Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn disease...Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.展开更多
Background Data of classical inborn errors of metabolism （IEM） of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IE...Background Data of classical inborn errors of metabolism （IEM） of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area.展开更多
Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 46...Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.展开更多
Background It has been 11 years since newborn screening started in Zhejiang in 1999.The aim of this study was to analyze and summarize the status of newborn screening in Zhejiang from 1999 to 2009.Methods Blood sample...Background It has been 11 years since newborn screening started in Zhejiang in 1999.The aim of this study was to analyze and summarize the status of newborn screening in Zhejiang from 1999 to 2009.Methods Blood samples were collected from the heels of newborns 72 hours after birth.We have conducted laboratory tests that the congenital hypothyroidism （CH） and circulating levels of thyroid-stimulating hormone （TSH） was detected.Blood phenylalanine （Phe） was detected for phenylketonuria （PKU）.Dissociation-enhanced lanthanide fluorescent immunoassay （DELFIA） was used for detection.Results From 1999 to 2009,3875228 newborns were screened and 2309 cases were confirmed as CH and 155 cases were confirmed as PKU.The incidence of CH and PKU were 1：1678 and 1：25 001 respectively.Conclusion In 11 years,the Zhejiang newborn screening center screened more than 3.8 million newboms,and helped more than 2000 CH and PKU patients to obtain early treatment in order to prevent physical disability and mental retardation.展开更多
Hyperphenylalaninemia is one of the commonest inborn errors of metabolism affecting approximately 1 in 15 000 live births. Among Chinese, BH4 deficiency leading to hyperphenylalaninemia is much commoner than in Caucas...Hyperphenylalaninemia is one of the commonest inborn errors of metabolism affecting approximately 1 in 15 000 live births. Among Chinese, BH4 deficiency leading to hyperphenylalaninemia is much commoner than in Caucasians. Exact diagnosis is important for the treatment and genetic counseling. In 2000, newborn screening for phenylketonuria is mandatory by law in China throughout the whole country. However, it is not yet included in the newborn screening program of the Hong Kong Special Administrative Region, China. Published data on hyperphenylalaninemia among Hong Kong Chinese are largely lacking. We report a 1-year-old Hong Kong Chinese girl with severe 6-pyruvoyl-tetrahydropterin synthase （PTPS） deficiency. The patient presented with infantile hypotonia and was misdiagnosed as cerebral palsy. She had very mild hyperphenylalaninemia （95 IJmol/L）, significantly high phenylalnine-to-tyrosine ratio （3.1）, and ele~,ated prolactin of 1109 m lU/L. Genetic analysis confirmed a homozygous known disease-causing mutation PTS NM_000317.1： c.259C〉T; NP_000308.1： p.P87S in the proband. In our local experience, while the estimated prevalence of hyperphenylalaninemia due to PTPS deficiency was reported to be 1 in 29 542 live births, not a single case of phenylalanine hydroxylase deficiency has been reported. Furthermore, there is a general lack of awareness of inherited metabolic diseases in the community as well as among the medical professionals. Very often, a low index of clinical suspicion will lead to delay in diagnosis, multiple unnecessary and costly investigations, prolonged morbidity and anxiety to the family affected. We strongly recommend that expanded newborn screening for hyperphenylalaninemia should be implemented for every baby born in the Hong Kong Special Administrative Region, China.展开更多
Background:Galactosemia due to complete or near-complete galactose-l-phosphate uridyltransferase(GALT)deficiency was the first disorder added to the pioneering newborn screening panel besides phenylketonuria.In the la...Background:Galactosemia due to complete or near-complete galactose-l-phosphate uridyltransferase(GALT)deficiency was the first disorder added to the pioneering newborn screening panel besides phenylketonuria.In the last 50 years,many criticisms have been focused on the opportunity of its inclusion.Consequently,long-term single center experiences with this issue are generally lacking.Methods:We reviewed the outcome of newborn screening for hypergalactosemia performed at our department since 1982 and the correspondent long-term clinical outcome.Results:Among 1123909 newborns screened for hypergalactosemia,33 showed abnormal results confirmed at second tier test.Thirteen patients were affected with classic galactosemia,8 partial GALT deficiency,3 severe galactokinase deficiency,7 transient galactosemia,one congenital porto-systemic shunt,and one glucose transporter 2 deficiency.Acute neonatal liver failure in the late first week of life(5.8±1.1 days)unavoidably complicated the clinical course of classic galactosemia,unless in three second-born siblings treated on the basis of presumptive diagnosis immediately after newborn screening sample collection on day 3.Despite early treatment and longterm steadily normal peripheral blood galactose,77%of patients with severe GALT deficiency present mild to severe intellectual disabilities.All patients with partial GALT deficiency showed normal intellectual development on a regular diet,as well as patients with galactokinase deficiency under treatment.Conclusions:Availability of screening results within the fifth day after birth would allow the prevention of acute decompensation in classic galactosemia.A systematic diagnostic work-up in all positive newborns is essential to unravel the etiology of hypergalactosemia.展开更多
Newborn screening(NBS)is a public health service aimed at identifying infants with severe genetic disorders,thus providing effective treatment early enough to prevent or ameliorate the onset of symptoms.Current NBS us...Newborn screening(NBS)is a public health service aimed at identifying infants with severe genetic disorders,thus providing effective treatment early enough to prevent or ameliorate the onset of symptoms.Current NBS uses biochemical analysis of dried blood spots,predominately with timeresolved fluorescence immunoassay and tandem mass spectrometry,which produces some false positives and false negatives.The application of enzymatic activity-based testing technology provides a reliable screening method for some disorders.Genetic testing is now commonly used for secondary or confirmatory testing after a positive result in some NBS programs.Recently,next-generation sequencing(NGS)has emerged as a robust tool that enables large panels of genes to be scanned together rapidly.Rapid advances in NGS emphasize the potential for genomic sequencing to improve NBS programs.However,some challenges still remain and require solution before this is applied for population screening.展开更多
Newborn hearing screening is an effective strategy for early identification of hearing loss in the newborn which result in early intervention and best outcome.However implementing universal screening strategy is a cha...Newborn hearing screening is an effective strategy for early identification of hearing loss in the newborn which result in early intervention and best outcome.However implementing universal screening strategy is a challenge in many resource constrained settings.There are various limitations towards successful implementation of hearing screening program in the developing countries.The cost effectiveness of the screening program also needs to be considered in a resource constrained settings.We attempt to provide a viewpoint that can be potentially helpful for the successful implementation of hearing screening in a resource constrained settings of the developing countries.展开更多
Mucopolysaccharidoses typeⅢB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase.This results in the aggregation of heparan sulfate polysaccharides within cell l...Mucopolysaccharidoses typeⅢB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase.This results in the aggregation of heparan sulfate polysaccharides within cell lysosomes that leads to progressive and severe debilitating neurological dysfunction.Current treatment options are expensive,limited,and presently there are no approved cures for mucopolysaccharidoses typeⅢB.Adeno-associated virus gene therapy has significantly advanced the field forward,allowing researchers to successfully design,enhance,and improve potential cures.Our group recently published an effective treatment using a codon-optimized triple mutant adeno-associated virus 8 vector that restores N-acetyl-alpha-glucosaminidase levels,auditory function,and lifespan in the murine model for mucopolysaccharidoses typeⅢB to that seen in healthy mice.Here,we review the current state of the field in relation to the capsid landscape,adeno-associated virus gene therapy and its successes and challenges in the clinic,and how novel adenoassociated virus capsid designs have evolved research in the mucopolysaccharidoses typeⅢB field.展开更多
Vitamin B 12 deficiency,mostly of maternal origin in newborns,is a well treatable condition but can cause severe neurologic sequelae.In women of childbearing age and pregnant women worldwide vitamin B12 deficiency has...Vitamin B 12 deficiency,mostly of maternal origin in newborns,is a well treatable condition but can cause severe neurologic sequelae.In women of childbearing age and pregnant women worldwide vitamin B12 deficiency has been reported with frequencies of 10%-50%.Children with vitam in B I2 deficiency are asym ptom atic at birth but may develop severe multisystemic symptoms,including irreversible developmental impairment in the second halfyear of life.Early detection of vitamin B12 deficiency allows for presymptomatic treatment.This article provides an overview over the function of vitamin B12 and discusses causes and frequency of vitamin B12 deficiency in newborns,infants,and women of childbearing age.It describes novel successful approaches to newborn screening(NBS)for vitamin B,2 deficiency and results of a pilot study which performed systematic NBS for vitamin B12 deficiency using so-called second-tier strategies by measuring homocysteine and methylmalonic acid in dried blood spots.Recommendations for diagnostics in mothers of children with vitamin B12 deficiency are described as well as results of systematic work-up in mothers and treatment and follow-up of children with vitamin B12 deficiency detected by NBS.Treatment options of vitamin B12 deficiency are presented including a newly developed standardized supplementation scheme with exclusively oral vitamin BI2 supplementation.Recommendations for preventive approaches to vitamin Bl2 deficiency for children and mothers are stated.Many children worldwide could benefit from systematic inclusion of vitamin B12 deficiency into NBS panels.In addition,preventive approaches to maternal vitamin B12 deficiency should be implemented systematically during maternal care.展开更多
Hemoglobinopathies, mainly Sickle cell disease (SCD), are the most common monogenic disorders in Africa. In Burkina Faso, data on these diseases are scarce, mainly hospital-based in Ouagadougou and its surroundings. I...Hemoglobinopathies, mainly Sickle cell disease (SCD), are the most common monogenic disorders in Africa. In Burkina Faso, data on these diseases are scarce, mainly hospital-based in Ouagadougou and its surroundings. In order to assess the incidence and allelic frequencies of the main hemoglobinopathies in newborns in Burkina Faso, we conducted a cross-sectional study from 2015 to 2019 in four hospitals. The study included babies of both sexes, regardless of ethnic group and parents’ hemoglobin status. It was a newborn screening and hemoglobin variants were detected using isoelectric focusing on cord blood samples and confirmed using hemoglobin electrophoresis by high-performance liquid chromatography. The proportions and cumulative incidences of the different hemoglobinopathies were computed. Hardy-Weinberg equilibrium law was applied to calculate genotypic and allelic frequencies. The significant level was p < 0.05. Out of 11,337 newborns included, 47.8% were males and 60.2% were from Bobo-Dioulasso. Abnormal hemoglobin was found in 27.1%, representing a cumulative incidence of 1:4 newborns. The incidence of SCD was 1.9% (1:53 newborns) with 27.9% of homozygous SS. Homozygous CC and compound heterozygous Cβ-Thalassemia accounted for 1.1%. SCD cases were 1.51 times higher in Bobo-Dioulasso (OR = 1.51;95% CI [1.09 - 2.10]: p = 0.013). The observed genotype frequencies were significantly different from the expected ones (p 0.001). The βS and βC alleles represented 5.1 and 9.9%, respectively. This study showed a high incidence of hemoglobinopathies. Such results raise the question of control strategies for these hemoglobinopathies in our country.展开更多
Background: Cochlear implantation is the best management option for children with profound hearing loss and has received no benefit from hearing aids. Early implantation for these children is associated with good spee...Background: Cochlear implantation is the best management option for children with profound hearing loss and has received no benefit from hearing aids. Early implantation for these children is associated with good speech and language outcomes. Objectives: To determine the barriers to early pediatric cochlear implantation. Methodology: A qualitative cross-sectional study was conducted at Hearing Implants Centre in Nairobi Kenya from August 2022 to February 2023. The target population was 40 children who had undergone cochlear implantation under the auspices of Cochlear Implant Group of Kenya but data was only collected from 30 of them. The remaining were ruled out because 3 were unreachable over the phone, 5 refused to participate and 2 did not meet the inclusion criteria. Results: Patient file reviews and parental telephone interviews were conducted to collect information and analyzed using Microsoft excel and presented using graphs, tables and pie charts. The analysis of the gender showed 46.67% were male and 53.33% were female. Analysis on newborn screening showed that none had it done. The mode age of hearing loss suspicion was between the ages of 2 - 3 years. The hearing loss suspicion done was done by the mothers at 20 children the reminder being 3 by the father, 1 by a family friend, 4 by the school-teacher and 2 by the child’s grandmother. A total of 17 participants noted a delayed in speech and language, 9 noted that the child did not respond to loud sounds, 4 noted that the children did not turn when called. Once hearing loss was identified, 73% saw the ENT, 17% saw a pediatrician, 7% went to see an Audiologist, and 3% saw a speech therapist. The mode age at diagnosis was 1.5 years. The mode age at implantation was 5 years. The mode time from diagnosis was 2 years. Conclusions: This study sought to investigate the barriers to pediatric cochlear implantation in Kenya. From the results it was determined that factors such as lack of newborn screening, high cost of cochlear implantation, lack of awareness have led to late cochlear implantation.展开更多
Biliary atresia(BA), a chronic progressive cholestatic disease of infants, is the leading cause for liver transplant in children, especially in patients under two years of age. BA can be successfully treated with the ...Biliary atresia(BA), a chronic progressive cholestatic disease of infants, is the leading cause for liver transplant in children, especially in patients under two years of age. BA can be successfully treated with the Kasai portoenterostomy; however most patients still require a liver transplant, with up to one half of BA children needing a transplant by age two. In the current pediatric end-stage liver disease system, children with BA face the risk of not receiving a liver in a safe and timely manner. In this review, we discuss a number of possible solutions to help these children. We focus on two general approaches:(1) preventing/delaying need for transplantation, by optimizing the success of the Kasai operation; and(2) expediting transplantation when needed, by performing techniques other than the standard deceased-donor, whole, ABO-matched organ transplant.展开更多
Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electro...Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electron transfer flavoprotein （ETF）-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicityon the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicat-ing glutaric acidemia type Ⅱ in newborn screening analysis. Urinary organic acids were evaluated for the confrmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, ribofavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor developmentwas normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.展开更多
Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited dis...Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spec-trometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.展开更多
Background:Although congenital hypothyroidism(CH)has been widely studied in Western countries,CH incidence at different administrative levels in China during the past decade remains unknown.This study aimed to update ...Background:Although congenital hypothyroidism(CH)has been widely studied in Western countries,CH incidence at different administrative levels in China during the past decade remains unknown.This study aimed to update the incidence and revealed the spatial pattern of CH incidence in the mainland of China,which could be helpful in the planning and implementation of preventative measures.Methods:The data used in our study were derived from 245 newborns screening centers that cover 30 provinces of the Chinese Newborn Screening Information System.Spatial auto-correlation was analyzed by Global Moran I and Getis-Ord Gi statistics at the provincial level.Kriging interpolation methods were applied to estimate a further detailed spatial distribution of CH incidence at city level throughout the mainland of China,and Kulldorff space scanning statistical methods were used to identify the spatial clusters of CH cases at the city level.Results:A total of 91,921,334 neonates were screened from 2013 to 2018 and 42,861 cases of primary CH were identified,yielding an incidence of 4.66 per 10,000 newborns screened(95%confidence interval[CI]:4.62–4.71).Neonates in central(risk ratio[RR]=0.84,95%CI:0.82–0.85)and western districts(RR=0.71,95%CI:0.69–0.73)had lower probability of CH cases compared with the eastern region.The CH incidence indicated a moderate positive global spatial autocorrelation(Global Moran I value=0.394,P<0.05),and the CH cases were significantly clustered in spatial distribution.A most likely city-cluster(log-likelihood ratio[LLR]=588.82,RR=2.36,P<0.01)and 25 secondary city-clusters of high incidence were scanned.The incidence of each province and each city in the mainland of China was estimated by kriging interpolation,revealing the most affected province and city to be Zhejiang Province and Hangzhou city,respectively.Conclusion:This study offers an insight into the space clustering of CH incidence at provincial and city scales.Future work on environmental factors need to focus on the effects of CH occurrence.展开更多
Direct infusion mass spectrometry(DIMS) is a powerful technique in clinical diagnosis for screening neonatal amino acid metabolic disorders from dried blood spots(DBS).However,DIMS sometimes generated false-positive r...Direct infusion mass spectrometry(DIMS) is a powerful technique in clinical diagnosis for screening neonatal amino acid metabolic disorders from dried blood spots(DBS).However,DIMS sometimes generated false-positive results for analysis of amino acids.In this work,we utilized a stable isotope derivatization method,combining with liquid chromatography tandem mass spectrometry(SID-LC-MS),to improve the specificity for screening amino acids in DBS specimens.A pair of isotope reagents,p-(dimethylamino)phenyl isothiocyanate(DMAP-NCS) and 4-isothiocyanato-N,N-bis(methyl-[2H2])aniline([2H4]DMAP-NCS),was synthesized and used to label amino acids in DBS specimens.The [2H4]DMAP-NCS labelled amino acid standards were used as internal standards to compensate the matrix effect.This method was validated by measuring linearity,recovery and accuracy.The results showed that the developed SID-LC-MS method can be used for sensitive and selective determination of 12 diagnostically important amino acids in DBS specimens.展开更多
Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psyc...Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psychophysiological disorder and of having affected offspring.Frequencies of FMR1 alleles in general newborns have been reported in Caucasians but have not been investigated in the large-scale population in the mainland of China.Methods The sizes of FMRI CGG-repeats were analyzed in 51,661 newborns(28,114 males and 23,547 females)and also in a cohort of 33 children diagnosed with developmental delay using GC-rich polymerase chain reaction(PCR)and triple repeat primed PCR.Results The frequency of CGG repeats>100 was 1/9371 in males and 1/5887 in females,and the frequency of CGG repeats>54 was 1/1561 in males and 1/1624 in females.FMRJ full mutation and premutation were identified in 27.27%of children who had Ages and Stages Questionnaire scores less than two standard deviations from the cutoff value.Conclusions Our study revealed the prevalence of FXS in China and improved the sample databases of FXS,suggesting that the prevalence of FXS in Chinese is higher than estimated previously and that FXS screening can be advised to high-risk families.展开更多
Hearing loss is the most common neurosensory deficit.It results froma variety of heritable and acquired causes and is linked to multiple deleterious effects on a child’s development that can be ameliorated by prompt ...Hearing loss is the most common neurosensory deficit.It results froma variety of heritable and acquired causes and is linked to multiple deleterious effects on a child’s development that can be ameliorated by prompt identification and individualized therapies.Diagnosing hearing loss in newborns is challenging,especially in mild or progressive cases,and its management requires a multidisciplinary team of healthcare providers comprising audiologists,pediatricians,otolaryngologists,and genetic counselors.While physiologic newborn hearing screening has resulted in earlier diagnosis of hearing loss than ever before,a growing body of knowledge supports the concurrent implementation of genetic and cytomegalovirus testing to offset the limitations inherent to a singular screening modality.In this review,we discuss the contemporary role of screening for hearing loss in newborns as well as future directions in its diagnosis and treatment.展开更多
Severe Combined Immunodeficiency(SCID)is an inherited group of rare,lifethreatening disorders due to the defect in T cell development and function.Clinical manifestations are characterised by recurrent and severe bact...Severe Combined Immunodeficiency(SCID)is an inherited group of rare,lifethreatening disorders due to the defect in T cell development and function.Clinical manifestations are characterised by recurrent and severe bacterial,viral,and fungal opportunistic infections that start from early infancy period.Haematopoietic stem cell transplantation(HSCT)is the treatment of choice.The pattern of inheritance of SCID may be X-linked or autosomal recessive.Though the diagnosis of SCID is usually established by flow cytometry-based tests,genetic diagnosis is often needed for genetic counselling,prognostication,and modification of pre-transplant chemotherapeutic agents.This review aims to highlight the genetic aspects of SCID.展开更多
基金the Foundation of National Key R&D Program of China of Research on Application Demonstration and Evaluation of Comprehensive Prevention And Control Technology of Birth Defects(Grant No.2018YFC1002700)Zhejiang R&D Research Project Research on New Technologies for Birth Health,Birth Safety and Perinatal Disease Diagnosis and Treatment(Grant No.2021C03099).
文摘Background Newborn screening(NBS)is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases.The develop-ment of next-generation sequencing(NGS)technology provides new opportunities to expand current newborn screening methodologies.Methods We designed a a newborn genetic screening(NBGS)panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS.With this panel,a large-scale,multicenter,prospective multidisease analysis was conducted on dried blood spot(DBS)profiles from 21,442 neonates nationwide.Results We presented the positive detection rate and carrier frequency of diseases and related variants in different regions;and 168(0.78%)positive cases were detected.Glucose-6-Phosphate Dehydrogenase deficiency(G6PDD)and phenylketonuria(PKU)had higher prevalence rates,which were significantly different in different regions.The positive detection of G6PD variants was quite common in south China,whereas PAH variants were most commonly identified in north China.In addi-tion,NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants,which were normal in conventional NBS,but were confirmed later as abnormal in repeated biochemical testing after recall.Eighty percent of high-frequency gene carriers and 60%of high-frequency variant carriers had obvious regional differences.On the premise that there was no significant difference in birth weight and gestational age,the biochemical indicators of SLC22A5 c.1400C>G and ACADSB c.1165A>G carriers were significantly different from those of non-carriers.Conclusions We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods.Our data also showed that the prevalence of diseases has significant regional charac-teristics,which provides a theoretical basis for screening diseases in different regions.
文摘Background Data of classical inborn errors of metabolism （IEM） of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area.
基金partially supported by grants from the Ministry of Science and Technology of China(2016YFC1000306)the Beijing Municipal Science and Technology Commission Foundation(Z181100001918003)+1 种基金the Beijing Municipal Commission of Health and Family Planning Foundation(2018-21141,2020-4-1144)Beihang University&Capital Medical University Advanced Innovation Center for Big Data-Based Precision Medicine Plan(BHME-201905)。
文摘Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.
文摘Background It has been 11 years since newborn screening started in Zhejiang in 1999.The aim of this study was to analyze and summarize the status of newborn screening in Zhejiang from 1999 to 2009.Methods Blood samples were collected from the heels of newborns 72 hours after birth.We have conducted laboratory tests that the congenital hypothyroidism （CH） and circulating levels of thyroid-stimulating hormone （TSH） was detected.Blood phenylalanine （Phe） was detected for phenylketonuria （PKU）.Dissociation-enhanced lanthanide fluorescent immunoassay （DELFIA） was used for detection.Results From 1999 to 2009,3875228 newborns were screened and 2309 cases were confirmed as CH and 155 cases were confirmed as PKU.The incidence of CH and PKU were 1：1678 and 1：25 001 respectively.Conclusion In 11 years,the Zhejiang newborn screening center screened more than 3.8 million newboms,and helped more than 2000 CH and PKU patients to obtain early treatment in order to prevent physical disability and mental retardation.
文摘Hyperphenylalaninemia is one of the commonest inborn errors of metabolism affecting approximately 1 in 15 000 live births. Among Chinese, BH4 deficiency leading to hyperphenylalaninemia is much commoner than in Caucasians. Exact diagnosis is important for the treatment and genetic counseling. In 2000, newborn screening for phenylketonuria is mandatory by law in China throughout the whole country. However, it is not yet included in the newborn screening program of the Hong Kong Special Administrative Region, China. Published data on hyperphenylalaninemia among Hong Kong Chinese are largely lacking. We report a 1-year-old Hong Kong Chinese girl with severe 6-pyruvoyl-tetrahydropterin synthase （PTPS） deficiency. The patient presented with infantile hypotonia and was misdiagnosed as cerebral palsy. She had very mild hyperphenylalaninemia （95 IJmol/L）, significantly high phenylalnine-to-tyrosine ratio （3.1）, and ele~,ated prolactin of 1109 m lU/L. Genetic analysis confirmed a homozygous known disease-causing mutation PTS NM_000317.1： c.259C〉T; NP_000308.1： p.P87S in the proband. In our local experience, while the estimated prevalence of hyperphenylalaninemia due to PTPS deficiency was reported to be 1 in 29 542 live births, not a single case of phenylalanine hydroxylase deficiency has been reported. Furthermore, there is a general lack of awareness of inherited metabolic diseases in the community as well as among the medical professionals. Very often, a low index of clinical suspicion will lead to delay in diagnosis, multiple unnecessary and costly investigations, prolonged morbidity and anxiety to the family affected. We strongly recommend that expanded newborn screening for hyperphenylalaninemia should be implemented for every baby born in the Hong Kong Special Administrative Region, China.
文摘Background:Galactosemia due to complete or near-complete galactose-l-phosphate uridyltransferase(GALT)deficiency was the first disorder added to the pioneering newborn screening panel besides phenylketonuria.In the last 50 years,many criticisms have been focused on the opportunity of its inclusion.Consequently,long-term single center experiences with this issue are generally lacking.Methods:We reviewed the outcome of newborn screening for hypergalactosemia performed at our department since 1982 and the correspondent long-term clinical outcome.Results:Among 1123909 newborns screened for hypergalactosemia,33 showed abnormal results confirmed at second tier test.Thirteen patients were affected with classic galactosemia,8 partial GALT deficiency,3 severe galactokinase deficiency,7 transient galactosemia,one congenital porto-systemic shunt,and one glucose transporter 2 deficiency.Acute neonatal liver failure in the late first week of life(5.8±1.1 days)unavoidably complicated the clinical course of classic galactosemia,unless in three second-born siblings treated on the basis of presumptive diagnosis immediately after newborn screening sample collection on day 3.Despite early treatment and longterm steadily normal peripheral blood galactose,77%of patients with severe GALT deficiency present mild to severe intellectual disabilities.All patients with partial GALT deficiency showed normal intellectual development on a regular diet,as well as patients with galactokinase deficiency under treatment.Conclusions:Availability of screening results within the fifth day after birth would allow the prevention of acute decompensation in classic galactosemia.A systematic diagnostic work-up in all positive newborns is essential to unravel the etiology of hypergalactosemia.
文摘Newborn screening(NBS)is a public health service aimed at identifying infants with severe genetic disorders,thus providing effective treatment early enough to prevent or ameliorate the onset of symptoms.Current NBS uses biochemical analysis of dried blood spots,predominately with timeresolved fluorescence immunoassay and tandem mass spectrometry,which produces some false positives and false negatives.The application of enzymatic activity-based testing technology provides a reliable screening method for some disorders.Genetic testing is now commonly used for secondary or confirmatory testing after a positive result in some NBS programs.Recently,next-generation sequencing(NGS)has emerged as a robust tool that enables large panels of genes to be scanned together rapidly.Rapid advances in NGS emphasize the potential for genomic sequencing to improve NBS programs.However,some challenges still remain and require solution before this is applied for population screening.
文摘Newborn hearing screening is an effective strategy for early identification of hearing loss in the newborn which result in early intervention and best outcome.However implementing universal screening strategy is a challenge in many resource constrained settings.There are various limitations towards successful implementation of hearing screening program in the developing countries.The cost effectiveness of the screening program also needs to be considered in a resource constrained settings.We attempt to provide a viewpoint that can be potentially helpful for the successful implementation of hearing screening in a resource constrained settings of the developing countries.
文摘Mucopolysaccharidoses typeⅢB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase.This results in the aggregation of heparan sulfate polysaccharides within cell lysosomes that leads to progressive and severe debilitating neurological dysfunction.Current treatment options are expensive,limited,and presently there are no approved cures for mucopolysaccharidoses typeⅢB.Adeno-associated virus gene therapy has significantly advanced the field forward,allowing researchers to successfully design,enhance,and improve potential cures.Our group recently published an effective treatment using a codon-optimized triple mutant adeno-associated virus 8 vector that restores N-acetyl-alpha-glucosaminidase levels,auditory function,and lifespan in the murine model for mucopolysaccharidoses typeⅢB to that seen in healthy mice.Here,we review the current state of the field in relation to the capsid landscape,adeno-associated virus gene therapy and its successes and challenges in the clinic,and how novel adenoassociated virus capsid designs have evolved research in the mucopolysaccharidoses typeⅢB field.
文摘Vitamin B 12 deficiency,mostly of maternal origin in newborns,is a well treatable condition but can cause severe neurologic sequelae.In women of childbearing age and pregnant women worldwide vitamin B12 deficiency has been reported with frequencies of 10%-50%.Children with vitam in B I2 deficiency are asym ptom atic at birth but may develop severe multisystemic symptoms,including irreversible developmental impairment in the second halfyear of life.Early detection of vitamin B12 deficiency allows for presymptomatic treatment.This article provides an overview over the function of vitamin B12 and discusses causes and frequency of vitamin B12 deficiency in newborns,infants,and women of childbearing age.It describes novel successful approaches to newborn screening(NBS)for vitamin B,2 deficiency and results of a pilot study which performed systematic NBS for vitamin B12 deficiency using so-called second-tier strategies by measuring homocysteine and methylmalonic acid in dried blood spots.Recommendations for diagnostics in mothers of children with vitamin B12 deficiency are described as well as results of systematic work-up in mothers and treatment and follow-up of children with vitamin B12 deficiency detected by NBS.Treatment options of vitamin B12 deficiency are presented including a newly developed standardized supplementation scheme with exclusively oral vitamin BI2 supplementation.Recommendations for preventive approaches to vitamin Bl2 deficiency for children and mothers are stated.Many children worldwide could benefit from systematic inclusion of vitamin B12 deficiency into NBS panels.In addition,preventive approaches to maternal vitamin B12 deficiency should be implemented systematically during maternal care.
文摘Hemoglobinopathies, mainly Sickle cell disease (SCD), are the most common monogenic disorders in Africa. In Burkina Faso, data on these diseases are scarce, mainly hospital-based in Ouagadougou and its surroundings. In order to assess the incidence and allelic frequencies of the main hemoglobinopathies in newborns in Burkina Faso, we conducted a cross-sectional study from 2015 to 2019 in four hospitals. The study included babies of both sexes, regardless of ethnic group and parents’ hemoglobin status. It was a newborn screening and hemoglobin variants were detected using isoelectric focusing on cord blood samples and confirmed using hemoglobin electrophoresis by high-performance liquid chromatography. The proportions and cumulative incidences of the different hemoglobinopathies were computed. Hardy-Weinberg equilibrium law was applied to calculate genotypic and allelic frequencies. The significant level was p < 0.05. Out of 11,337 newborns included, 47.8% were males and 60.2% were from Bobo-Dioulasso. Abnormal hemoglobin was found in 27.1%, representing a cumulative incidence of 1:4 newborns. The incidence of SCD was 1.9% (1:53 newborns) with 27.9% of homozygous SS. Homozygous CC and compound heterozygous Cβ-Thalassemia accounted for 1.1%. SCD cases were 1.51 times higher in Bobo-Dioulasso (OR = 1.51;95% CI [1.09 - 2.10]: p = 0.013). The observed genotype frequencies were significantly different from the expected ones (p 0.001). The βS and βC alleles represented 5.1 and 9.9%, respectively. This study showed a high incidence of hemoglobinopathies. Such results raise the question of control strategies for these hemoglobinopathies in our country.
文摘Background: Cochlear implantation is the best management option for children with profound hearing loss and has received no benefit from hearing aids. Early implantation for these children is associated with good speech and language outcomes. Objectives: To determine the barriers to early pediatric cochlear implantation. Methodology: A qualitative cross-sectional study was conducted at Hearing Implants Centre in Nairobi Kenya from August 2022 to February 2023. The target population was 40 children who had undergone cochlear implantation under the auspices of Cochlear Implant Group of Kenya but data was only collected from 30 of them. The remaining were ruled out because 3 were unreachable over the phone, 5 refused to participate and 2 did not meet the inclusion criteria. Results: Patient file reviews and parental telephone interviews were conducted to collect information and analyzed using Microsoft excel and presented using graphs, tables and pie charts. The analysis of the gender showed 46.67% were male and 53.33% were female. Analysis on newborn screening showed that none had it done. The mode age of hearing loss suspicion was between the ages of 2 - 3 years. The hearing loss suspicion done was done by the mothers at 20 children the reminder being 3 by the father, 1 by a family friend, 4 by the school-teacher and 2 by the child’s grandmother. A total of 17 participants noted a delayed in speech and language, 9 noted that the child did not respond to loud sounds, 4 noted that the children did not turn when called. Once hearing loss was identified, 73% saw the ENT, 17% saw a pediatrician, 7% went to see an Audiologist, and 3% saw a speech therapist. The mode age at diagnosis was 1.5 years. The mode age at implantation was 5 years. The mode time from diagnosis was 2 years. Conclusions: This study sought to investigate the barriers to pediatric cochlear implantation in Kenya. From the results it was determined that factors such as lack of newborn screening, high cost of cochlear implantation, lack of awareness have led to late cochlear implantation.
文摘Biliary atresia(BA), a chronic progressive cholestatic disease of infants, is the leading cause for liver transplant in children, especially in patients under two years of age. BA can be successfully treated with the Kasai portoenterostomy; however most patients still require a liver transplant, with up to one half of BA children needing a transplant by age two. In the current pediatric end-stage liver disease system, children with BA face the risk of not receiving a liver in a safe and timely manner. In this review, we discuss a number of possible solutions to help these children. We focus on two general approaches:(1) preventing/delaying need for transplantation, by optimizing the success of the Kasai operation; and(2) expediting transplantation when needed, by performing techniques other than the standard deceased-donor, whole, ABO-matched organ transplant.
文摘Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electron transfer flavoprotein （ETF）-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicityon the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicat-ing glutaric acidemia type Ⅱ in newborn screening analysis. Urinary organic acids were evaluated for the confrmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, ribofavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor developmentwas normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.
文摘Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spec-trometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.
基金supported by a grant from the National Key Research and Development Program of China(No.2017YFC1001700).
文摘Background:Although congenital hypothyroidism(CH)has been widely studied in Western countries,CH incidence at different administrative levels in China during the past decade remains unknown.This study aimed to update the incidence and revealed the spatial pattern of CH incidence in the mainland of China,which could be helpful in the planning and implementation of preventative measures.Methods:The data used in our study were derived from 245 newborns screening centers that cover 30 provinces of the Chinese Newborn Screening Information System.Spatial auto-correlation was analyzed by Global Moran I and Getis-Ord Gi statistics at the provincial level.Kriging interpolation methods were applied to estimate a further detailed spatial distribution of CH incidence at city level throughout the mainland of China,and Kulldorff space scanning statistical methods were used to identify the spatial clusters of CH cases at the city level.Results:A total of 91,921,334 neonates were screened from 2013 to 2018 and 42,861 cases of primary CH were identified,yielding an incidence of 4.66 per 10,000 newborns screened(95%confidence interval[CI]:4.62–4.71).Neonates in central(risk ratio[RR]=0.84,95%CI:0.82–0.85)and western districts(RR=0.71,95%CI:0.69–0.73)had lower probability of CH cases compared with the eastern region.The CH incidence indicated a moderate positive global spatial autocorrelation(Global Moran I value=0.394,P<0.05),and the CH cases were significantly clustered in spatial distribution.A most likely city-cluster(log-likelihood ratio[LLR]=588.82,RR=2.36,P<0.01)and 25 secondary city-clusters of high incidence were scanned.The incidence of each province and each city in the mainland of China was estimated by kriging interpolation,revealing the most affected province and city to be Zhejiang Province and Hangzhou city,respectively.Conclusion:This study offers an insight into the space clustering of CH incidence at provincial and city scales.Future work on environmental factors need to focus on the effects of CH occurrence.
基金supported by the National Key R&D Program of China(No.2018YFA0900400)the National Natural ScienceFoundation of China(Nos.21635006,31670373,21721005,21904099)the Postdoctoral Science Foundation of China(No.2018M642893)。
文摘Direct infusion mass spectrometry(DIMS) is a powerful technique in clinical diagnosis for screening neonatal amino acid metabolic disorders from dried blood spots(DBS).However,DIMS sometimes generated false-positive results for analysis of amino acids.In this work,we utilized a stable isotope derivatization method,combining with liquid chromatography tandem mass spectrometry(SID-LC-MS),to improve the specificity for screening amino acids in DBS specimens.A pair of isotope reagents,p-(dimethylamino)phenyl isothiocyanate(DMAP-NCS) and 4-isothiocyanato-N,N-bis(methyl-[2H2])aniline([2H4]DMAP-NCS),was synthesized and used to label amino acids in DBS specimens.The [2H4]DMAP-NCS labelled amino acid standards were used as internal standards to compensate the matrix effect.This method was validated by measuring linearity,recovery and accuracy.The results showed that the developed SID-LC-MS method can be used for sensitive and selective determination of 12 diagnostically important amino acids in DBS specimens.
基金supported by the Key Research and Development Program of Zhejiang Province(2017C03009 to Q.S.)the National Key Research and Development Program of China(2017YFC1001703 to Q.S.)Q.S.was also supported by the Fundamental Research Funds for the Central Universities(2014QNA6002).
文摘Background Fragile X syndrome(FXS).caused by CGG-repeat expansion in FMR1 promoter,is one of the most common causes of mental retardation.Individuals with full mutation and premutation alleles have a high risk of psychophysiological disorder and of having affected offspring.Frequencies of FMR1 alleles in general newborns have been reported in Caucasians but have not been investigated in the large-scale population in the mainland of China.Methods The sizes of FMRI CGG-repeats were analyzed in 51,661 newborns(28,114 males and 23,547 females)and also in a cohort of 33 children diagnosed with developmental delay using GC-rich polymerase chain reaction(PCR)and triple repeat primed PCR.Results The frequency of CGG repeats>100 was 1/9371 in males and 1/5887 in females,and the frequency of CGG repeats>54 was 1/1561 in males and 1/1624 in females.FMRJ full mutation and premutation were identified in 27.27%of children who had Ages and Stages Questionnaire scores less than two standard deviations from the cutoff value.Conclusions Our study revealed the prevalence of FXS in China and improved the sample databases of FXS,suggesting that the prevalence of FXS in Chinese is higher than estimated previously and that FXS screening can be advised to high-risk families.
基金This project was supported by NIH-NIDCD(Grants No.R01 DC002842,DC012049,and DC017955)(RJHS)NIH-NIDCD(Grant No.5T32DC000040)(RKT).
文摘Hearing loss is the most common neurosensory deficit.It results froma variety of heritable and acquired causes and is linked to multiple deleterious effects on a child’s development that can be ameliorated by prompt identification and individualized therapies.Diagnosing hearing loss in newborns is challenging,especially in mild or progressive cases,and its management requires a multidisciplinary team of healthcare providers comprising audiologists,pediatricians,otolaryngologists,and genetic counselors.While physiologic newborn hearing screening has resulted in earlier diagnosis of hearing loss than ever before,a growing body of knowledge supports the concurrent implementation of genetic and cytomegalovirus testing to offset the limitations inherent to a singular screening modality.In this review,we discuss the contemporary role of screening for hearing loss in newborns as well as future directions in its diagnosis and treatment.
文摘Severe Combined Immunodeficiency(SCID)is an inherited group of rare,lifethreatening disorders due to the defect in T cell development and function.Clinical manifestations are characterised by recurrent and severe bacterial,viral,and fungal opportunistic infections that start from early infancy period.Haematopoietic stem cell transplantation(HSCT)is the treatment of choice.The pattern of inheritance of SCID may be X-linked or autosomal recessive.Though the diagnosis of SCID is usually established by flow cytometry-based tests,genetic diagnosis is often needed for genetic counselling,prognostication,and modification of pre-transplant chemotherapeutic agents.This review aims to highlight the genetic aspects of SCID.
