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

作者全名："Sun, Liwei; Yang, Xueting; Khan, Amjad; Yu, Xue; Zhang, Han; Han, Shirui; Habulieti, Xiaerbati; Sun, Yang; Wang, Rongrong; Zhang, Xue"

作者地址："[Sun, Liwei; Yang, Xueting; Khan, Amjad; Yu, Xue; Zhang, Han; Han, Shirui; Habulieti, Xiaerbati; Sun, Yang; Wang, Rongrong; Zhang, Xue] Chinese Acad Med Sci, Peking Union Med Coll, McKusick Zhang Ctr Genet Med,Inst Basic Med Sci, State Key Lab Complex Severe & Rare Dis,Sch Basic, Beijing 100005, Peoples R China; [Sun, Liwei] Chongqing Hlth Ctr Women & Children, Ctr Reprod Med, Natl Key Clin Special Construct Project Obstetr &, Chongqing Key Lab Human Embryo Engn, Chongqing 400013, Peoples R China; [Sun, Liwei] Chongqing Med Univ, Chongqing Clin Res Ctr Reprod Med, Women & Childrens Hosp, Chongqing 400013, Peoples R China; [Khan, Amjad] Univ Lakki Marwat, Fac Biol Sci, Dept Zool, Khyber Pakhtunkhwa 28420, Pakistan; [Khan, Amjad] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany; [Khan, Amjad] Alexander von Humboldt Fellowship Fdn, D-10117 Berlin, Germany; [Yu, Xue] Guangxi Med Univ, Affiliated Hosp 1, Dept Pediat, Nanning 530000, Peoples R China; [Zhang, Han] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Lab Med, State Key Lab Complex Severe and Rare Dis, Beijing 100730, Peoples R China"

通信作者："Khan, A; Wang, RR (通讯作者)，Chinese Acad Med Sci, Peking Union Med Coll, McKusick Zhang Ctr Genet Med,Inst Basic Med Sci, State Key Lab Complex Severe & Rare Dis,Sch Basic, Beijing 100005, Peoples R China.; Khan, A (通讯作者)，Univ Lakki Marwat, Fac Biol Sci, Dept Zool, Khyber Pakhtunkhwa 28420, Pakistan.; Khan, A (通讯作者)，Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany.; Khan, A (通讯作者)，Alexander von Humboldt Fellowship Fdn, D-10117 Berlin, Germany."

来源：FRONTIERS OF MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001084690400001

JCR分区：Q2

影响因子：8.1

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：neurodevelopmental disorder; autosomal recessive intellectual disability; consanguinity; spastic paraplegia; hearing loss; TMEM141

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."

基金机构："We would like to thank all the individuals for their collaboration. This work was financially supported by the National Natural Science Foundation of China (NSFC) (Nos. 82001221 and 81788101), the National Key Research and Development Program of China (Nos [82001221, 81788101]; National Natural Science Foundation of China (NSFC) [2022YFC2703900, 2022YFC2703903]; National Key Research and Development Program of China [2021-I2M-1-018, 2022-I2M-JB-004, 2017-I2M-B, R-05]; CAMS Innovation Fund for Medical Sciences (CIFMS)"

基金资助正文："We would like to thank all the individuals for their collaboration. This work was financially 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), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2021-I2M-1-018, 2022-I2M-JB-004 and 2017-I2M-B&R-05)."