Background Newborn screening(NBS)through disease biomarkers has significantly reduced severe outcomes of congenital disorders.Moreover,exploratory newborn genetic screening programs are increasingly being implemented....Background Newborn screening(NBS)through disease biomarkers has significantly reduced severe outcomes of congenital disorders.Moreover,exploratory newborn genetic screening programs are increasingly being implemented.This consensus,developed by multidisciplinary experts,aims to standardize the combined screening of genes and biomarkers for neonatal diseases in China,balancing ethical,technical,and clinical considerations.Data sources This consensus synthesizes evidence from peer-reviewed literature(PubMed,CNKI,etc.)up to 2024 and integrates clinical experiences from multidisciplinary experts in neonatology,genetics,and laboratory medicine,focusing on disease biomarker-based NBS,newborn genetic screening,and the clinical utility of combined screening.Results The consensus defines principles for combined screening:(1)disease/gene selection:154 disease-causing genes covering 67 inherited metabolic disorders(e.g.,amino acid metabolism disorders,organic acid metabolism disorders),prioritized by treatability,onset age(<5 years),and cost-effectiveness;(2)methodology:integrating dried blood spot biomarker analysis with next-generation sequencing-based targeted capture(coverage>300×),validated by MLPA/Sanger and longrange sequencing for complex variants(e.g.,CYP21A2,SLC25A13);and(3)operational workflow:standardized workflows for informed consent,sample collection/delivery,and result interpretation,with dual reporting of marker and genetic findings within 15 days.Positive cases require family verification and/or other genetic sequencing techniques.Conclusions This consensus establishes a practical framework for integrating marker and genetic screening,aiming to improve diagnostic accuracy and achieve rapid and effective interventions,thereby saving lives and reducing the occurrence of severe complications.Implementation requires interdisciplinary collaboration and ongoing quality control to maximize clinical utility.展开更多
Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene(MMACHC)c.482G>A mutation in 195 Chinese ca...Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene(MMACHC)c.482G>A mutation in 195 Chinese cases with CblC disease.Methods We carried out a national,retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G>A variant either in a homozygous or compound heterozygous state.The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G>A mutation.Clinical features,including disease onset,symptoms,biochemical metabolites,gene mutation,and follow-up outcomes were reviewed and analyzed in detail.The median follow-up period spanned 3 years and 8 months,with a range of 1 year and 2 months to 12 years and 10 months.Results Among 195 patients carrying the c.482G>A variant,125(64.1%)cases were diagnosed by newborn screening(NBS),60(30.8%)cases were detected due to disease onset,and 10(5.1%)cases were identified from sibling diagnoses.One hundred and seventeen(93.6%)individuals who were diagnosed by NBS,and nine patients who came from sibling diagnoses remained asymptomatic in this study.From 69 symptomatic patients of the c.482G>A group,more patients presented with later onset,and the top six common clinical symptoms at disease onset were developmental delay(59.4%),lower limb weakness and poor exercise tolerance(50.7%),cognitive decline(37.7%),gait instability and abnormal posture(36.2%),seizures(26.1%),and psychiatric and behavioral disturbances(24.6%).In the 159 symptomatic patients lacking c.482G>A variants,the most frequently observed clinical manifestations at disease onset included developmental delay(81.8%),lethargy and feeding difficulty(62.9%),lower limb weakness and poor exercise tolerance(54.7%),prolonged neonatal jaundice(51.6%),vomiting(47.2%),and seizures(32.7%).Before treatment,the levels of blood propionylcarnitine,propionylcarnitine/acetylcarnitine ratio,and homocysteine in the c.482G>A group were significantly lower(P<0.05)than those in the non-c.482G>A group,while the concentration of urinary methylmalonic acid was slightly lower(P>0.05).The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels(P<0.05).In patients carrying the c.482G>A variant compared with the non-c.428G>A group,there were markedly lower rates of mortality(0.5%vs.2.0%)and developmental delay(20.5%vs.65.5%).When compared with individuals diagnosed due to disease onset,those identified through NBS in either group exhibited a reduced proportion of disease onset(6.7%vs.100%in the c.482G>A group,54.4%vs.100%in the non-c.482G>A group),lower mortality(0.0%vs.1.7%in the c.482G>A group,0.0%vs.3.6%in the non-c.482G>A group),and had a higher percentage of patients exhibiting normal psychomotor and language development(99.3%vs.33.3%in the c.482G>A group,58.9%vs.10.9%in the non-c.482G>A group).Conclusions The c.482G>A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease.Patients with this mutation tend to have a relatively better response to hydroxocobalamin,better metabolic control,and more favorable neurological outcomes.NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis,resulting in favorable clinical outcomes.展开更多
基金supported by grants from the"Pioneer"and"Leading Goose"R&D Program of Zhejiang Province(No.2024C03152 to H.F.).
文摘Background Newborn screening(NBS)through disease biomarkers has significantly reduced severe outcomes of congenital disorders.Moreover,exploratory newborn genetic screening programs are increasingly being implemented.This consensus,developed by multidisciplinary experts,aims to standardize the combined screening of genes and biomarkers for neonatal diseases in China,balancing ethical,technical,and clinical considerations.Data sources This consensus synthesizes evidence from peer-reviewed literature(PubMed,CNKI,etc.)up to 2024 and integrates clinical experiences from multidisciplinary experts in neonatology,genetics,and laboratory medicine,focusing on disease biomarker-based NBS,newborn genetic screening,and the clinical utility of combined screening.Results The consensus defines principles for combined screening:(1)disease/gene selection:154 disease-causing genes covering 67 inherited metabolic disorders(e.g.,amino acid metabolism disorders,organic acid metabolism disorders),prioritized by treatability,onset age(<5 years),and cost-effectiveness;(2)methodology:integrating dried blood spot biomarker analysis with next-generation sequencing-based targeted capture(coverage>300×),validated by MLPA/Sanger and longrange sequencing for complex variants(e.g.,CYP21A2,SLC25A13);and(3)operational workflow:standardized workflows for informed consent,sample collection/delivery,and result interpretation,with dual reporting of marker and genetic findings within 15 days.Positive cases require family verification and/or other genetic sequencing techniques.Conclusions This consensus establishes a practical framework for integrating marker and genetic screening,aiming to improve diagnostic accuracy and achieve rapid and effective interventions,thereby saving lives and reducing the occurrence of severe complications.Implementation requires interdisciplinary collaboration and ongoing quality control to maximize clinical utility.
基金funded by the Scientific research Project Plan of Shanghai Municipal Health Commission(No.202140346)the National Key Research and Development Program of China(No.2016YFC0901505).
文摘Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene(MMACHC)c.482G>A mutation in 195 Chinese cases with CblC disease.Methods We carried out a national,retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G>A variant either in a homozygous or compound heterozygous state.The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G>A mutation.Clinical features,including disease onset,symptoms,biochemical metabolites,gene mutation,and follow-up outcomes were reviewed and analyzed in detail.The median follow-up period spanned 3 years and 8 months,with a range of 1 year and 2 months to 12 years and 10 months.Results Among 195 patients carrying the c.482G>A variant,125(64.1%)cases were diagnosed by newborn screening(NBS),60(30.8%)cases were detected due to disease onset,and 10(5.1%)cases were identified from sibling diagnoses.One hundred and seventeen(93.6%)individuals who were diagnosed by NBS,and nine patients who came from sibling diagnoses remained asymptomatic in this study.From 69 symptomatic patients of the c.482G>A group,more patients presented with later onset,and the top six common clinical symptoms at disease onset were developmental delay(59.4%),lower limb weakness and poor exercise tolerance(50.7%),cognitive decline(37.7%),gait instability and abnormal posture(36.2%),seizures(26.1%),and psychiatric and behavioral disturbances(24.6%).In the 159 symptomatic patients lacking c.482G>A variants,the most frequently observed clinical manifestations at disease onset included developmental delay(81.8%),lethargy and feeding difficulty(62.9%),lower limb weakness and poor exercise tolerance(54.7%),prolonged neonatal jaundice(51.6%),vomiting(47.2%),and seizures(32.7%).Before treatment,the levels of blood propionylcarnitine,propionylcarnitine/acetylcarnitine ratio,and homocysteine in the c.482G>A group were significantly lower(P<0.05)than those in the non-c.482G>A group,while the concentration of urinary methylmalonic acid was slightly lower(P>0.05).The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels(P<0.05).In patients carrying the c.482G>A variant compared with the non-c.428G>A group,there were markedly lower rates of mortality(0.5%vs.2.0%)and developmental delay(20.5%vs.65.5%).When compared with individuals diagnosed due to disease onset,those identified through NBS in either group exhibited a reduced proportion of disease onset(6.7%vs.100%in the c.482G>A group,54.4%vs.100%in the non-c.482G>A group),lower mortality(0.0%vs.1.7%in the c.482G>A group,0.0%vs.3.6%in the non-c.482G>A group),and had a higher percentage of patients exhibiting normal psychomotor and language development(99.3%vs.33.3%in the c.482G>A group,58.9%vs.10.9%in the non-c.482G>A group).Conclusions The c.482G>A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease.Patients with this mutation tend to have a relatively better response to hydroxocobalamin,better metabolic control,and more favorable neurological outcomes.NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis,resulting in favorable clinical outcomes.
