biostudies-literatureJi LJiangxi Provincial Department of Science and TechnologyShanghai Jiao Tong University STAR GrantNatural Science Foundation of ShanghaiChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaInnovation Program of Shanghai Municipal Education CommissionMajor Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan ProvinceNSF GRFPShanghai Municipal Science and Technology Major ProjectRuixin project of Hunan Provincial Maternal and Child Health Care HospitalNatural Science Foundation of Hunan ProvinceMunicipal Public Welfare ProjectKey Technology Breakthrough Program of Ningbo Sci-Tech Innovation YONGJIANG 2035Shanghai Leading Academic Discipline ProjectNational Key Research and Development Program of Chinae186119https://www.ebi.ac.uk/biostudies/studies/S-EPMC12435841biostudies-literatureUnknown135(18)The spliceosome is a critical cellular machinery responsible for pre-mRNA splicing that is essential for the proper expression of genes. Mutations in its core components are increasingly linked to neurodevelopmental disorders, such as primary microcephaly. Here, we investigated the role of SNW domain-containing protein 1 (SNW1), a spliceosomal protein, in splicing integrity and neurodevelopment. We identified 9 heterozygous mutations in the SNW1 gene in patients presenting with primary microcephaly. These mutations impaired SNW1's interactions with core spliceosomal proteins, leading to defective RNA splicing and reduced protein functionality. Using Drosophila melanogaster and human embryonic stem cell-derived cerebral organoids models, we demonstrated that SNW1 depletion resulted in signiThe Journal of clinical investigationMutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly.PMC124358412023M7322662022S0352024YFC2707002,2020YFA0112500,2021YFA11004002024Z22120ZR1427200,20511101900,21ZR1433000,22ZR14626002023RX01B20520203BBGL7313221393222022JJ4020682071262,32300464,3227101920JC14186002019SK1010,2019SK10142023ZKZD16YG2023ZD26,YG2023LC14Bibo AMusante LSchmuel ELiu LGuo ZWang GWang HZhang LLiu XMurali ALiu ZBian STizzano EWang PKing KZhan HMao XWang YCueto-Gonzalez AMHan CSSan Nicolas Fernandez HYan JLink NYang KHe GLiao WGu WJi LAbi Farraj LAbou Jamra RRuaud LMartinez Gil NLi KRen DLosurdo NAXu JYang FFaletra FPan HCosta PZanus CHu JZacher PXiang ZLuo YHuang AYZhong JCouque NfalseMutations in the spliceosomal gene SNW1 cause neurodevelopment disorders with microcephaly.The spliceosome is a critical cellular machinery responsible for pre-mRNA splicing that is essential for the proper expression of genes. Mutations in its core components are increasingly linked to neurodevelopmental disorders, such as primary microcephaly. Here, we investigated the role of SNW domain-containing protein 1 (SNW1), a spliceosomal protein, in splicing integrity and neurodevelopment. We identified 9 heterozygous mutations in the SNW1 gene in patients presenting with primary microcephaly. These mutations impaired SNW1's interactions with core spliceosomal proteins, leading to defective RNA splicing and reduced protein functionality. Using Drosophila melanogaster and human embryonic stem cell-derived cerebral organoids models, we demonstrated that SNW1 depletion resulted in signi2025-01-01T00:00:00Z2025 Sep2026-04-08T19:54:40.888Z2026-04-08T14:36:19.564ZS-EPMC124358414060841410.1172/JCI186119