Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020-2023).

Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert "Bob" Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.

Integrating Genetic Services in the Philippine Public Health Delivery System: The Value of Networks.

The delivery of genetic services in developing countries is faced with significant challenges, despite medical and technological advances globally. The Philippines, being an archipelago, faces even more challenges, with significant disparities in access to healthcare, and tertiary medical centers and specialists being concentrated in the major cities. The utilization of different networks for the integration of genetic services in the existing public health delivery system has been valuable. Using the well-established network of the national newborn screening program, genetic services have been successfully integrated into the delivery of healthcare, even at the grassroot level. Equitable access to healthcare, including genetic services, was highlighted and supported by the enactment of the Rare Disease Law in 2016. The support of the academe to assure the sustainability of services was evident in the establishment of a genetic counseling program to augment the work of a handful of clinical geneticists. Professional societies and support groups have been instrumental in identifying genetic conditions to be prioritized and lobbying for increased public awareness, leading to national programs and policies. This paper primarily discusses the value of networks in the delivery of genetic services, specifically newborn screening, programs for rare diseases, birth defects, and genetic counseling.

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

Successful Implementation of Expanded Newborn Screening in the Philippines Using Tandem Mass Spectrometry.

Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, NBS programs in countries with developed economies have also expanded, not only in the number of newborns screened but also in the number of conditions included in the screening. Various approaches have been taken regarding selection of conditions to be screened. With limited resources, low- and middle-income countries face significant challenges in selecting conditions for screening and in implementing sustainable screening programs. Building on expansion experiences in the U.S. and data from California on Filipinos born and screened there, the Philippine NBS program has recently completed its expansion to include 29 screening conditions. This report focuses on those conditions detectable through tandem mass spectrometry. Expanded screening was implemented in a stepwise fashion across the seven newborn screening laboratories in the Philippines. A university-based biochemical genetics laboratory provides confirmatory testing. Follow-up care for confirmed cases is monitored and provided through the NBS continuity clinics across the archipelago. Pre-COVID-19 pandemic, the coverage was 91.6% but dropped to 80.4% by the end of 2020 due to closure of borders between cities, provinces, and islands.

Newborn Screening Long-Term Follow-Up Clinics (Continuity Clinics) in the Philippines during the COVID-19 Pandemic: Continuing Quality Patient Care.

The COVID-19 pandemic has challenged healthcare systems worldwide. In the Philippines, long-term care for patients with conditions identified through newborn screening (NBS) is coordinated through Newborn Screening Continuity Clinics (NBSCCs). These clinics are integral to achieving optimal outcomes by providing follow-up oversight and assistance for individuals identified through screening. Continuity of NBSCC care for NBS during the COVID-19 pandemic was both challenging and necessary and was accomplished through innovative strategies of dedicated personnel. Following the discontinuation of the community quarantine, a situation assessment survey was completed by each NBSCC to better understand the challenges encountered and their effect on patient care. Performance data from each NBSCC were reviewed both before and after an extended community quarantine (2018-2021) to evaluate the impact of NBSCC disaster contingency plans in overcoming the resultant challenges (transportation, supply chain, etc.). Thematic analysis of the survey showed three primary challenges: Operations, communications, and safety. In 2018 and 2019, successful patient contacts were 70.6% and 70.2%, respectively. During the pandemic, successful contacts were 74.9% in 2020 and 76.8% in 2021, demonstrating that the contact approaches taken by the NBSCCs were sufficient to maintain (and even improve) patient contacts. The number of unresponsive patients decreased during the pandemic likely due to decreased mobility and improved follow-up actions from the NBSCCs.

Estimating the annual dengue force of infection from the age of reporting primary infections across urban centres in endemic countries.

BACKGROUND: Stratifying dengue risk within endemic countries is crucial for allocating limited control interventions. Current methods of monitoring dengue transmission intensity rely on potentially inaccurate incidence estimates. We investigated whether incidence or alternate metrics obtained from standard, or laboratory, surveillance operations represent accurate surrogate indicators of the burden of dengue and can be used to monitor the force of infection (FOI) across urban centres. METHODS: Among those who reported and resided in 13 cities across the Philippines, we collected epidemiological data from all dengue case reports between 2014 and 2017 (N 80,043) and additional laboratory data from a cross-section of sampled case reports (N 11,906) between 2014 and 2018. At the city level, we estimated the aggregated annual FOI from age-accumulated IgG among the non-dengue reporting population using catalytic modelling. We compared city-aggregated FOI estimates to aggregated incidence and the mean age of clinically and laboratory diagnosed dengue cases using Pearson's Correlation coefficient and generated predicted FOI estimates using regression modelling. RESULTS: We observed spatial heterogeneity in the dengue average annual FOI across sampled cities, ranging from 0.054 [0.036-0.081] to 0.249 [0.223-0.279]. Compared to FOI estimates, the mean age of primary dengue infections had the strongest association (ρ -0.848, p value<0.001) followed by the mean age of those reporting with warning signs (ρ -0.642, p value 0.018). Using regression modelling, we estimated the predicted annual dengue FOI across urban centres from the age of those reporting with primary infections and revealed prominent spatio-temporal heterogeneity in transmission intensity. CONCLUSIONS: We show the mean age of those reporting with their first dengue infection or those reporting with warning signs of dengue represent superior indicators of the dengue FOI compared to crude incidence across urban centres. Our work provides a framework for national dengue surveillance to routinely monitor transmission and target control interventions to populations most in need.

Serological Evidence of Widespread Zika Transmission across the Philippines.

Zika virus (ZIKV) exposure across flavivirus-endemic countries, including the Philippines, remains largely unknown despite sporadic case reporting and environmental suitability for transmission. Using laboratory surveillance data from 2016, 997 serum samples were randomly selected from suspected dengue (DENV) case reports across the Philippines and assayed for serological markers of short-term (IgM) and long-term (IgG) ZIKV exposure. Using mixture models, we re-evaluated ZIKV IgM/G seroprevalence thresholds and used catalytic models to quantify the force of infection (attack rate, AR) from age-accumulated ZIKV exposure. While we observed extensive ZIKV/DENV IgG cross-reactivity, not all individuals with active DENV presented with elevated ZIKV IgG, and a proportion of dengue-negative cases (DENV IgG-) were ZIKV IgG-positive (14.3%, 9/63). We identified evidence of long-term, yet not short-term, ZIKV exposure across Philippine regions (ZIKV IgG+: 31.5%, 314/997) which was geographically uncorrelated with DENV exposure. In contrast to the DENV AR (12.7% (95%CI: 9.1-17.4%)), the ZIKV AR was lower (5.7% (95%CI: 3-11%)) across the country. Our results provide evidence of widespread ZIKV exposure across the Philippines and suggest the need for studies to identify ZIKV infection risk factors over time to better prepare for potential future outbreaks.

Successful Implementation of Newborn Screening for Hemoglobin Disorders in the Philippines.

The Philippine newborn bloodspot screening (NBS) program began in 1996 with 24 hospitals and was formalized by legislation in 2004. The NBS panel was recently expanded to include a number of additional hereditary congenital conditions. Expertise and experiences from other NBS programs already screening for hemoglobinopathies were essential to its successful integration into the ongoing dried bloodspot NBS program in the Philippines. Building on clinical experiences and population data from Filipinos born in California, USA, hemoglobinopathies (including thalassemias) were selected for inclusion in the expanded screening panel. Hemoglobinopathy NBS, using high performance liquid chromatography, was implemented in a stepwise manner into the seven regional NBS screening laboratories. A central university laboratory provides confirmatory testing using both capillary electrophoresis and molecular methodologies. NBS results indicating carriers are followed up with educational fact sheets, while results of presumptive disease are referred for confirmatory testing and follow-up with a hematologist. Long-term care is provided through newborn screening continuity clinics across the country. Hemoglobinopathy NBS is now included in the national insurance package and screening uptake continues to increase nationally, exceeding 90% of all newborns in 7400+ hospitals and birthing centers nationwide prior to the COVID-19 pandemic.

Pregnancy in an adolescent with maple syrup urine disease: Case report.

Maple syrup urine disease (MSUD, MIM #248600) is an autosomal recessive metabolic disorder that results in elevation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Elevation of BCAA and certain alpha keto-acids is associated with a catabolic state and may result in neurological and developmental delays, feeding problems, and a urine and cerumen odor of maple syrup. Pregnancy is a period of multiple adaptations necessary to support fetal growth and development. Both the third trimester of pregnancy and the postpartum period present the possibility for catabolic states. We describe our treatment of an adolescent patient with intermittent MSUD and her resulting positive pregnancy outcome.

TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation.

TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.

Philippine Performance Evaluation and Assessment Scheme (PPEAS): Experiences in Newborn Screening System Quality Improvement.

Newborn Bloodspot Screening (NBS) has existed for over 60 years, having been initiated by Guthrie in the U.S. In the Philippines, NBS was introduced in 1996 and later was supported by legislation. The NBS program now includes 29 conditions, covering 91.6% of the newborn population in 2019. Program growth and expansion necessitated development of a formal performance evaluation and assessment scheme (PEAS) for monitoring performance and for continuously improving quality. This study's objective was to present the development, implementation, and results to date of the Philippine Performance PEAS (PPEAS). Using the comprehensive listing of laboratory and non-laboratory elements in the model PEAS system in the U.S., PPEAS tools were developed for critical Philippine NBS system components: regional Department of Health (national health agency, Philippines) (DOH) offices (CHDs), NBS laboratories (NSCs), NBS specimen submitters (NSFs), and long-term case management centers (NBSCCs). Data generated from the various PPEAS have been periodically reviewed and analyzed for NBS system impact. PPEAS were developed to facilitate quality improvement at various levels of the Philippine NBS system. PPEAS identified successes, gaps, and challenges to be addressed by NSCs, NSFs, CHDs, and NBSCCs with the assistance of the Newborn Screening Reference Center and the Department of Health.

A serological framework to investigate acute primary and post-primary dengue cases reporting across the Philippines.

BACKGROUND: In dengue-endemic countries, targeting limited control interventions to populations at risk of severe disease could enable increased efficiency. Individuals who have had their first (primary) dengue infection are at risk of developing more severe secondary disease, thus could be targeted for disease prevention. Currently, there is no reliable algorithm for determining primary and post-primary (infection with more than one flavivirus) status from a single serum sample. In this study, we developed and validated an immune status algorithm using single acute serum samples from reporting patients and investigated dengue immuno-epidemiological patterns across the Philippines. METHODS: During 2015/2016, a cross-sectional sample of 10,137 dengue case reports provided serum for molecular (anti-DENV PCR) and serological (anti-DENV IgM/G capture ELISA) assay. Using mixture modelling, we re-assessed IgM/G seroprevalence and estimated functional, disease day-specific, IgG:IgM ratios that categorised the reporting population as negative, historical, primary and post-primary for dengue. We validated our algorithm against WHO gold standard criteria and investigated cross-reactivity with Zika by assaying a random subset for anti-ZIKV IgM and IgG. Lastly, using our algorithm, we explored immuno-epidemiological patterns of dengue across the Philippines. RESULTS: Our modelled IgM and IgG seroprevalence thresholds were lower than kit-provided thresholds. Individuals anti-DENV PCR+ or IgM+ were classified as active dengue infections (83.1%, 6998/8425). IgG- and IgG+ active dengue infections on disease days 1 and 2 were categorised as primary and post-primary, respectively, while those on disease days 3 to 5 with IgG:IgM ratios below and above 0.45 were classified as primary and post-primary, respectively. A significant proportion of post-primary dengue infections had elevated anti-ZIKV IgG inferring previous Zika exposure. Our algorithm achieved 90.5% serological agreement with WHO standard practice. Post-primary dengue infections were more likely to be older and present with severe symptoms. Finally, we identified a spatio-temporal cluster of primary dengue case reporting in northern Luzon during 2016. CONCLUSIONS: Our dengue immune status algorithm can equip surveillance operations with the means to target dengue control efforts. The algorithm accurately identified primary dengue infections who are at risk of future severe disease.

Empowering newborn screening programs in African countries through establishment of an international collaborative effort.

In an effort to explore new knowledge and to develop meaningful collaborations for improving child health, the First Pan African Workshop on Newborn Screening was convened in June 2019 in Rabat, Morocco. Participants included an informal network of newborn screening stakeholders from across Africa and global experts in newborn screening and sickle cell disease. Over 150 attendees, representing 20 countries, were present including 11 African countries. The agenda focused on newborn screening rationale, techniques, system development, implementation barriers, ongoing research, and collaborations both globally and across Africa. We provide an overview of the workshop and a description of the newborn screening activities in the 11 African countries represented at the workshop, with a focus on sickle cell disease.

Newborn screening in the developing countries.

PURPOSE OF REVIEW: We review newborn screening (NBS) publications from the developing countries to identify global progress in improving child health. RECENT FINDINGS: Many developing countries do not yet have national NBS. As infant mortality rates decline, NBS gains in public health priority. Local incidence and outcome data are used to persuade health officials to include screening in priority health spending. Congenital hypothyroidism is the most cost-effective screened condition in most countries. In sub-Saharan Africa, India and some parts of Asia, screening for hemoglobinopathies and glucose-6-dehydrogenase deficiency are also important. Expanded screening for metabolic conditions is most needed in areas of high consanguinity. Screening for hearing disorders and critical congenital heart defects is increasing globally. The largest birth cohorts are India and China, but only China has successful NBS. Reports from completed government research projects in India support initiation of NBS. SUMMARY: Government activities around NBS are increasing in India and there is increased emphasis on pilot programs for sickle cell NBS in sub-Saharan Africa. Genetic counseling training in Asia and Africa is increasing and will be helpful as part of NBS. To build successful screening programs, partnerships among health professionals, parents, policy makers and industry stakeholders are essential.

Communication about Congenital Adrenal Hyperplasia: Perspective of Filipino Families.

Congenital adrenal hyperplasia (CAH), like other genetic conditions, is a relational disease from both the biological and psychosocial perspectives since the diagnosis gives rise to a variety of health, reproductive, and psychosocial implications. It is in these contexts that family communication of genetic information is important to study. Hence, this research aimed to explore genetic information communication in Filipino families affected with CAH. Using a qualitative descriptive design, families with a child affected with CAH were recruited through the CAH parent support group and were interviewed. Semi-structured interviews explored flow and content of genetic information communicated, the meanings the families attach to the communicated information, and the motivating and hindering factors in communication. Thematic analysis was used to analyze the findings. A total of five families participated, which included 11 individuals. Findings revealed that the diagnosis of CAH is not kept secret and it is openly shared with the family. The decision to communicate is influenced by several factors including the family's desire to seek further information about their family history. Initially, the focus of the communicated information is on the health implications and while communication about genetics occurs, this is almost always confined to the immediate family. The mother and grandmother serve as primary communicators in the family. The families have limited understanding of CAH especially its genetic implications including recurrence risk and carrier status. The findings can guide genetic counselors in supporting families in communicating information about CAH with the rest of the family.

Genetics and genomic medicine in the Philippines.

Genetics and genomic medicine in the Philippines.

Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population.

OBJECTIVE: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population. STUDY DESIGN: Cross-sectional study. SETTING: Indigenous Filipino community. SUBJECTS AND METHODS: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster. RESULTS: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1-variant carriers. CONCLUSION: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.

Prevention of Congenital Disorders and Care of Affected Children: A Consensus Statement.

As the Sustainable Development Goals are adopted by United Nations member states, children with congenital disorders remain left behind in policies, programs, research, and funding. Although this finding was recognized by the creation and endorsement of the 63rd World Health Assembly Resolution in 2010 calling on United Nations member states to strengthen prevention of congenital disorders and the improvement of care of those affected, there has been little to no action since then. The Sustainable Development Goals call for the global health and development community to focus first and foremost on the most vulnerable and those left behind in the Millennium Development Goal era. To maximize the opportunity for every woman and couple to have a healthy child and to reduce the mortality and severe disability associated with potentially avoidable congenital disorders and their consequences for the children affected, their families and communities, and national health care systems, we propose priority measures that should be taken urgently to address this issue.

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.