OBJECTIVES: To investigate the molecular epidemiology of children with phenylketonuria (PKU) in Gansu, China, providing foundational data for intervention strategies. METHODS: A retrospective analysis was conducted on 1 159 PKU families who attended Gansu Provincial Maternity and Child Care Hospital from January 2012 to December 2024. Sanger sequencing, multiplex ligation-dependent probe amplification, whole exome sequencing, and deep intronic variant analysis were used to analyze the <i>PAHi> gene. RESULTS: For the 1 159 children with PKU, 2 295 variants were identified in 2 318 alleles, resulting in a detection rate of 99.01%. The detection rates were 100% (914/914) in 457 classic PKU families, 99.45% (907/912) in 456 mild PKU families, and 96.34% (474/492) in 246 mild hyperphenylalaninemia families. The 2 295 variants detected comprised 208 distinct mutation types, among which c.728G>A (14.95%, 343/2 295) had the highest frequency, followed by c.611A>G (4.88%, 112/2 295) and c.721C>T (4.79%, 110/2 295). The cumulative frequency of the top 23 hotspot variants reached 70.28% (1 613/2 295), and most variant alleles were detected in exon 7 (29.19%, 670/2 295). CONCLUSIONS Deep intronic variant analysis of the <i>PAHi> gene can improve the genetic diagnostic rate of PKU. The development of targeted detection kits for <i>PAHi> hotspot variants may enable precision screening programs and enhance preventive strategies for PKU.
Humans ; Phenylketonurias/epidemiology* ; Female ; Male ; Retrospective Studies ; Phenylalanine Hydroxylase/genetics* ; Mutation ; Child, Preschool ; China/epidemiology* ; Child ; Infant

Case 1: A 19-day-old male infant presented with poor feeding and decreased activity for 2 weeks, worsening with poor responsiveness for 3 days. At 5 days old, he developed poor feeding and poor responsiveness, was hospitalized, and was found to have elevated blood ammonia and thrombocytopenia. Whole-genome genetic analysis revealed a pathogenic homozygous mutation in the <i>PCCAi> gene, NM-000282.4: c.1834-1835del (p.Arg612AspfsTer44), leading to a diagnosis of propionic acidemia. Case 2: A 4-day-old male infant presented with poor responsiveness and feeding difficulties since birth, with elevated blood ammonia for 1 day. He showed weak sucking and deteriorating responsiveness, with blood ammonia >200 µmol/L. Genetic testing identified two heterozygous mutations in the <i>MMUTi> gene: NM_000255.4: c.1677-1G>A and NM_000255.4: ex.5del, confirming methylmalonic acidemia. Case 3: A 20-day-old male infant presented with poor feeding for 15 days and skin petechiae for 8 days. He developed feeding difficulties at 5 days old and lower limb petechiae at 12 days old, with blood ammonia measured at 551.6 µmol/L. Genetic analysis found two heterozygous mutations in the <i>PCCAi> gene: NM_000282.4: c.1118T>A (p.Met373Lys) and NM_000282.4: ex.16-18del, confirming propionic acidemia. In the first two cases, continuous hemodiafiltration was performed for 30 hours and 20 hours, respectively, before administering carglumic acid. In the third case, carglumic acid was administered orally without continuous hemodiafiltration, resulting in a decrease in blood ammonia from 551.6 µmol/L to 72.0 µmol/L within 6 hours, with a reduction rate of approximately 20-25 µmol/(kg·h), similar to the first two cases. Carglumic acid was effective in all three cases, suggesting it may help optimize future treatment protocols for organic acidemia.
Humans ; Male ; Infant, Newborn ; Propionic Acidemia/drug therapy* ; Amino Acid Metabolism, Inborn Errors/genetics* ; Mutation ; Methylmalonyl-CoA Decarboxylase/genetics* ; Citrates/administration & dosage* ; Carbon-Carbon Ligases/genetics* ; Glutamates

OBJECTIVES: To investigate the growth parameters of children with phenylketonuria and assess the impact of a phenylalanine-restricted diet on their physical development. METHODS: The study involved 39 children diagnosed with phenylketonuria through newborn screening at the Central Child Teaching Hospital, Baghdad, Iraq. Data were collected during scheduled monthly check-ups, including phenylalanine levels, diet compliance, and anthropometric measurements. The children were divided into two groups based on their phenylalanine levels during the 3-year follow-up period: well-controlled group (average phenylalanine level of less than 360 μmol/L, with no single reading exceeding 600 μmol/L; <i>ni>=14) and poorly-controlled group (one or more phenylalanine readings above 600 μmol/L during the follow-up period; <i>ni>=25). RESULTS: The mean height readings for all time points (at birth and 3, 6, 9, 12, 15, 18, 21, 24 and 36 months of age) were higher in the well-controlled group than the poorly-controlled group, however, only at 3 months of age the difference was statistically significant. Height Z-scores revealed a clearer pattern: although the poorly-controlled group had higher height Z-scores at birth (<i>Pi>=0.001), the well-controlled group showed significantly higher height Z-scores at 3, 6, 12, 15, 18, 24, and 36 months (<i>Pi><0.05). The well-controlled group exhibited significantly higher mean weight measurements compared to the poorly-controlled group at 3, 6, 9, 15, 18 months and 21 months (<i>Pi><0.05). From 6 to 36 months, the well-controlled group consistently had significantly higher weight Z-scores than the poorly-controlled group (<i>Pi><0.05). The well-controlled group showed more favorable height and weight Z-score distributions at 36 months of age compared to the poorly-controlled group, but the differences were not statistically significant (<i>Pi>>0.05). Both groups had height and weight Z-scores within the normal range at 36 months of age. CONCLUSIONS The children with phenylketonuria who receive good dietary control show better improvements in growth parameters compared to those with poor dietary control, however, both groups maintain height and weight Z-scores within the normal range, indicating generally adequate physical development across the cohort.
Humans ; Phenylketonurias/diet therapy* ; Male ; Female ; Child, Preschool ; Infant ; Body Height ; Infant, Newborn ; Child Development ; Phenylalanine/blood*

OBJECTIVES: To develop a quality control indicator system for neonatal screening of inherited metabolic diseases in obstetric settings, so as to provide a standardized tool for quality control in clinical neonatal screening of inherited metabolic diseases. METHODS: From March to May 2024, a literature review combined with expert clinical experience was conducted to develop a preliminary questionnaire on quality control indicators for neonatal screening of inherited metabolic diseases. The final indicator system was established after two rounds of the Delphi method, and the Analytic Hierarchy Process was used to determine indicator weights. RESULTS: Sixteen questionnaires were distributed in each of the two consultation rounds, with a valid response rate of 100% for both. The expert authority coefficients were 0.863 and 0.876, respectively. Kendall's coefficient of concordance for the importance and feasibility of the indicators ranged from 0.091 to 0.125. The final indicator system comprised 3 primary indicators, 8 secondary indicators, and 28 tertiary indicators for neonatal screening of inherited metabolic diseases in obstetric settings. CONCLUSIONS The quality control indicator system developed using the Delphi method demonstrates a strong systematic structure, high clinical adaptability, and strong operability, and can be effectively applied to quality control in neonatal screening of inherited metabolic diseases in obstetric settings.
Humans ; Infant, Newborn ; Neonatal Screening/standards* ; Quality Control ; Metabolism, Inborn Errors/diagnosis* ; Metabolic Diseases/diagnosis* ; Delphi Technique ; Female ; Quality Indicators, Health Care ; Pregnancy

Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS; OMIM: 143500) are rare autosomal recessive diseases that cause unconjugated hyperbilirubinemia due to decreased UGT1A1 enzyme activity. Crigler-Najjar syndrome type 2 (CNS2; OMIM: 606785) increases the risk of gallbladder stone formation and cholecystitis, while GS seldom causes health issues. We found a 28-year-old male patient with recurring right upper abdomen pain who experienced persistent jaundice from birth. CNS2 with gallbladder stones and cholecystitis was diagnosed after genetic testing revealed rare double homozygous mutations A(TA)₇TAA (rs3064744) and P229Q (rs35350960) in the UGT1A1 gene. After pedigree investigation, we found that the patient's parents with modestly increased bilirubin had compound heterozygous mutations A(TA)₇TAA and P229Q, which were GS. Bioinformatics analysis showed that A(TA)₇TAA is in the TATA-box region of the gene UGT1A1 promoter, affecting gene transcriptional initiation, whereas P229Q modifies protein three-dimensional structure and may be harmful. In this pedigree, double homozygous mutations have a more severe phenotype than compound heterozygous mutations. Inherited causes of hyperbilirubinemia should be suspected after ruling out biliary obstruction, and early bilirubin reduction (< 103 µmol/L (6 mg/dL)) may reduce the risk of complications like cholecystitis in CNS2 patients, though further studies with longer follow-up are needed to confirm this observation.
Humans ; Male ; Glucuronosyltransferase/genetics* ; Adult ; Crigler-Najjar Syndrome/complications* ; Cholecystitis/etiology* ; Homozygote ; Mutation ; Pedigree

BACKGROUND

Newborns screened positive for Galactosemia through Expanded Newborn Screening (ENBS) with borderline levels undergo lactose challenge that requires interruption of breastfeeding temporarily then shifting to soy-based formula.

To determine the percentage of Classical Galactosemia (CGal), Non-classical Galactosemia (NCGal), probable mild variant form, and negative Galactosemia among newborns screened positive for Galactosemia who underwent lactose challenge.

This is a retrospective study. NBS records were reviewed and data were collected from January 2015 to December 2020.

Out of the 117 newborns screened positive for Galactosemia, 58 underwent lactose challenge. Majority were male, term with a birth weight of 2500-4000g and received a final disposition in 4-6 months. Fifteen patients underwent 1-week lactose challenge wherein six reached a resolution on first challenge. Majority, 35 (60.3%) were negative for Galactosemia, six (10.3%) probable mild variant Galactosemia, three (5.2%) NCGal, and no CGal were observed. Fourteen suspected cases (24.1%) are pending final disposition.

This study describes the demographics of newborns flagged for Galactosemia who underwent lactose challenge. A 1-week lactose challenge may be recommended to further detect patients who are negative for Galactosemia.

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with pseudohypoparathyroidism. METHODS: Peripheral blood samples of the proband and his parents were collected and subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified among the pedigree and 50 randomly selected healthy individuals through analysis of restriction fragment length polymorphism. Short tandem repeat (STR) linkage analysis was used to verify the parental origin of the pathogenic variants. RESULTS: Trio-WES and Sanger sequencing showed that the proband and his mother had both harbored a c.121C>G (p.His41Asp) variant of the GNAS gene, which was not found in other family members and the 50 healthy controls. The variant was not found in international databases. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic. CONCLUSION The novel c.121C>G variant of the GNAS gene probably underlay the disease in this pedigree. Above finding has enriched the spectrum of GNAS gene variants.
Female ; Humans ; Pedigree ; East Asian People ; Mothers ; Exome Sequencing ; Pseudohypoparathyroidism/genetics* ; Mutation ; China ; Chromogranins/genetics* ; GTP-Binding Protein alpha Subunits, Gs/genetics*

OBJECTIVE: To carry out preimplantation genetic testing for monogenic/single gene disorders (PGT-M) for a Chinese family affected with Molybdenum co-factor deficiency due to pathogenic variant of MOCS2 gene. METHODS: A family with molybdenum co-factor deficiency who attended to the Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region in April 2020 was selected as the research subject. Trophoblast cells were biopsied from blastocysts fertilized by intracytoplasmic sperm injection. Embryos carrying the MOCS2 gene variant and chromosome copy number variation (CNV) of more than 4 Mb were detected by single-cell whole genome amplification, high-throughput sequencing and single nucleotide polymorphism typing. Embryos without or carrying the heterozygous variant and without abnormal chromosome CNV were transplanted. During mid-pregnancy, amniotic fluid sample was collected for prenatal diagnosis to verify the results of PGT-M. RESULTS: Eleven oocytes were obtained, among which three blastocysts were formed through culturing. Results of genetic testing suggested that one embryo was heterozygous for the maternally derived MOCS2 gene variant and without chromosomal CNV. Following embryo transfer, intrauterine singleton pregnancy was attained. Prenatal diagnosis by amniocentesis at 18 weeks of gestation revealed that the MOCS2 gene variant and chromosomal analysis results were both consistent with that of PGT-M, and a healthy male infant was born at 37⁺⁵ weeks of gestation. CONCLUSION PGT-M has helped the couple carrying the MOCS2 gene variant to have a healthy offspring, and may become an important method for couples carrying other pathogenic genetic variants.
Female ; Humans ; Pregnancy ; Aneuploidy ; China ; DNA Copy Number Variations ; Genetic Testing/methods* ; Preimplantation Diagnosis/methods* ; Metal Metabolism, Inborn Errors/genetics*

OBJECTIVE: To investigate the clinical manifestations, biochemical abnormalities and pathogenic variants among children with Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency detected by neonatal screening. METHODS: A total of 2 730 852 newborns were screened from January 2016 to December 2021 with liquid chromatography tandem mass spectrometry. Suspected SBCAD deficiency patients were diagnosed by urine organic acid analysis and high-throughput gene sequencing analysis. The clinical, biochemical and genetic changes of the confirmed cases were analyzed, in addition with guidance for diet and life management, L-carnitine supplement, and survey of growth and intellectual development. RESULTS: Twelve cases of SBCAD deficiency were diagnosed, which yielded a prevalence of 1/227 571. The lsovaleryl carnitine (C5) of primary screening blood samples was between 0.6 and 2.1 µmol/L, all exceeded the normal range. C5/acety1 carnitine (C2) was between 0.02 and 0.12, with 6 cases exceeding the normal range. C5/propionyl carnitine (C3) was between 0.1 and 1.16, with 5 cases exceeding the normal range. Free carnitine (C0) was between 18.89 and 58.12 µmol, with 1 case exceeding the normal range. Three neonates with abnormal screening results were recommended to have appropriate restriction for protein intake and two were given L-carnitine. During follow-up, their C5 has ranged from 0.22 to 2.32 µmol/L, C5/C2 has ranged from 0.01 to 0.31, C5/C3 has ranged from 0.14 to 1.7. C5 or C5/C2 and C5/C3 were transiently normal in all patients except for case 8 during the neonatal screening and follow-up. C0 was 17.42 ∼ 76.83 µmol/L Urine organic acid analysis was carried out in 9 of the 12 cases, and 2-methylbutyroglycine was elevated in 8 cases. Urine organic acid analysis was carried out in 9 cases, and 2-methylbutyrylglycine was increased in 8 cases. Genetic analysis was carried out for 11 children, and in total 6 ACADSB gene variants were identified, which included 4 missense variants (c.655G>A, c.923G>A, c.461G>A, c.1165A>G), 1 frameshift variant (c.746del) and 1 nonsense variant (c.275C>G). Among these, the C.461G>A variant was unreported previously. The most common variants were c.1165A>G (40.9%) and C.275C>G (22.7%). The patients were followed up for 18 days to 55 months. Only one patient had mental retardation, with the remainders having normal physical and mental development. CONCLUSION SBCAD deficiency is a rare disease. The detection rate of newborn screening in this study was 1/227 571. Early intervention can be attained in most asymptomatic patients through neonatal screening. In this study, the common gene variants are c.1165A>G and c.275C>G.
Humans ; Infant, Newborn ; Amino Acid Metabolism, Inborn Errors/genetics* ; Carnitine ; Neonatal Screening/methods*

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child with acute form of tyrosinemia type I (TYRSN1). METHODS: A child with TYRSN1 who presented at the Gansu Provincial Maternal and Child Health Care Hospital in October 2020 was selected as the subject. The child was subjected to tandem mass spectrometry (MS-MS) and urine gas chromatography-mass spectrometry (GC-MS) for the detection of inherited metabolic disorders, in addition with whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: The child's clinical features included abdominal distension, hepatomegaly, anemia and tendency of bleeding. By mass spectrometry analysis, her serum and urine tyrosine and succinylacetone levels have both exceeded the normal ranges. WES and Sanger sequencing revealed that she has harbored c.1062+5G>A and c.943T>C (p.Cys315Arg) compound heterozygous variants of the FAH gene, which were inherited from her father and mother, respectively. Among these, the c.943T>C was unreported previously. CONCLUSION Considering her clinical phenotype and result of genetic testing, the child was diagnosed with TYRSN1 (acute type). The compound heterozygous variants of the FAH gene probably underlay the disease in this child. Above finding has further expanded the spectrum of FAH gene variants, and provided a basis for accurate treatment, genetic counseling and prenatal diagnosis for her family.
Female ; Humans ; Gas Chromatography-Mass Spectrometry ; Genetic Testing ; Mutation ; Phenotype ; Prenatal Diagnosis ; Tyrosinemias/genetics* ; Child