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

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

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
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 Tmem141p.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.

neurodevelopmental disorderautosomal recessive intellectual disabilityconsanguinityspastic paraplegiahearing lossTMEM141

Liwei Sun、Xueting Yang、Amjad Khan、Xue Yu、Han Zhang、Shirui Han、Xiaerbati Habulieti、Yang Sun、Rongrong Wang、Xue Zhang

展开 >

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

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

Chongqing Clinical Research

Faculty of Biological Sciences,Department of Zoology,University of Lakki Marwat,Khyber Pakhtunkhwa 28420,Pakistan

Institute for Medical Genetics and Applied Genomics,University of Tübingen,Tübingen 72076,Germany

Alexander von Humboldt fellowship Foundation,Berlin

Department of Pediatrics,the First Affiliated Hospital of Guangxi Medical University,Nanning 530000,China

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

展开 >

国家自然科学基金国家自然科学基金国家重点研发计划国家重点研发计划Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical SciencesChinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical SciencesChinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences

82001221817881012022YFC27039002022YFC27039032021-I2M-1-0182022-I2M-JB-0042017-I2M-B&R-05

2024

10.1007/s11684-023-1006-x

医学前沿
高等教育出版社

医学前沿

CSTPCD
影响因子：1.362
ISSN：2095-0217
年,卷(期)：2024.18(1)
  • 31