Yinan Ma

In China, research on expanded carrier screening (ECS) has exhibited significant inconsistencies due to regional variations, with a lack of large-scale data analysis of the population nationwide. This study aimed to review the carrier rates of monogenic disorders throughout China comprehensively. The study was conducted in two stages, with the carrier rate of monogenic diseases as the primary outcome. In the first stage, 1449 articles were identified, of which 11 were ultimately included for data extraction. In the second stage, all 307 genes identified by the first stage were specifically investigated, and both carrier rates and allele frequencies of pathogenic or likely pathogenic (P/LP) variants were extracted. Nineteen genes were associated with monogenic disorders exhibiting carrier frequencies above 1/100, including GJB2 (7.78%), HBA1/2 (6.19%), PAH (2.76%), ATP7B (2.51%), DUOX2 (2.50%), HBB (2.48%), GALC (2.37%), CYP21A2 (2.11%), SLC26A4 (1.96%), POLG (1.92%), USH2A (1.91%), SLC25A13 (1.87%), SLC22A5 (1.78%), SMN1 (1.75%), MMACHC (1.66%), G6PD (1.38%), GAA (1.05%), UGT1A1 (1.02%), and TYR (1.01%). Twenty-seven conditions had carrier rates between 1/100 and 1/200, and thirty had carrier frequencies between 1/200 and 1/400. The ten most common pathogenic/likely pathogenic (P/LP) variants with the highest allele frequencies were: GJB2 c.109G>A (7.3%), POLG c.2890C>T (0.94%), GALC c.1901T>C (0.90%), SMN1 exon 7 deletion (0.87%), SLC25A13 c.2T>C (0.59%), SLC22A5 c.1472C>G (0.52%), GJB2 c.235del (0.50%), SLC22A5 c.1400C>G (0.48%), SLC22A5 c.43G>T (0.44%), and SLC25A13 c.852_855del (0.43%). This review provides the first comprehensive summary of carrier rates for monogenic diseases in the Chinese Han population. It not only describes but also ranks the carrier rates and variant frequencies of related genes, offering critical evidence for the tiered inclusion of gene categories in ECS panels or newborn screening programs. The online version contains supplementary material available at 10.1186/s40246-026-00940-z.

Background: The advent of next‐generation sequencing (NGS) has enhanced the diagnostic efficacy for monogenic diseases, while presenting challenges in achieving consistent diagnoses.Method: We retrospectively analyzed the concordance rate and reasons for the inconsistency between the original diagnostic result from the genetic testing laboratory and the variant validation result from the prenatal diagnostic center. The validation procedure comprised three stages: validation of variant detection, reevaluation of variant classification, and assessment of recurrence risk, which involved verifying the mode of inheritance and parental carriage.Result: In total, 17 (6%) of the 286 families affected by rare monogenic diseases showed different results during the variant validation procedure. These cases comprised four (23.5%) with variant detection errors, 12 (70.5%) with inconsistent interpretation, and one (6%) with non‐Mendelian inheritance patterns. False‐positive NGS results confirmed by Sanger sequencing were related to pseudogenes and GC‐rich regions. The classification of the 17 variants was altered in the 12 cases owing to various factors. The case with an atypical inheritance pattern was originally considered autosomal recessive inheritance, but was diagnosed as maternal uniparental disomy after additional genetic analysis.Conclusion: We underscored the significance of variant validation by prenatal diagnostic centers. Families affected by monogenic diseases with reproductive plans should be referred to prenatal genetic centers as early as possible to avoid different results that may postpone subsequent prenatal diagnosis.

In the postgenomic era, variant interpretation is crucial for diagnosing monogenic diseases, which is the premise of precision medicine. The bottleneck and difficulty of genetic disease diagnosis have switched from the inaccessibility of detection technology to the interpretation of sequencing results. Multiple studies have suggested that the inconsistency rate of interlaboratory variant interpretation is approximately 10~40%. However, many clinicians have not paid enough attention to this area at present. In this review, we summarized the reasons for inconsistency, including classification methodology, information obtained by the interpreter, evidence application, and expert judgement. For clinicians, genetic counsellors, and molecular pathologists, it is necessary to reevaluate genetic reports, especially those supported by old literature and databases in clinical practice. For unresolvable cases, pedigree analysis, collaboration with research labs for functional experiments, and long-term follow-up to combine advanced clinical presentations with updated data and literature are needed.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by the degeneration of motor neurons and progressive muscle atrophy. Accurate detection of SMN1 and SMN2 copy numbers is essential for SMA diagnosis, carrier screening, disease severity prediction, therapy, and prognosis. However, a method for SMN1 and SMN2 copy number determination that is simultaneously accurate, simple, rapid, multitargeted, and applicable to various samples has not previously been reported. Here, we developed a single-tube multiplex digital polymerase chain reaction (dPCR) assay for simultaneous determination of the copy numbers of SMN1 exons 7 and 8 and SMN2 exons 7 and 8. A total of 317 clinical samples, including peripheral blood, amniotic fluid, chorionic villus, buccal swabs, and dried blood spots, were collected to evaluate the performance of this dPCR-based assay. The test results were accurate for all the clinical samples. Our assay is accurate, rapid, easy to handle, and applicable to many types of samples and uses a small amount of DNA; it is a powerful tool for SMA molecular diagnosis, large-scale screening, and disease severity assessment.

Background: Variants in the ATP binding cassette protein subfamily D member 1 (ABCD1) gene are known to cause X‐linked adrenoleukodystrophy (X‐ALD). This study focused on the characteristics of ABCD1 variants in Chinese X‐ALD families and elucidated the value of genetic approaches for X‐ALD.Methods: 68 male probands diagnosed as X‐ALD were screened for ABCD1 variants by the Sanger sequencing of polymerase chain reaction (PCR) products and multiplex ligation‐dependent probe amplification (MLPA) combined with long‐range PCR. Prenatal diagnosis was performed in 20 foetuses of 17 probands’ mothers. Descriptive statistics were used to summarise the gene variants and prenatal diagnosis characteristics and outcomes.Results: This study allowed the identification of 61 variants occurring in 68 families, including 58 single nucleotide variants or small deletion/insertion variants and 3 large deletions. Three probands with no variants detected by next‐generation sequencing were found to have variants by PCR‐sequencing. Prenatal diagnosis found that 10 of the 20 foetuses had no variants in ABCD1.Conclusion: PCR primers that do not amplify the pseudogenes must be used for PCR‐sequencing. MLPA combined with long‐range PCR can detect large deletions and insertions, which are usually undetectable by PCR‐sequencing. Prenatal diagnosis could help to prevent the birth of infants with X‐ALD.

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Global developmental delay/intellectual disability (GDD/ID), used to be named as mental retardation (MR), is one of the most common phenotypes in neurogenetic diseases. In this study, we described the diagnostic courses, clinical and genetic characteristics and prenatal diagnosis of a cohort with patients presented GDD/ID with monogenic causes, from the perspective of a tertiary genetic counseling and prenatal diagnostic center. We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectrum of patients presented GDD/ID with rare monogenic causes. We also conducted a follow-up study on prenatal diagnosis in these families. Pathogenicity of variants was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Among 81 patients with GDD/ID caused by rare monogenic variants it often took 0.5–4.5 years and 2–8 referrals to obtain genetic diagnoses. Devlopmental delay typically occurred before 3 years of age, and patients usually presented severe to profound GDD/ID. The most common co-existing conditions were epilepsy (58%), microcephaly (21%) and facial anomalies (17%). In total, 111 pathogenic variants were found in 62 different genes among the 81 pedigrees, and 56 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal dominant (AD; 47%), following autosomal recessive (AR; 37%), and X-linked (XL; 16%). SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot variants were rarely found. By the follow-up, 33 affected families, including 15, 13 and 5 families inherited in AR, AD and XL modes respectively, had undergone prenatal diagnosis. And the recurrence rates are 26.7%, 15.4% and 20% for families inherited in AR, AD, and XL patterns. Patients presented with GDD/ID caused by rare single gene variants are characterized by early onset, relatively severe symptoms and great clinical variability and genetic heterogeneity. Timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

Background: Global developmental delay/intellectual disability (GDD/ID), used to be named as mental retardation (MR), is one of the most common phenotypes in neurogenetic diseases. In this study, we described the diagnostic courses, clinical and genetic characteristics and prenatal diagnosis of a cohort with patients presented GDD/ID with monogenic causes, from the perspective of a tertiary genetic counseling and prenatal diagnostic center.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectrum of patients presented GDD/ID with rare monogenic causes. We also conducted a follow-up study on prenatal diagnosis in these families. Pathogenicity of variants was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics (ACMG).Results:Among 81 [1] patients with GDD/ID caused by rare monogenic variants it often took 0.5-4.5 years and 2-8 referrals to obtain genetic diagnoses. Devlopmental delay typically occurred before 3 years of age, and patients usually presented severe to profound GDD/ID. The most common co-existing conditions were epilepsy (58%), microcephaly (21%) and facial anomalies (17%). In total, 111 pathogenic variants were found in 62 different genes among the 81 pedigrees, and 56 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal dominant (AD; 47%), following autosomal recessive (AR; 37%), and X-linked (XL; 16%). SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot variants were rarely found. By the follow-up, 33 affected families, including 15, 13 and 5 families inherited in AR, AD and XL modes respectively, had undergone prenatal diagnosis. And the recurrence rates are 26.7%, 15.4% and 20% for families inherited in AR, AD, and XL patterns.Conclusion:Patients presented with GDD/ID caused by rare single gene variants are characterized by early onset, relatively severe symptoms and great clinical variability and genetic heterogeneity. Timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

Background Phenylketonuria (PKU) is a genetic metabolic disease with a relatively higher incidence, but only a few studies about the prenatal diagnosis of PKU have been reported so far in China. The aim of this study was to characterize the spectrum of mutations in PAH gene in PKU probands and the prenatal diagnosis of PKU in north China.Methods A total of 157 families in which PKU patients had been diagnosed were included in the study. The 13 exons and their flanking sequences of PAH gene were amplified by PCR and sequenced in the probands. If none or only one mutant allele was found in the probands, the sample was subjected to MLPA for large deletions/duplication detection in PAH gene. Prenatal diagnosis was performed for pregnant women in these families.Results Pathogenic mutation in PAH was found in 2 alleles in 148 probands and in one allele in 7 probands, and the mutation was not detected in 2 probands. There were 289 point mutants, 10 frame-shift mutations and 4 large deletions with a total of 80 kinds of mutations. The most prevalent mutations were R243Q (17.2%), EX6-96A>G (8.6%) and V399V (8.0%). We also found a novel mutation of 163_164insATAT. Prenatal diagnosis of 95 families found 21 healthy fetus (20.4%), 52 carriers (50.5%) and 30 patients (29.1%), and the accuracy of prenatal diagnosis was confirmed after birth of the fetuses.Conclusion We present here a spectrum of mutations in PAH gene in PKU patients in north China. Prenatal diagnosis for PKU is useful for PKU families to prevent birth of another PKU case.