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Cytomegalovirus causes the most common congenital infection worldwide. With most infants asymptomatic at birth, the few affected may present with variable clinical scenarios, from isolated hearing loss to severe neurologic impairment. Public health interventions include all actions at the health system, community, and individual levels that aim at reducing the burden of congenital Cytomegalovirus. This review examines the literature on maternal and neonatal screening programs in light of current evidence for treatment and the development of vaccines against Cytomegalovirus. Potential biases and benefits of these interventions are outlined, with the objective of increasing awareness about the problem and providing readers with data and critical tools to participate in this ongoing debate. [ABSTRACT FROM AUTHOR]

(1) Background: Sudden Infant Death Syndrome (SIDS) represents sudden and unexplained deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for a prolonged QTc interval, a marker for Long QT Syndrome (LQTS), should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiograms (ECGs) could identify congenital heart defects (CHDs) early, especially those not detected at birth. Infants with prolonged QTc intervals typically undergo genetic analysis for Long QT Syndrome. (2) Methods: The study involved infants aged 20–40 days, born with no apparent clinical signs of heart disease, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHDs identified immediately after birth, as well as infants who had previously had an ECG or echocardiogram for other medical reasons, were excluded from the study. We used statistical software (SPSS version 22.0) to analyze the data. (3) Results: Of the 42,200 infants involved, 2245 were enrolled, with 39.9% being males. Following this initial screening, 164 children (37.8% males) with prolonged QTc intervals underwent further evaluation. Out of these 164 children, 27 children were confirmed to have LQTS. However, only 18 children were finally investigated for genetic mutations, and mutations were identified in 11 tests. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Treatment options included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%. (4) Conclusions: This screening approach has demonstrated effectiveness in the early identification of LQTS and other cardiac rhythm anomalies, with additional identification of mutations and/or prolonged QTc intervals in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening. [ABSTRACT FROM AUTHOR]

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit–harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a chronic and potentially life-threatening condition, wherein timely diagnosis assumes paramount significance for the prompt initiation of therapeutic interventions, thereby ameliorating pulmonary function, addressing nutritional deficits, averting complications, mitigating morbidity, and ultimately enhancing the quality of life and extending longevity. This review aims to amalgamate existing knowledge to provide a comprehensive appraisal of contemporary diagnostic modalities pertinent to CF in the 21st century. Deliberations encompass discrete delineations of each diagnostic modality and the elucidation of potential diagnostic quandaries encountered in select instances, as well as the delineation of genotype–phenotype correlations germane to genetic counseling endeavors. The synthesis underscores that, notwithstanding the availability and strides in diagnostic methodologies, including genetic assays, the sweat test (ST) retains its position as the preeminent diagnostic standard for CF, serving as a robust surrogate for CFTR functionality. Prospective clinical investigations in the realm of CF should be orchestrated with the objective of discerning novel diagnostic modalities endowed with heightened specificity and sensitivity. [ABSTRACT FROM AUTHOR]

Developmental hip dysplasia or developmental dysplasia of the hip (DDH) includes a wide range of deformities of the hip, such as congenital dysplasia, subluxation, and dislocation. It is usually identified through neonatal screening during the first 6–8 weeks of life. The incidence of DDH ranges from 1–7% in neonates among some populations, but this may vary among different ethnicities and countries. A consensus about the ideal age for screening has not been reached to date. The aim of this study is to summarize the existing data regarding the incidence of congenital hip dysplasia and screening tests among European countries. The authors conducted a systematic search in PubMed/Medline and Scopus and collected original studies published in English, French or German. The incidence of DDH presents fluctuations, not only among European countries, but also within the same country. There is no unanimity regarding the screening methods of DDH; in some countries, universal ultrasound is proposed as the basic screening method for neonates for DDH; in other countries screening is performed only in high-risk cases. More robust data are needed to conclude which screening approach is associated with improved long-term outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The diagnosis of cystic fibrosis has improved in the last few years due to greater access to diagnostic tools and the evolution of molecular biology; the knowledge obtained has contributed to the understanding of its death profile. In this context, an epidemiological study was developed focusing on deaths from cystic fibrosis in Brazil from 1996 to 2019. The data were collected from the Data-SUS (Unified National Health System Information Technology Department from Brazil). The epidemiological analysis included patients' age groups, racial groups, and sex. In our data, between 1996 and 2019, Σ3050 deaths were recorded, totaling a ≅330% increase in the number of deaths resulting from cystic fibrosis. This fact might be related to a better diagnosis of the disease, mainly in patients from racial groups that are not commonly associated with cystic fibrosis, such as Black individuals, Hispanic or Latino (mixed individuals/Pardos) individuals, and American Indians (Indigenous peoples from Brazil). Regarding of race, the Σ of deaths was: nine (0.3%) in the American Indian group, 12 (0.4%) in the Asian group, 99 (3.6%) in the Black or African American group, 787 (28.6%) in the Hispanic or Latino group, and 1843 (67.0%) in the White group. The White group showed the highest prevalence of deaths, and the increase in mortality was ≅150 times in this group, while, in the Hispanic or Latino group, it was ≅75 times. Regarding sex, the numbers and percentage of deaths of both male (N = 1492; 48.9%) and female (N = 1557; 51.1%) patients were seen to be relatively close. As for age groups, the >60-year-old group presented the most significant results, with an increase of ≅60 times in the registered deaths. In conclusion, in Brazil, despite the number of deaths from cystic fibrosis being prevalent in the White group, it increased in all racial groups (Hispanic or Latino, Black or African American, American Indian, or Asian individuals) and was associated with older age. [ABSTRACT FROM AUTHOR]

Objective: to verify the frequency of congenital infections in newborns and their possible associations with the universal-neonatal-hearing-screening (UNHS) results, and evaluate a reference UNHS service in the Unified Health System (Sistema Único de Saúde—SUS), according to quality indicators. Methods: Historical cohort study with data analysis of newborns attending prestigious hearing-health SUS services from January 2017 to December 2021, in Santa Catarina, Brazil. The quality of screening coverage was assessed based on the quality indicators proposed by the Brazilian neonatal-hearing-screening-care guidelines (Diretrizes de Atenção da Triagem Auditiva Neonatal—DATAN). Logistic-regression analysis, crude OR calculations, Cochran–Mantel–Haenszel OR calculation, and chi-square test were performed to estimate the association between risk indicators for hearing loss and UNHS failure. Results: In the last five years, the prestigious services performed UNHS on 34,801 newborns and met the DATAN quality indicators. Congenital syphilis was the most frequent (1.59%) congenital infection in newborns, followed by HIV (0.87%), whereas the least frequent was rubella (0.029%). Conclusion: Prestigious UNHS services reached ≥95% hearing screening coverage. Considering all congenital infections, the prevalence was 2.87%, with congenital syphilis the most frequent. Newborns with congenital syphilis or HIV are more likely to fail UNHS. [ABSTRACT FROM AUTHOR]

Isovaleric aciduria (IVA) is a rare disorder of leucine metabolism and part of newborn screening (NBS) programs worldwide. However, NBS for IVA is hampered by, first, the increased birth prevalence due to the identification of individuals with an attenuated disease variant (so-called "mild" IVA) and, second, an increasing number of false positive screening results due to the use of pivmecillinam contained in the medication. Recently, machine learning (ML) methods have been analyzed, analogous to new biomarkers or second-tier methods, in the context of NBS. In this study, we investigated the application of machine learning classification methods to improve IVA classification using an NBS data set containing 2,106,090 newborns screened in Heidelberg, Germany. Therefore, we propose to combine two methods, linear discriminant analysis, and ridge logistic regression as an additional step, a digital-tier, to traditional NBS. Our results show that this reduces the false positive rate by 69.9 % from 103 to 31 while maintaining 100 % sensitivity in cross-validation. The ML methods were able to classify mild and classic IVA from normal newborns solely based on the NBS data and revealed that besides isovalerylcarnitine (C5), the metabolite concentration of tryptophan (Trp) is important for improved classification. Overall, applying ML methods to improve the specificity of IVA could have a major impact on newborns, as it could reduce the newborns' and families' burden of false positives or over-treatment. [ABSTRACT FROM AUTHOR]

Background and aims: Although the significance of primary congenital hypothyroidism (CH) is supported by an increasing amount of evidence, the clinical and genetic characteristics of this condition are still poorly understood. This study aimed to explore the underlying genetic etiologies in a cohort of primary CH patients. Subjects and Methods: The clinical data of 33 patients with primary CH were collected and analyzed via a cross-sectional study. Genetic analysis was performed by high-throughput sequencing and Sanger verification, and the pathogenicity of the novel missense variants was predicted using a variety of comprehensive bioinformatic tools. Results: Among the 33 patients, 22 (22/33, 66.7%) harbored pathogenic variants in the causative genes of thyroid dysgenesis or dyshormonogenesis, with DUOX2 (15/33, 45.5%) topping the list, followed by TG, TPO, DUOXA2 and PAX8. Four novel genetic variants were detected, including a pathogenic frameshift and three likely pathogenic missense variants. Positive neonatal screening for TSH, neonatal jaundice and abnormal thyroid morphology were the main positive findings among all cases. Although 31 of the total 33 CH patients exhibited normal anthropometric and social performance, the other 2 had poor prognosis in this study. Conclusions: This study reported 33 new CH patients bearing four novel genetic variants, which enriched the variant spectrum of CH genes. In this cohort, genetic factors causing thyroid dyshormonogenesis were the main etiologies of CH development. Most patients exhibited a favorable prognosis; however, systematic management remains a challenge in achieving improved clinical outcomes for CH patients. [ABSTRACT FROM AUTHOR]

Background: Objectives of the present work were to analyze the prevalence of hearing loss in our population of screened newborns during the first 9 years of the universal newborn hearing screening (UNHS) program at University Hospital Sassari (Italy) (AOU Sassari), to analyze the risk factors involved, and to analyze our effectiveness in terms of referral rates and dropout rates. Methods: Monocentric retrospective study whose target population included all the newborns born or referred to our hospital between 2011 and 2019. Results: From 2011 to 2019, a total of 11,688 babies were enrolled in our screening program. In total, 3.9‰ of wellborn babies and 3.58% of neonatal intensive care unit (NICU) babies had some degree of hearing loss. The most frequently observed risk factors among non-NICU babies were family history of hearing loss (3.34%) and craniofacial anomalies (0.16%), among NICU babies were low birth weight (54.91%) and prematurity (24.33%). In the multivariate analysis, family history of hearing loss (p < 0.001), NICU (p < 0.001), craniofacial anomalies (p < 0.001), low birth weight (<1500 g) (p = 0.04) and HIV (p = 0.03) were confirmed as risk factors. Conclusions: Our data are largely consistent with the literature and most results were expected, one relevant exception being the possible role of NICU as a confounding factor and the limited number of risk factors confirmed in the multivariate analysis. [ABSTRACT FROM AUTHOR]

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype-phenotype correlation in patients with THD and candidate variants in DUOX2 . A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895&#95;2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype-phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants.

Brazil is a continent-size country with 203 million inhabitants, classified as a developing upper-middle-income country, although inequities remain significant. Most of the population is assisted by the public Unified Health System (SUS), along with a thriving private health sector. Congenital malformations are the second leading cause of infant mortality and chronic/genetic disorders and a significant burden in hospital admissions. The past two decades have been crucial for formalizing medical genetics as a recognized medical specialty in the SUS, as well as for implementing a new health policy by the Ministry of Health for comprehensive care for rare diseases. These public health policies had the broad support of the Brazilian Society of Medical Genetics and Genomics and patient organizations. Most comprehensive genetic services are concentrated in large urban centers in the South and Southeast regions of Brazil; with this new policy, new services throughout the country are progressively being integrated. The number of medical geneticists increased by 103% in a decade. Details on the policy and an overview of the availability of services, testing, human resources, newborn screening, research projects, patient organizations, and relevant issues regarding medical genetics in this vast and diverse country are presented.

The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted.

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.

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.

Newborn screening (NBS) for spinal muscular atrophy (SMA) is necessary, as favorable outcomes can be achieved by treatment with disease-modifying drugs in early infancy. Although SMA-NBS has been initiated in Japan, its clinical results have not been fully reported. We report the findings of the initial 2.5 years of a pilot SMA-NBS of approximately 16,000 infants conducted from February 2021 in Hyogo Prefecture, Japan. Clinical data of 17 infants who tested positive were retrospectively obtained from the NBS follow-up centers participating in this multicenter cohort observational study. Genetic testing revealed 14 false positives, and three infants were diagnosed with SMA. Case 1 had two copies of survival motor neuron ( SMN ) 2 and showed SMA-related symptoms at diagnosis. Case 2 was asymptomatic, with two copies of SMN2 . Asymptomatic case 3 had four copies of SMN2 exon 7, including the SMN1/2 hybrid gene. Cases 1 and 2 were treated within 1 month and case 3 at 8 months. All the patients showed improved motor function scores and did not require respiratory support. The identification of infants with SMA via NBS and early treatment improved their motor and respiratory outcomes. Thus, implementation of SMA-NBS at a nationwide scale should be considered.

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.

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1 , was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1 -deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.

Diagnosing a child by newborn screening with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) causes multiple challenges for the affected parents and the whole family. We aimed to examine the health-related Quality of Life (HrQoL), coping, and needs of parents caring for a child with CAH to develop demand-responsive interventions for improving the psychosocial situation of affected families. In a retrospective cross-sectional design, we assessed HrQoL, coping patterns, and the needs of parents caring for a CAH-diagnosed child using specific questionnaires. Data of 59 families with at least one child diagnosed with CAH were analyzed. The results show that mothers and fathers in this study reached significantly higher HrQoL scores compared to reference cohorts. Decisive for the above-average parental HrQoL were effective coping behaviors and the parental needs being met. These findings verify the importance of helpful coping patterns and rapid fulfillment of parental needs for maintaining a good and stable HrQoL of parents with a child diagnosed with CAH. It is crucial to strengthen the parental HrQoL to build a reasonable basis for a healthy upbringing and improve the medical care of CAH-diagnosed children.

Newborn screening (NBS) for congenital hypothyroidism (CH) was introduced in Switzerland in 1977, which allowed for the preclinical, biochemical diagnosis. The aim of this study was to evaluate the prevalence of transient CH (tCH) in the canton of Zurich. In this analytical cohort study, all newborns born in the canton of Zurich, between the 1st of January 2000 and the 30st of June 2016, with a TSH value above 15 mU/L (whole blood) were included. There were 115 cases out of 247,918 babies born during the study period. However, 23 cases had to be excluded due to missing data. The definite diagnosis was made after a thyroxine withdrawal at 2 years of age. The total prevalence of confirmed CH and the female to male ratio (f/m) were 1:2695 and 2.17:1; for permanent CH (pCH), 1:3443 and 2.8:1; and for tCH, 1:12,396 and 1:1, respectively. The TSH value was significantly higher in pCH compared to tCH, at 130.3 (62.9-171.9) and 36.4 (26.5-53.3) (median and interquartile range), respectively ( p < 0.001). The prevalences found for congenital hypothyroidism and its transient form are comparable to previous studies. TSH concentration at birth was predictive for the further course of the disease. Low birth weight correlated with a tCH, whereas low gestational age did not. The dominance of the female sex in congenital hypothyroidism is supported by a gender ratio of 2.17:1.

Next Generation Sequencing (NGS) technologies are rapidly entering clinical practice. A promising area for their use lies in the field of newborn screening. The mass screening of newborns using NGS technology leads to the discovery of a large number of new missense variants that need to be assessed for association with the development of hereditary diseases. Currently, the primary analysis and identification of pathogenic variations is carried out using bioinformatic tools. Although extensive efforts have been made in the computational approach to variant interpretation, there is currently no generally accepted pathogenicity predictor. In this study, we used the sequence-structure-property relationships (SSPR) approach, based on the representation of protein fragments by molecular structural formula. The approach predicts the pathogenic effect of single amino acid substitutions in proteins related with twenty-five monogenic heritable diseases from the Uniform Screening Panel for Major Conditions recommended by the Advisory Committee on Hereditary Disorders in Newborns and Children. In order to create SSPR models of classification, we modified a piece of cheminformatics software, MultiPASS, that was originally developed for the prediction of activity spectra for drug-like substances. The created SSPR models were compared with traditional bioinformatic tools (SIFT 4G, Polyphen-2 HDIV, MutationAssessor, PROVEAN and FATHMM). The average AUC of our approach was 0.804 ± 0.040. Better quality scores were achieved for 15 from 25 proteins with a significantly higher accuracy for some proteins ( IVD , HADHB , HBB ). The best SSPR models of classification are freely available in the online resource SAV-Pred (Single Amino acid Variants Predictor).

Newborn hearing screening (NHS) has been covered by national health insurance since October 2018 in Korea. However, the results of the NHS are not reported due to the absence of a follow-up tracking system. This study analyzed the status and the predicted referral rates of NHS after the Korean national health insurance coverage by analyzing the National Health Insurance Service database in 2019 and 2020. The NHS coverage was 91.7% of total birth in 2019 and 92.1% in 2020. The predicted referral rate of NHS calculated by the duplicated NHS cases was 1.05% in 2019 and 0.99% in 2020. However, another predicted referral rate calculated by the number of diagnostic auditory brainstem responses (ABRs) performed was 1.44% in 2019 and 1.43% in 2020. The first NHS was performed within one day of birth for 96.5% of the babies and within three days of birth for 97%. However, diagnostic ABR was adequately performed within three months of birth for only 4.3%, while 82.3% performed the test after six months which delays appropriate intervention for hearing loss. National support such as national coordinators, follow-up tracking, and data management systems are needed for early hearing detection and intervention of newborns and infants in Korea.

Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE , IDUA , PTS , ASS1 and OTC , all affecting the splicing process, and two located in the promoters of IDUA and PTS , thus affecting these genes' expression. All the new variants were subjected to functional analysis to verify their pathogenic effects. This work underscores how the combination of different omics technologies and functional analysis can solve elusive cases in clinical practice.

Genetic testing for SMA diagnosis, newborn screening, and carrier screening has become a significant public health interest worldwide, driven largely by the development of novel and effective molecular therapies for the treatment of spinal muscular atrophy (SMA) and the corresponding updates to testing guidelines. Concurrently, understanding of the underlying genetics of SMA and their correlation with a broad range of phenotypes and risk factors has also advanced, particularly with respect to variants that modulate disease severity or impact residual carrier risks. While testing guidelines are beginning to emphasize the importance of these variants, there are no clear guidelines on how to utilize them in a real-world setting. Given the need for clarity in practice, this review summarizes several clinically relevant variants in the SMN1 and SMN2 genes, including how they inform outcomes for spinal muscular atrophy carrier risk and disease prognosis., Competing Interests: John N. Milligan is an employee of Asuragen, a Bio-Techne Brand.

Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.

Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not recycled. BD meets the major criteria for a population screening program. Newborn bloodspot screening (NBS) allows early diagnosis of BD, thus preventing the high morbidity and mortality associated with untreated disease. Both profound and partial BD variant can be detected by NBS test, and serum enzyme activity and/or mutational analysis are required for definitive diagnosis. In Italy, BD is included in the screening panel for inborn errors of metabolism (IEMs) that has been declared mandatory in 2016. We analyzed the data of the first 3 years of the NBS for BD in our region (Abruzzo, Italy), with the aim to describe the outcomes of this recently introduced screening program. In over 26,393 newborns screened, we found 2 carriers and 16 cases with genotype associated with partial BD. Since the serum biotinidase assay has been recently introduced in our algorithm, only three of our newborns met the criteria of genetic and biochemical confirmation, with an incidence of 1:8797, which is in the high range of what has been reported in the literature. All affected infants carried the 1330G>C (D444H) variant in compound heterozygosis, with variants known to be associated with profound BD. A variant previously not described and likely pathogenic was found in one newborn. None of the infants had signs or symptoms. The study of the distribution of the enzyme activity in our population allowed us to validate the adopted cutoff with which the program has a positive predictive value of 18% and to analyze some preanalytical factors influencing biotinidase activity: A correlation of the enzyme activity with gestational age and time at specimen collection was found. Lower mean values of enzyme activity were found in infants born in the summer.

Simple Summary: Adrenocortical tumor (ACT) is rare in children and fatal if not detected early. Children who inherit a mutation of the TP53 gene tend to develop ACT early in life. In the 1990s, scientists revealed that a TP53 variant (R337H) was frequent in South Brazil. Therefore, the incidence of ACT in children is 20 times higher in this region than in other countries. We reviewed the records of 16 children with ACT treated in a pediatric hospital in Parana state (southern Brazil) and 134 children registered in the state public registry data. We found a high number of cases with advanced disease, leading to an unacceptable number of deaths. These observations contradict newborn R337H screening and surveillance data, showing that surgical intervention in early cases of ACT is associated with a 100% cure. Newborn screening/surveillance should be implemented in regions with a high frequency of the R337H variant. The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012–2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance. [ABSTRACT FROM AUTHOR]

Newborn screening (NBS) programmes are considered to be one of the most successful secondary prevention measures in childhood to prevent or reduce morbidity and/or mortality via early disease identification and subsequent initiation of therapy. However, while many rare diseases can now be detected at an early stage using appropriate diagnostics, the introduction of a new target disease requires a detailed analysis of the entire screening process, including a robust scientific background, analytics, information technology, and logistics. In addition, ethics, financing, and the required medical measures need to be considered to allow the benefits of screening to be evaluated at a higher level than its potential harm. Infantile nephropathic cystinosis (INC) is a very rare lysosomal metabolic disorder. With the introduction of cysteamine therapy in the early 1980s and the possibility of renal replacement therapy in infancy, patients with cystinosis can now reach adulthood. Early diagnosis of cystinosis remains important as this enables initiation of cysteamine at the earliest opportunity to support renal and patient survival. Using molecular technologies, the feasibility of screening for cystinosis has been demonstrated in a pilot project. This review aims to provide insight into NBS and discuss its importance for nephropathic cystinosis using molecular technologies.

The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype-phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1 . The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1-2 (transmembrane domain spanning region) and 6-9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.

The study aim was to explore the effects of multisensory breastmilk interventions on short-term pain of infants during newborn screening. This is a randomized controlled trial. A total of 120 newborns were recruited and assigned by randomization to one of three treatment conditions: Condition 1 = routine care (gentle touch + verbal comfort); Condition 2 = breastmilk odor + routine care; or Condition 3 = breastmilk odor + taste + routine care. Pain was scored with the Neonatal Infant Pain Scale (NIPS). Data were collected from video recordings at 1 min intervals over the 11 phases of heel sticks: phase 1, 5 min before heel stick without stimuli (baseline); phase 2 to phase 6 (during heel stick); and phase 7 to phase 11 (recovery). Generalized estimating equations compared differences in pain scores for newborns over phases among the three conditions. Compared with the routine care, provision of the odor and taste of breastmilk reduce NIPS scores during heel sticks (B = -4.36, SE = 0.45, p < 0.001 [phase 6 ]), and during recovery (B = -3.29, SE = 0.42, p < 0.001 [phase 7 ]). Our findings provide new data, which supports the use of multisensory interventions that include breastmilk odor and taste in combination with gentle touch and verbal comfort to relieve pain in infants undergoing newborn screening.

Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene ( PAH) mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational PAH spectrum in the largest cohort of HPA/PKU Mexican patients ( N = 124) reported to date. The biallelic PAH genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH 4 ) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625&#95;626insC and c. 1315 + 5&#95;1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G > T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH 4 responsiveness based on the PAH genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G > T, which predicts the absence of BH 4 responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype-phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico.

The acetylated fetal hemoglobin (AcHbF) derives from an enzyme-mediated post-translational modification occurring on the N-terminal glycine residues of γ-chains. At present, no established data are available on reference intervals for AcHbF in newborns. A total of 92 healthy infants, with gestational age between 37 and 41 weeks were selected for the establishment of AcHbF reference intervals. Blood samples were collected by heel pricking, when collecting routine neonatal screening, and the hemoglobin pattern was analyzed by high-performance liquid chromatography. AcHbF results were then normalized for HbF content in order to account for differences in hemoglobin switch. No difference was found in AcHbF values between genders (P=0.858). AcHbF results were as follow: 12.8±0.8% (mean±standard deviation), reference interval: 11.3-14.3%. This finding could facilitate further studies aimed to assess the possible use of AcHbF, for instance as a possible fetal metabolic biomarker during pregnancy. [ABSTRACT FROM AUTHOR]

Background and Objectives : The main reason for Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) is to prevent adrenal insufficiency that can lead to life-threatening conditions. On the other hand, screening programs are not always sensitive and effective enough to detect the disease. We aimed to evaluate impact of the national NBS on the clinical presentation of patients with CAH in Lithuania. Materials and Methods : A retrospective study was performed on data of 88 patients with CAH from 1989 to 2020. Patients with confirmed CAH were divided into two groups: (1) 75 patients diagnosed before NBS: 52 cases with salt-wasting (SW), 21 with simple virilising (SV) and two with non-classical (NC) form; (2) 13 patients diagnosed with NBS: 12 cases with SW and 1 case with SV form. For the evaluation of NBS effectiveness, data of only male infants with salt-wasting CAH were analysed ( n = 36, 25 unscreened and nine screened). Data on gestational age, birth weight, weight, symptoms, and laboratory tests (serum potassium and sodium levels) on the day of diagnosis, were analysed. Results : A total of 158,486 neonates were screened for CAH from 2015 to 2020 in Lithuania and CAH was confirmed in 13 patients (12 SW, one-SV form), no false negative cases were found. The sensitivity and specificity of NBS program for classical CAH forms were 100%; however, positive predictive value was only 4%. There were no significant differences between unscreened and screened male infant groups in terms of age at diagnosis, serum potassium, and serum sodium levels. Significant differences were found in weight at diagnosis between the groups (-1.67 ± 1.12 SDS versus 0.046 ± 1.01 SDS of unscreened and screened patients respectively, p = 0.001). Conclusions : The sensitivity and specificity of NBS for CAH program were 100%, but positive predictive value-only 4%. Weight loss was significantly lower and the weight SDS at diagnosis was significantly higher in the group of screened patients.

Identifying multiple ultra-rare genetic syndromes with overlapping phenotypes is a diagnostic conundrum in clinical genetics. This study investigated the pathogenicity of a homozygous missense variant in GNB5 ( GNB5L; NM&#95;016194.4: c.920T > G (p. Leu307Arg); GNB5S; NM&#95;006578.4: c.794T > G (p. Leu265Arg)) identified through exome sequencing in a female child who also had 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (newborn screening positive) and hemoglobin E trait. The proband presented with early-onset intellectual disability, the severity of which was more in keeping with GNB5 -related disorder than 3-MCC deficiency. She later developed bradycardia and cardiac arrest, and upon re-phenotyping showed cone photo-transduction recovery deficit, all known only to GNB5 -related disorders. Patient-derived fibroblast assays showed preserved GNB5S expression, but bioluminescence resonance energy transfer assay showed abolished function of the variant reconstituted Gβ5S containing RGS complexes for deactivation of D2 dopamine receptor activity, confirming variant pathogenicity. This study highlights the need for precise phenotyping and functional assays to facilitate variant classification and clinical diagnosis in patients with complex medical conditions.

In Austria, newborns have been screened for cystic fibrosis (CF) by analyzing immunoreactive trypsinogen (IRT) from dried blood spots (DBS)s for nearly 20 years. Recently, pancreatitis-associated protein (PAP) analysis was introduced as a second-tier test with the aim of reducing recalls for second DBS cards while keeping sensitivity high. For 28 months, when IRT was elevated (65–130 ng/mL), PAP was measured from the first DBS (n = 198,927) with a two-step cut-off applied. For the last 12 months of the observation period (n = 85,421), an additional IRT×PAP cut-off was introduced. If PAP or IRT×PAP were above cut-off, a second card was analyzed for IRT and in case of elevated values identified as screen-positive. Above 130 ng/mL IRT in the first DBS, newborns were classified as screen-positive. IRT analysis of first DBS resulted in 1961 (1%) tests for PAP. In the first 16 months, 26 of 93 screen-positive were confirmed to have CF. Two false-negatives have been reported (sensitivity = 92.8%). Importantly, less than 30% of families compared to the previous IRT-IRT screening scheme had to be contacted causing distress. Adding IRT×PAP caused a marginally increased number of second cards and sweat tests to be requested during this period (15 and 3, respectively) compared to the initial IRT-PAP scheme. One case of confirmed CF was found due to IRT×PAP, demonstrating an increase in sensitivity. Thus, the relatively simple and economical algorithm presented here performs effectively and may be a useful model for inclusion of CF into NBS panels or modification of existing schemes. [ABSTRACT FROM AUTHOR]