Importancia del citomegalovirus congénito en el programa de cribado auditivo neonatal / Importance of congenital cytomegalovirus in the neonatal hearing screening program

Introducción En recién nacidos, la hipoacusia secundaria a una infección congénita por citomegalovirus (CMVc), pese a su baja prevalencia, puede generar un grave problema en el desarrollo personal y la integración social de los pacientes. Por ello, es importante incluir la determinación del ADN de CMV como herramienta del cribado neonatal. Materiales y métodos Hemos realizado un estudio retrospectivo de 5 años, mediante la descripción de las CMVc en la Comunidad Autónoma del País Vasco en los recién nacidos que no superaron el cribado auditivo en el programa de detección precoz de hipoacusia. Se describen los tiempos de detección, confirmación (incidencia) e intervención (tratamiento). Resultados De 18.782 sujetos estudiados, 58 (3 por cada 1.000 nacidos vivos) presentaron hipoacusia. De ellos, se confirmó CMVc en 4pacientes (una mujer y 3hombres).El tiempo promedio para el cribado auditivo fue de 6,5 días (DE:±3,69) y para detectar el CMV mediante reacción en cadena de la polimerasa en orina y saliva fue de 4,2 días (DE:±3,94).El tiempo para confirmar la hipoacusia mediante PEATC e intervención audiológica fue de 2,2 meses (DE:±0,957) y 5 meses (DE:±3,741), respectivamente. Se realizaron 4adaptaciones audioprotésicas y un implante coclear. Discusión y conclusión El cribado auditivo neonatal se ha consolidado como un buen programa de salud pública. La determinación del ADN viral permite un diagnóstico y tratamiento precoz, específico e interdisciplinar, en el que la otorrinolaringología tiene un papel fundamental. Nuestro estudio resalta la importancia de incluir la reacción en cadena de la polimerasa del CMV como herramienta de cribado universal. (AU)

Introduction In newborns, hearing loss secondary to congenital cytomegalovirus (CMVc) infection, despite its low prevalence, can cause a serious problem in the personal development and social integration of patients. Therefore, it is important to include the determination of CMV DNA as a neonatal screening tool. Materials and methods We have carried out a 5-year retrospective study, by describing the CMVc in the Autonomous Community of the Basque Country (Spain) in newborns who did not pass the hearing screening in the early hearing loss detection program. The times of detection, confirmation (incidence) and intervention (treatment) are described. Results Of 18,782 subjects studied, 58 (3 per 1,000 live births) presented hearing loss. Of these, CMVc is guaranteed in 4patients (one woman and 3men). The mean time to hearing screening was 6.5 days (SD: ±3.69) and to detect CMV by polymerase chain reaction in urine and saliva was 4.2 days (SD: ±3.94). Time to confirm hearing loss by BAEP and audiological intervention 2.2 (SD: ±0.957) and 5 months (SD: ±3.741), respectively. Four hearing aid adaptations and one cochlear implant were performed. Discussion and conclusion Neonatal hearing screening has established itself as a good public health program. The determination of viral DNA allows an early, specific and interdisciplinary diagnosis and treatment, in which otorhinolaryngology plays a fundamental role. Our study highlights the importance of including CMV polymerase chain reaction as a universal screening tool. (AU)

Genetic newborn screening and digital technologies: A project protocol based on a dual approach to shorten the rare diseases diagnostic path in Europe.

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

[Analysis of disease spectrum for abnormal 3-hydroxyisovalerylcarnitine metabolism identified through newborn screening and clinical diagnosis].

OBJECTIVE: To explore the disease spectrum for abnormal 3-hydroxyisovalerylcarnitine (C5OH) metabolism identified through newborn screening and clinical diagnosis patients and the key points for differential diagnosis so as to raise the awareness of pediatricians for such diseases. METHODS: Clinical data of 85 neonates with abnormal C5OH metabolism identified from February 2004 to January 2022 at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were collected. Their clinical manifestations and results of tandem mass spectrometry (MS/MS), gas chromatography mass spectrometry (GC-MS) and genetic testing were retrospectively analyzed. RESULTS: Among the 85 cases, 46 (54.1%) were identified by neonate screening, whilst 39 (45.9%) were clinically diagnosed patients. Five diseases were diagnosed, including 28 cases with multiple carboxylase deficiency (MCD, 32.9%), 29 cases with 3-methylcrotonyl-coenzymeAcarboxylasedeficiency (MCCD, 34.1%), 4 cases with 3-methylglutaconic acid (3-MGA, 4.7%), 7 cases with 3-hydroxy-3-methylglutaric acid (3-HMG, 8.2%), and 17 cases with beta-ketothiolase deficiency (BKD, 20.0%). The disorders were characterized by sudden onset, anorexia, vomiting, diarrhea, abnormal breathing, consciousness disorder, spasm and developmental delay. CONCLUSION: Among newborns with abnormal C5OH metabolism, MCCD is the most common disorder, which was followed by BKD and MCD. For patients with abnormal C5OH metabolism, MCD is the most common, followed by BKD and 3-HMG. C5OH related diseases have great heterogeneity. Combination of blood acylcarnitine levels, urinary organic acid levels and genetic testing based on clinical characteristics can help to attain the diagnosis.

New challenges in management of phenylketonuria in pregnancy: a case report.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disease that belongs to a group of disorders resulting from inborn errors of protein metabolism. It was the first disease included in neonatal screening. Neonatal screening has allowed an early diagnosis and treatment of the disease. As a result, an increasing number of women diagnosed with phenylketonuria have reached the reproductive phase of life in good health, and management of pregnancy in women with PKU is becoming more frequent. CASE PRESENTATION: In this study, we report the case of a 28-year-old Caucasian patient being followed up for phenylketonuria at Ramón y Cajal Hospital's Metabolic Diseases Unit. We describe the patient's gestation, impacted by her and her partner's diagnosis of PKU, classic and mild phenotypes, respectively, resulting in the fetus affectation. CONCLUSIONS: The description of PKU management-diagnosis, follow-up, and treatment-for both that of patient and that of the gestation with fetus affectation covers a wide sample scenario that shows the effectiveness of pregnancy planning and monitoring of females with PKU and questions the need to carry out a genetic study of gene PKU in the study of fertility.

Incidence of Inborn Errors of Metabolism in Newborn Infants: Five Years' Single-Center Experience, Jeddah, Saudi Arabia.

Inborn errors of metabolism (IEMs) are inherited biochemical/metabolic disorders that are commonly present in the immediate neonatal period. The aim of this retrospective study was to determine the incidence and distribution of IEMs in newborn infants delivered in our hospital and to evaluate its outcome. A total of 16 494 (99.9%) newborn infants were screened for IEMs. We found 29 newborn infants diagnosed with IEMs, representing an incidence of 1 per ~569 live births and a cumulative incidence of 176 per 100 000 live births of the IEM-positive newborn infants. We detected 11 different types of IEMs, and the top 6 categories were endocrinopathies followed by carbohydrates disorders, vitamin-responsive disorders, organic acid defects, and ketogenesis and ketolysis defects. This study does reflect upon the importance of educating the general population about the perils of Consanguineous Marriages (CMs) in order to reduce related disorders significantly, especially in families who have a history of IEMs.

Universal in-house neonatal hips ultrasonography screening in the United Arab Emirates.

OBJECTIVES: To investigate if the incidence of developmental dysplasia of the hip (DDH) differs considering the geographical origin, clinical picture, or presence of risk factors in homogenous cohort of neonates born in Mediclinic Al Jowhara hospital, Al Ain, United Arab of Emirates (UAE). METHODS: Universal ultrasonography hips screening of the neonates in the maternity ward of Mediclinic Al Jowhara hospital, Al Ain, UAE, was carried out using the Graf method. The average age of the neonates was 3 days. Two groups were formed for comparison: I) the Gulf Cooperation Council (GCC) group (n=169, 47.7%), and II) the non-GCC group (n=185, 52.3%). RESULTS: The incidence of DDH was 1.7%. It was higher among neonates from the GCC region (2.9%) and significantly higher among girls from this region (6.3%). The incidence of immature hips (type IIa) was 9% and was similar regardless of origin or gender. CONCLUSION: Neonates from the GCC region, girls in particular, have a higher incidence of DDH. These results highlight the emergency to establish a national ultrasonography DDH screening program.

Can machine learning methods be used for identification of at-risk neonates in low-resource settings? A prospective cohort study.

INTRODUCTION: Timely identification of at-risk neonates (ARNs) in the community is essential to reduce mortality in low-resource settings. Tools such as American Academy of Pediatrics pulse oximetry (POx) and WHO Young Infants Clinical Signs (WHOS) have high specificity but low sensitivity to identify ARNs. Our aim was assessing the value of POx and WHOS independently, in combination and with machine learning (ML) from clinical features, to detect ARNs in a low/middle-income country. METHODS: This prospective cohort study was conducted in a periurban community in Pakistan. Eligible live births were screened using WHOS and POx along with clinical information regarding pregnancy and delivery. The enrolled neonates were followed for 4 weeks of life to assess the vital status. The predictive value to identify ARNs, of POx, WHOS and an ML model using maternal and neonatal clinical features, was assessed. RESULTS: Of 1336 neonates, 68 (5%) had adverse outcomes, that is, sepsis (n=40, 59%), critical congenital heart disease (n=2, 3%), severe persistent pulmonary hypertension (n=1), hospitalisation (n=8, 12%) and death (n=17, 25%) assessed at 4 weeks of life. Specificity of POx and WHOS to independently identify ARNs was 99%, with sensitivity of 19% and 63%,respectively. Combining both improved sensitivity to 70%, keeping specificity at 98%. An ML model using clinical variables had 44% specificity and 76% sensitivity. A staged assessment, where WHOS, POx and ML are sequentially used for triage, increased sensitivity to 85%, keeping specificity 75%. Using ML (when WHOS and POx negative) for community follow-up detected the majority of ARNs. CONCLUSION: Classic screening, combined with ML, can help maximise identifying ARNs and could be embedded in low-resource clinical settings, thereby improving outcome. Sequential use of classic assessment and clinical ML identifies the most ARNs in the community, still optimising follow-up clinical care.

Allan-Herndon-Dudley syndrome in Hong Kong: Implication for newborn screening.

BACKGROUND: Allan-Herndon-Dudley syndrome (MCT 8 deficiency) is an X-linked recessive condition caused by hemizygous pathogenic variants in SLC16A2 encoding the monocarboxylate transporter 8 (MCT8). Patients present with global developmental delay and neurological impairment, and abnormal serum thyroid function tests. The drug, 3,3',5 triiodothyroacetic acid (TRIAC), was recently demonstrated to improve the endocrinological profile. Improvement in diagnostic approach is key to earlier start of treatment. PATIENT FINDINGS: We described four Chinese patients with MCT8 deficiency undergoing different diagnostic odysseys. Their initial presentation included global developmental delay and dystonia. Patient 2 also had epilepsy. Patients 1 and 2 presented with two novel variants: (1)hemizygous NM_006517.4(SLC16A2):c.1170 + 2 T > A; p.(?), and (2)hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17) respectively. Patients 3 and 4 were biological brothers harboring hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17), which was first reported in 2004. We obtained the measurement of triiodothyronine (T3) and reverse T3 (rT3) from dried blood spot samples collected on Day 1 of life from Patient 1 and studied the biomarkers (rT3 and T3/rT3 ratio) proposed by Iwayama et al. for the detection of MCT8 deficiency at birth. Our data verified the significantly reduced rT3 level in Patient 1, compared with healthy newborns, although low T3 level and comparable T3/rT3 ratio with controls were detected. SUMMARY: Patients with MCT8 deficiency often undergo diagnostic odysseys. An early diagnosis could be missed by a normal newborn thyroid function screening result based on biochemical measurement of TSH and/or T4/fT4. Early detection of rT3 is key to improving current diagnostic approach. CONCLUSION: We recommend that full thyroid function profile (TSH, T4/fT4, T3/fT3, rT3) be considered early for all pediatric patients presenting with unexplained developmental delay and/or dystonia. The potential inclusion of rT3 measurement in newborn screening may prove promising.

Fibrosis quística: epidemiología, clínica, diagnóstico y tratamiento / Cystic fibrosis: Epidemiology, clinical manifestations, diagnosis and treatment

La fibrosis quística es una enfermedad genética y multisistémica. La principal comorbilidad en la edad adulta es la afectación respiratoria, con la presencia de bronquiectasias, infección bronquial crónica y obstrucción al flujo aéreo. Hasta hace una década los tratamientos estaban dirigidos a favorecer el drenaje de secreciones, reducir las exacerbaciones respiratorias, controlar la infección bronquial crónica y enlentecer el deterioro funcional, pero con la llegada de los moduladores del gen cystic fibrosis transmembrane conductance regulator (CFTR) el paradigma de la fibrosis quística se ha modificado. Este novedoso tratamiento da un paso más frente al tratamiento de esta enfermedad, es capaz de mejorar la producción de proteína CFTR defectuosa y aumentar su expresión en la superficie celular, para así conseguir un mejor funcionamiento del intercambio iónico fluidificando las secreciones respiratorias y reduciendo la obstrucción al flujo aéreo. Además, en la actualidad hay diferentes líneas de investigación orientadas a corregir el defecto genético causante de la fibrosis quística (AU)

Cystic fibrosis is a genetic and multisystemic disease. The main comorbidity in adulthood is respiratory involvement, with the presence of bronchiectasis, chronic bronchial infection and airflow obstruction. Until a decade ago, treatments were aimed at favoring secretion drainage, reducing respiratory exacerbations, controlling chronic bronchial infection and slowing functional deterioration, but with the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, the cystic fibrosis paradigm has changed. This novel treatment goes a step further in the management of this disease, it is able to improve the production of defective CFTR protein and increase its expression on the cell surface, thus achieving a better functioning of ion exchange, fluidizing respiratory secretions and reducing airflow obstruction. In addition, there are currently different lines of research aimed at correcting the genetic defect that causes cystic fibrosis (AU)

Neonatal Hearing Screening Programme And Challenges Faced By The Developing Country: A Tertiary Care Hospital Experience.

OBJECTIVE: To screen new-borns to diagnose any hearing impairment early. METHODS: The prospective, cross-sectionalstudy was conducted at the Department of Otorhinolaryngology, Head and Neck Surgery Liaquat National Hospital, Karachi, from November 1, 2020, to April 30, 2021, and new- borns of either gender aged >12h born via spontaneous vaginal delivery, induced labour, and Caesarean section. A predesigned questionnaire was used to collect detailed case history, including gestational age, duration of labour, and other prenatal, natal, and postnatal risk factors. Otoacoustic emission test was performed, and infants referred twice were scheduled for complete diagnostic evaluation and brainstem evoked response audiometry. Data was analysed using SPSS 23. RESULTS: Of the 267 neonates, 249(93.3%) passed the first screening. Of the remaining 18(6.7%) neonates, 8(44.4%) passed the second screening, while 10(55.5%) were asked to come for a follow-up after three weeks. Of them, 3(30%) returned for check-up, while 7(70%) did not show up. CONCLUSIONS: Neonatal risk factors associated with hearing loss need to be identified, and a comprehensive hearing screening programme is required for neonates.

Factors Associated With Awareness Of Literate Mothers About Newborn Screening: A Cross-Sectional Study From A Low-Middle-Income Country.

Objectives: To explore the awarenesslevel of literate mothersregarding newborn screening programmes, and to evaluate the associated factors. METHODS: The descriptive, cross-sectional study was conducted at the Section of Chemical Pathology, Department of Pathology andLaboratoryMedicine,AgaKhanUniversity,Karachi,fromJanuary toSeptember 2021, andcomprisedmothers aged 18 years or more. Data was collected using a structured questionnaire about newborn screening, and the subjects were compared in terms of age, residential background, education and parity. Data was analysed using SPSS 23. RESULTS: Of the 1016 responses, 896(88.2%) were analysed. The mean age of the sample was 37.7±10.87 years. There were 470(52.4%) mothers aged 31-45 years, 859(95.87%) were from urban areas, 751(84%) had a graduate degree, 652(72.7%) weremultiparous andhad824(91.9%)hadhealthy children.Overall, 386 (43%)mothershadawarenessofnewbornscreening programmes. The main factors associated with awareness were age, education, primiparity, having healthy children, and province ofresidencebeing Sindh andPunjab(p<0.05),while the urban-ruraldividedwas not a significantfactor(p=0.737). Cost of healthcare 417(46.5%) and lack of awareness among physicians 356(39.7%) were identified asthe main challenges in establishing newborn screening servicesin the country. CONCLUSIONS: The awareness among mothers about new born screening programmes was generally low among the subjects studied.

The prevalence of risk for hearing impairment in newborns with congenital syphilis in a newborn hearing screening program (NHS).

Objective: To study the prevalence of risk for hearing impairment in neonates with congenital syphilis in a newborn hearing screening program. Study design: The study design is retrospective, documentary, and is cross-sectional. The sample consisted of newborns who were born between January 2019 and December 2021 and who underwent neonatal hearing screening in a public maternity hospital. Demographic data and the presence and specification of risk indicators for hearing impairment (RIHL) were collected. In retest cases, the results and the final score were also collected. For data analysis, the Kruskal-Wallis and Conover-Iman post-hoc tests were used, comparing the groups that passed and failed the hearing screening that had RIHL, using a significance level of p of <0.5. Results: Among the RIHL observed in the sample, prematurity was more frequent in newborns who passed the screening (55.26%) than in those who failed the test (45.67%). Congenital syphilis was the ninth most frequent RIHL (8.04%) among the newborns who passed the test and the 15th factor (3.03%), with the highest occurrence in those who failed the hearing screening. When comparing the two groups (pass and fail), we found significant differences (p < 0.05) between them. Conclusion: Congenital syphilis was the ninth risk indicator for the most common hearing impairment and, in isolation, did not present a risk for failure in neonatal hearing screening. Notably, congenital syphilis can cause late hearing loss during child development. Thus, there is an indication of audiological monitoring of these neonates.

Newborn genetic screening is highly effective for high-risk infants: A single-centre study in China.

Background: Newborn genetic screening (NBGS) is promising for early detection of genetic diseases in newborns. However, little is known about its clinical effectiveness in special groups like high-risk infants. To address this gap, we aimed to investigate the impact of NBGS on high-risk infants. Methods: We screened 10 334 healthy newborns from the general maternity unit and 886 high-risk infants from the neonatal ward using both traditional newborn screening (tNBS) and NBGS, and collected clinical data from electronic medical records. Results: We found that high-risk infants had a higher proportion of eutocia (P < 0.01) and prematurity (P < 0.01). For high-risk infants vs healthy newborns screened by tNBS, the primary screening positive rate was 3.84% vs 1.31%, the false positive rate (FPR) was 3.62% vs 1.18% (P < 0.001), and the positive predictive value (PPV) was 5.88% vs 8.27%. For NBGS vs tNBS in high-risk infants, the primary screening positive rate was 0.54% vs 3.68%, the FPR was 0.22% vs 3.47%, and the PPV was 60.00% vs 5.88%. Conclusions: We found that combined newborn screening can effectively reduce the FPR caused by the high-risk symptoms and improve the PPV in high-risk infants, sufficient for more accurately showing the true status of the disease.

Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies.

Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000-10,000 live births, being long considered a leading cause of hereditary mortality in infancy, worldwide. The classification of SMA is based on the natural history of the disease, with a wide clinical spectrum of onset and severity. We are currently in a new therapeutic era, that, thanks to the widespread use of the newly approved disease-modifying therapies and the possibility of an early administration, should lead to a deep change in the clinical scenario and, thus, in the history of SMA. With the aim to achieve a new view of SMA, in this review we consider different aspects of this neuromuscular disease: the historical perspective, the clinical features, the diagnostic process, the psychological outcome, innovation in treatments and therapies, the possibility of an early identification of affected infants in the pre-symptomatic phase through newborn screening programs.

The use of liquid chromatography-tandem mass spectrometry in newborn screening for congenital adrenal hyperplasia: improvements and future perspectives.

Newborn screening for congenital adrenal hyperplasia using 17-hydroxyprogesterone by immunoassay remains controversial despite screening been available for almost 40 years. Screening is confounded by poor immunoassay specificity, fetal adrenal physiology, stress, and illness which can result in a large number of false positive screening tests. Screening programmes apply higher screening thresholds based on co-variates such as birthweight or gestational age but the false positive rate using immunoassay remains high. Mass spectrometry was first applied to newborn screening for congenital adrenal hyperplasia over 15 years ago. Elevated 17-hydroxprogesterone by immunoassay can be retested with a specific liquid chromatography tandem mass spectrometry assay that may include additional steroid markers. Laboratories register with quality assurance programme providers to ensure accurate steroid measurements. This has led to improvements in screening but there are additional costs and added laboratory workload. The search for novel steroid markers may inform further improvements to screening. Studies have shown that 11-oxygenated androgens are elevated in untreated patients and that the adrenal steroidogenesis backdoor pathway is more active in babies with congenital adrenal hyperplasia. There is continual interest in 21-deoxycortisol, a specific marker of 21-hydroxylase deficiency. The measurement of androgenic steroids and their precursors by liquid chromatography tandem mass spectrometry in bloodspots may inform improvements for screening, diagnosis, and treatment monitoring. In this review, we describe how liquid chromatography tandem mass spectrometry has improved newborn screening for congenital adrenal hyperplasia and explore how future developments may inform further improvements to screening and diagnosis.

Newborn Hearing Screening: Early Ear Examination Improves the Pass Rate.

BACKGROUND: Temporary conductive hearing loss due to vernix accumulation in the external ear canal may lead to a false-positive result in newborn hearing screening tests. The aim of this study was to evaluate whether ear examination and intervention may reduce the false-positive rate prior to hospital discharge. METHODS: A case series of 42 newborns who failed initial otoacoustic emissions screening were studied in our institution between May and December 2020. RESULTS: During the study period, a total of 735 neonates (1470 ears) were screened by otoacoustic emissions in our hospital. Forty-two newborns who failed otoacoustic emissions were included in our study. They constituted 3.9% (n=58 ears) of the total number of ears screened. Forty-four ears (75.9%) passed and 14 ears (24.1%) failed otoacoustic emissions rescreening performed shortly following vernix cleaning. Twelve of the remaining 14 ears passed at 10-day rescreening. The remaining 2 ears presented true bilateral hearing loss. During the study period, the general false-positive rate decreased from 56/735 (7.61%) to 12/735(1.63%) (P < .00001). CONCLUSION: Cleaning the vernix of infants who failed otoacoustic emissions prior to hospital discharge lowers the false-positive rate of universal neonatal hearing screening. We may assume that vernix cleaning will reduce significant healthcare workload, costs of unnecessary investigations, as well as parental anxiety.

Rare diseases' genetic newborn screening as the gateway to future genomic medicine: the Screen4Care EU-IMI project.

Following the reverse genetics strategy developed in the 1980s to pioneer the identification of disease genes, genome(s) sequencing has opened the era of genomics medicine. The human genome project has led to an innumerable series of applications of omics sciences on global health, from which rare diseases (RDs) have greatly benefited. This has propelled the scientific community towards major breakthroughs in disease genes discovery, in technical innovations in bioinformatics, and in the development of patients' data registries and omics repositories where sequencing data are stored. Rare diseases were the first diseases where nucleic acid-based therapies have been applied. Gene therapy, molecular therapy using RNA constructs, and medicines modulating transcription or translation mechanisms have been developed for RD patients and started a new era of medical science breakthroughs. These achievements together with optimization of highly scalable next generation sequencing strategies now allow movement towards genetic newborn screening. Its applications in human health will be challenging, while expected to positively impact the RD diagnostic journey. Genetic newborn screening brings many complexities to be solved, technical, strategic, ethical, and legal, which the RD community is committed to address. Genetic newborn screening initiatives are therefore blossoming worldwide, and the EU-IMI framework has funded the project Screen4Care. This large Consortium will apply a dual genetic and digital strategy to design a comprehensive genetic newborn screening framework to be possibly translated into the future health care.