OBJECTIVE: To investigate the current status of clinical genetics specialization development and the diagnostic and therapeutic capabilities for hereditary diseases across medical institutions in Shanghai, and to assess the necessity and feasibility of establishing training bases for clinical genetics specialists. METHODS: By employing a cross-sectional survey design, the Clinical Genetics Committee of Shanghai Medical Association has conducted questionnaire surveys from March to April 2025 across 54 healthcare institutions in Shanghai (including 33 tertiary hospitals and 21 secondary hospitals). The survey involved administrative departments and medical personnel from 15 clinical specialties. The survey has covered current genetic disease diagnosis and treatment practices, relevant and specialised disease types, genetic department establishment, testing capabilities, personnel teams, and training requirements. RESULTS: The results revealed that 78.0% of clinical departments surveyed had treated patients with hereditary disorders. Shanghai possesses diagnostic and therapeutic expertise for over 95% of hereditary diseases listed in its rare disease catalogue, reflecting both the practical clinical demand for such conditions and the city's overall diagnostic and therapeutic strengths in this field. Nevertheless, significant disparities exist in the development of genetics departments across different tiers of healthcare institutions. Resources for genetic testing capabilities (including molecular, cellular, and biochemical testing) are also unevenly distributed across different tiers of hospitals. The survey further revealed that only 26.0% of departments believe that their current physician structure fully meets the diagnostic and treatment demands. Over 90% of departments consider standard training for clinical genetic specialists necessary, with 74.0% expressing willingness to participate in establishing training bases. Based on above findings and thorough deliberation, the Clinical Genetics Committee of the Shanghai Medical Association proposes advancing specialist training and discipline development through establishing a standard training system. The committee has drafted a three-year training protocol featuring a "joint training"-centered model, recommending a pilot-first, dynamically optimized strategy for steadily advancing training base development. CONCLUSION Shanghai faces substantial demand for genetic disease diagnosis and treatment, yet exhibits shortcomings in clinical genetics specialization development, resource allocation, and talent pipeline cultivation. To establish a standard training system holds significant practical importance and is underpinned by a broad demand.
Humans ; China ; Surveys and Questionnaires ; Genetic Diseases, Inborn/genetics* ; Cross-Sectional Studies ; Genetics, Medical/education* ; Genetic Testing

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

Objective:To explore the application value of single-sperm-based single-nucleotide polymorphism (SNP) haplotyping in preimplantation genetic testing of monogenic disorders (PGT-M) associated with de novo mutations. Methods:Whole genome amplification (WGA) of the isolated single sperm was performed based on the multiple displacement amplification (MDA). WGA products were tested for the pathogenic mutation site and informative polymorphic SNP loci located within 2M upstream or downstream of the target gene to establish a sperm-based SNP haplotype. Biopsy samples obtained from embryos were subjected to WGA and next-generation sequencing (NGS). All embryos were verified via haplotype analysis and normal embryos were selected for transfer.Results:Totally 16 sperm samples were selected. Haplotypes of the affected male in 3 families with monogenic hereditary diseases including primary hyperoxaluria type 1 (PH1), Kabuki syndrome and Epidermolysis bullosa (EB) were successfully constructed using single sperm cell sequencing. PGT-M results showed that there were 10 embryos carrying paternal pathogenic variations, while the other 6 embryos did not carry paternal pathogenic variations, 2 of them had chromosomal copy number variations (CNVs). Four embryos obtained from 2 families were found to be normal after NGS according to single-sperm-based SNP haplotype analysis. However, no successful pregnancy was obtained.Conclusion:For males carrying de novo mutations, single-sperm-based SNP haplotyping can be applied for PGT to construct paternal haplotype.

Objective:To explore the application value of single-sperm-based single-nucleotide polymorphism (SNP) haplotyping in preimplantation genetic testing of monogenic disorders (PGT-M) associated with de novo mutations. Methods:Whole genome amplification (WGA) of the isolated single sperm was performed based on the multiple displacement amplification (MDA). WGA products were tested for the pathogenic mutation site and informative polymorphic SNP loci located within 2M upstream or downstream of the target gene to establish a sperm-based SNP haplotype. Biopsy samples obtained from embryos were subjected to WGA and next-generation sequencing (NGS). All embryos were verified via haplotype analysis and normal embryos were selected for transfer.Results:Totally 16 sperm samples were selected. Haplotypes of the affected male in 3 families with monogenic hereditary diseases including primary hyperoxaluria type 1 (PH1), Kabuki syndrome and Epidermolysis bullosa (EB) were successfully constructed using single sperm cell sequencing. PGT-M results showed that there were 10 embryos carrying paternal pathogenic variations, while the other 6 embryos did not carry paternal pathogenic variations, 2 of them had chromosomal copy number variations (CNVs). Four embryos obtained from 2 families were found to be normal after NGS according to single-sperm-based SNP haplotype analysis. However, no successful pregnancy was obtained.Conclusion:For males carrying de novo mutations, single-sperm-based SNP haplotyping can be applied for PGT to construct paternal haplotype.

OBJECTIVE: To carry out prenatal diagnosis for families with high risk for spinal muscular atrophy (SMA) by using multiplex ligation-dependent probe amplification (MLPA). METHODS: Twenty-one families were enrolled. MLPA was used to detect copy numbers of SMN1 and SMN2 genes. Maternal contamination was excluded by using a short tandem repeat method. RESULTS: For 23 fetuses from the 21 families, 14 were identified as carriers, 1 as SMA patient, and 8 as normal. By linkage analysis of parental samples, three individuals were determined as silent (2+0) carriers. CONCLUSION MLPA can determine the carrier status of SMA. The identification of three silent (2+0) carriers among the 44 parental samples indicated a risk for such families, for which genetic counseling and reproduction guidance should be provided.
Female ; Genetic Counseling ; Heterozygote ; Humans ; Multiplex Polymerase Chain Reaction ; Muscular Atrophy, Spinal/genetics* ; Pregnancy ; Prenatal Diagnosis ; Survival of Motor Neuron 1 Protein/genetics*

Based on next generation sequencing, preimplantation genetic testing (PGT), with novel strategy of mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) is an economic and effective primary measure to control rare diseases by helping patients to select embryo free of monogenic diseases and aneuploidy (chromosome abnormality). With the commercialization of 5th generation mobile networks (5G) technology, "5G+blockchain" has brought a new development trend to PGT in the field of accurately control rare diseases. Therefore, in the present study, we summarize the current status of PGT and the characteristics of 5G and blockchain, then propose a plan to build a genetic diagnosis cloud service platform, a collaborative diagnosis and treatment platform for rare diseases, and a gene mutation database of Chinese population genetic disease, based on technology of 5G and blockchain in order to grasp the bonus of 5G era and promote the development of prevention and control of rare disease.

Based on next generation sequencing, preimplantation genetic testing (PGT), with novel strategy of mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) is an economic and effective primary measure to control rare diseases by helping patients to select embryo free of monogenic diseases and aneuploidy (chromosome abnormality). With the commercialization of 5th generation mobile networks (5G) technology, "5G+blockchain" has brought a new development trend to PGT in the field of accurately control rare diseases. Therefore, in the present study, we summarize the current status of PGT and the characteristics of 5G and blockchain, then propose a plan to build a genetic diagnosis cloud service platform, a collaborative diagnosis and treatment platform for rare diseases, and a gene mutation database of Chinese population genetic disease, based on technology of 5G and blockchain in order to grasp the bonus of 5G era and promote the development of prevention and control of rare disease.