Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141,DDHD2,and LHFPL5  

作　　者：Liwei Sun Xueting Yang Amjad Khan Xue Yu Han Zhang Shirui Han Xiaerbati Habulieti Yang Sun Rongrong Wang Xue Zhang 

机构地区：[1]McKusick-Zhang Center for Genetic Medicine,State Key Laboratory for Complex Severe and Rare Diseases,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences,School of Basic Medicine Peking Union Medical College,Beijing,100005,China [2]Chongqing Key Laboratory of Human Embryo Engineering,Center for Reproductive Medicine,National Key Clinical Speciality Construction Project(Obstetrics and Gynecology),Chongqing Health Center for Women and Children,Chongqing,400013,China [3]Chongqing Clinical Research Center for Reproductive Medicine,Women and Children’s Hospital of Chongqing Medical University,Chongqing,400013,China [4]Faculty of Biological Sciences,Department of Zoology,University of Lakki Marwat,Khyber Pakhtunkhwa,28420,Pakistan [5]Institute for Medical Genetics and Applied Genomics,University of Tübingen,Tübingen,72076,Germany [6]Alexander von Humboldt fellowship Foundation,Berlin,10117,Germany [7]Department of Pediatrics,The First Affiliated Hospital of Guangxi Medical University,Nanning,530000,China [8]Department of Laboratory Medicine,State Key Laboratory for Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Chinese Academy of Medical Science and Peking Union Medical College,Beijing,100730,China

出　　处：《Frontiers of Medicine》2024年第1期81-97,共17页医学前沿（英文版）

基　　金：supported by the National Natural Science Foundation of China(NSFC)(Nos.82001221 and 81788101);the National Key Research and Development Program of China(Nos.2022YFC2703900 and 2022YFC2703903);the CAMS Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-I2M-1-018,2022-I2M-JB-004 and 2017-I2M-B&R-05).

摘　　要：Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine.Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation.Here,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and deafness.Homozygosity mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,p.Trp90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,p.Leu84^(*))were identified.A Tmem141^(p.Trp90^(*)/p.Trp90^(*))mouse model was generated.Behavioral studies showed impairments in learning ability and motor coordination.Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells.Transmission electron microscopy showed abnormal mitochondrial morphology.Furthermore,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model.Conclusively,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in patient.Notably,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

关 键 词：neurodevelopmental disorder autosomal recessive intellectual DISABILITY CONSANGUINITY spastic paraplegia hearing loss TMEM141 

分 类 号：R749.94[医药卫生—神经病学与精神病学]