OBJECTIVE: To assess the value of whole exome sequencing (WES) for the diagnosis of early-onset genetic diseases among infants aged 0 to 6 month in Ningbo region. METHODS: 268 infants presented at the Women and Children's Hospital Affiliated to Ningbo University from January 2022 to June 2024 undergoing WES-based genetic testing were enrolled. Peripheral blood samples were collected from the infants and their parents and subjected to WES. Pathogenic variants were identified by clinical manifestations. This study has been approved by the Medical Ethics Committee of the Hospital (Ethics No. EC2023-017). RESULTS: Among the 268 infants, 124 (46.3%) had phenotype-explaining genetic variants. For 42 family-based WES tests, 20 (47.62%) were abnormal, whilst in 226 single-person WES tests, 104 (46.02%) had abnormalities, with 76 (33.63%) verified by parental testing. In 96 fully family-verified cases, 31 were de novo, 40 were parent-inherited, 25 were single-parent-inherited. These included 35 inborn metabolic errors, 28 rare syndromes, 9 neurodevelopmental disorders, 4 musculoskeletal diseases, 5 congenital deafness, 2 mitochondrial diseases, 4 endocrine diseases, and 9 others. Among these, there were 7 pathogenic copy number variations (all deletions), 3 chromosomal abnormalities, and 85 single-nucleotide variations. One case of Beckwith-Wiedemann syndrome was detected by methylation MLPA. Among the single-nucleotide variants, 114 pathogenic/likely pathogenic variants were identified in 61 genes, with common ones including missense variants (64.04%), frameshifting variants (20.18%) and splicing variants (4.39%). CONCLUSION WES can offer effective diagnosis for hereditary diseases with specific/non-specific manifestations. For early-age infants, higher detection rates may be attained for inborn metabolic errors, rare syndromes, neurodevelopmental disorders, congenital deafness, and musculoskeletal diseases. Compared with single-person WES, family-based WES can attain a higher diagnostic efficiency.
Humans ; Exome Sequencing/methods* ; Infant ; Female ; Male ; Infant, Newborn ; Genetic Diseases, Inborn/diagnosis* ; Genetic Testing/methods*

Optical genome mapping (OGM) is an emerging technology for the detection of genetic diseases based on physical mapping, which can detect numerical chromosomal abnormalities, copy number variation (CNV) and structural variation (SV) on a genome-wide scale. In recent years, a number of studies have proved that OGM, as a new generation of cytogenomic technique, has higher resolution and stronger ability to discover genomic variants compared with conventional genetic techniques. This article has systematically reviewed the principles, characteristics, advantages and limitations of OGM technology, and its applications in the diagnosis of genetic disorders.
Humans ; DNA Copy Number Variations ; Chromosome Mapping/methods* ; Genetic Diseases, Inborn/diagnosis* ; Genome, Human

Follow-up is a crucial step for the screening of neonatal genetic and metabolic diseases, which can directly influence the detection, diagnosis, efficacy of treatment, as well as the quality of neonatal screening. In view of the lack of follow-up, full understanding, and inconsistent requirement between various agencies and personnel in China, there is an urgent need for standardization. The Committee for Proficiency Testing of the Neonatal Genetic Metabolic Disease Screening Center of the National Health Committee of China has organized the writing of expert consensus for follow-up of neonatal genetic and metabolic disease screening after thorough discussion, so as to guide the follow-up work and improve its quality.
China ; Consensus ; Follow-Up Studies ; Genetic Diseases, Inborn ; diagnosis ; Humans ; Infant, Newborn ; Metabolic Diseases ; diagnosis ; genetics ; Neonatal Screening

Consensus ; Genetic Diseases, Inborn ; diagnosis ; genetics ; Genome, Human ; genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Practice Guidelines as Topic ; Sequence Analysis, DNA ; Whole Genome Sequencing

OBJECTIVETo assess the value of droplet digital PCR (ddPCR) for non-invasive prenatal diagnosis of single gene disease in two families.

METHODSPaternal mutation in cell-free DNA derived from the maternal blood and amniotic fluid DNA was detected by ddPCR. Suspected mutation in the amniotic fluid DNA was verified with Sanger sequencing.

RESULTSThe result of ddPCR and Sanger sequencing indicated that the fetuses have carried pathogenic mutations from the paternal side in both families.

CONCLUSIONDroplet digital PCR can accurately detect paternal mutation carried by the fetus, and it is sensitive and reliable for analyzing trace samples. This method may be applied for the diagnosis of single gene diseases caused by paternal mutation using peripheral blood sample derived from the mother.

Fathers ; Female ; Genetic Diseases, Inborn ; diagnosis ; Humans ; Male ; Maternal Serum Screening Tests ; Mutation ; Polymerase Chain Reaction ; methods ; Prenatal Diagnosis ; methods ; Sequence Analysis, DNA

More than 7000 single gene diseases have been identified and most of them lack effective treatment. As an early form of prenatal diagnosis, preimplantation genetic diagnosis (PGD) is a combination of in vitro fertilization and genetic diagnosis. PGD has been applied in clinics for more than 20 years to avoid the transmission of genetic defects through analysis of embryos at early stages of development. In this paper, a review for the recent advances in PGD for single gene diseases is provided.
Animals ; Female ; Fertilization in Vitro ; Genetic Diseases, Inborn ; diagnosis ; embryology ; genetics ; Humans ; Pregnancy ; Preimplantation Diagnosis ; methods ; trends ; Prenatal Diagnosis ; methods ; trends

Thalassemia is hereditary disease characterized by impaired production of the normal globin peptide. Beta-thalassemia, a common disorder in Central Africa, the Middle East, and Southeast Asia, has been rarely reported in Korea. It should be considered in the differential diagnosis of hypochromic, microcytic anemia. The genetic subtypes among the different ethnic groups vary; this may pose challenges in prenatal diagnosis or genetic counselling. During pregnancy, women with thalassemia will often show more significant anemia. Recently we have experienced Korean pregnant woman with beta-thalassemia associated with anemia. We describe this case with a brief review of the literature.
Africa, Central ; Anemia ; Asia, Southeastern ; beta-Thalassemia* ; Diagnosis, Differential ; Ethnic Groups ; Female ; Genetic Diseases, Inborn ; Globins ; Humans ; Korea ; Middle East ; Pregnancy ; Pregnant Women* ; Prenatal Diagnosis ; Thalassemia

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome) is a neurometabolic disorder with highly variable clinical severity ranging from mild learning disability to severe encephalopathy. Diagnosis of HHH syndrome can easily be delayed or misdiagnosed due to insidious symptoms and incomplete biochemical findings, in that case, genetic testing should be considered to confirm the diagnosis. HHH syndrome is caused by biallelic mutations of SLC25A15, which is involved in the urea cycle and the ornithine transport into mitochondria. Here we report a boy with spastic paraplegia and asymptomatic younger sister who have compound heterozygous mutations of c.535C>T (p.R179*) and c.116C>A (p.T39K) in the SLC25A15 gene. We identified that p.T39K mutation is a novel pathogenic mutation causing HHH syndrome and that p.R179*, which is prevalent in Japanese and Middle Eastern heritage, is also found in the Korean population.
Asian Continental Ancestry Group ; Brain Diseases ; Diagnosis ; Genetic Testing ; Genetics ; Humans ; Learning Disorders ; Male ; Mitochondria ; Ornithine ; Paraplegia ; Siblings ; Urea ; Urea Cycle Disorders, Inborn

BACKGROUND: A newborn screening (NBS) program has been utilized to detect asymptomatic newborns with inherited metabolic diseases (IMDs). There have been some bottlenecks such as false-positives and imprecision in the current NBS tests. To overcome these issues, we developed a multigene panel for IMD testing and investigated the utility of our integrated screening model in a routine NBS environment. We also evaluated the genetic epidemiologic characteristics of IMDs in a Korean population. METHODS: In total, 269 dried blood spots with positive results from current NBS tests were collected from 120,700 consecutive newborns. We screened 97 genes related to NBS in Korea and detected IMDs, using an integrated screening model based on biochemical tests and next-generation sequencing (NGS) called NewbornSeq. Haplotype analysis was conducted to detect founder effects. RESULTS: The overall positive rate of IMDs was 20%. We identified 10 additional newborns with preventable IMDs that would not have been detected prior to the implementation of our NGS-based platform NewbornSeq. The incidence of IMDs was approximately 1 in 2,235 births. Haplotype analysis demonstrated founder effects in p.Y138X in DUOXA2, p.R885Q in DUOX2, p.Y439C in PCCB, p.R285Pfs*2 in SLC25A13, and p.R224Q in GALT. CONCLUSIONS: Through a population-based study in the NBS environment, we highlight the screening and epidemiological implications of NGS. The integrated screening model will effectively contribute to public health by enabling faster and more accurate IMD detection through NBS. This study suggested founder mutations as an explanation for recurrent IMD-causing mutations in the Korean population.
Computational Biology ; DNA/chemistry/isolation & purification/metabolism ; Dried Blood Spot Testing ; Galactokinase ; Genomics ; Haplotypes ; High-Throughput Nucleotide Sequencing ; Humans ; Incidence ; Infant, Newborn ; Membrane Proteins/genetics ; Metabolic Diseases/*diagnosis/epidemiology/genetics ; Metabolism, Inborn Errors/diagnosis/epidemiology/genetics ; Mitochondrial Membrane Transport Proteins/genetics ; Neonatal Screening ; Polymorphism, Genetic ; Republic of Korea/epidemiology ; Sequence Analysis, DNA

Next-generation sequencing, such as whole-genome sequencing, whole-exome sequencing, and targeted panel sequencing have been applied for diagnosis of many genetic diseases, and are in the process of replacing the traditional methods of genetic analysis. Clinical exome sequencing (CES), which provides not only sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to genetic diagnosis. Sequencing of genes with clinical relevance rather than whole exome sequencing might be more suitable for the diagnosis of known hereditary disease with genetic heterogeneity. Here, we present the clinical usefulness of CES for the diagnosis of hereditary spastic paraplegia (HSP). We report a case of patient who was strongly suspected of having HSP based on her clinical manifestations. HSP is one of the diseases with high genetic heterogeneity, the 72 different loci and 59 discovered genes identified so far. Therefore, traditional approach for diagnosis of HSP with genetic analysis is very challenging and time-consuming. CES with TruSight One Sequencing Panel, which enriches about 4,800 genes with clinical relevance, revealed compound heterozygous mutations in SPG11. One workflow and one procedure can provide the results of genetic analysis, and CES with enrichment of clinically relevant genes is a cost-effective and time-saving diagnostic tool for diseases with genetic heterogeneity, including HSP.
Diagnosis ; Exome* ; Genetic Diseases, Inborn ; Genetic Heterogeneity ; Humans ; Spastic Paraplegia, Hereditary*