeneity uncovered was larger as anticipated from previous c.985A>G (Lys329Glu) carrier screening data. In addition, we show that MCADD appears to occur as frequently in Turkish newborns as in the native German population. Our data validate that biochemical NBS for MCADD is a highly specific procedure for disease detection, with the identification of a significant share of milder biochemical phenotypes, such as c.199T>C (Tyr67His). These show statistically lower acylcarnitine markers, allowing us to distinguish subgroups within the spectrum of ACADM sequence variations that correlate to biochemical MCADD disease expression. Our data might provide technical and medical guidance for decision making in the worldwide efforts to introduce MCADD population screening.