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Journal Article 2

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2007 1

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TMEM141 1

LQTS-causing 1

autosomal dominant 1

autosomal recessive intellectual disability 1

consanguinity 1

hearing loss 1

neurodevelopmental disorder 1

population 1

recessive Jervell 1

spastic paraplegia 1

syndrome 1

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Mutation analysis of KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes in Chinese patients with long QT syndrome

DU Rong, TIAN Li, YUAN Guohui, LI Jin, REN Faxin, GUI Le, LI Wei, ZHANG Shouyan, KANG Cailian, YANG Junguo

Frontiers of Medicine 2007, Volume 1, Issue 3, Pages 312-315 doi: 10.1007/s11684-007-0060-0

Abstract: dominant Romano-ward syndrome (RWS), which is not accompanied by congenital deafness, and the autosomal recessiveJervell and Lange-Nielsen syndrome (JLNS), which is accompanied by congenital deafness.

Keywords： recessive Jervell LQTS-causing population autosomal dominant syndrome

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

Frontiers of Medicine doi: 10.1007/s11684-023-1006-x

Abstract: 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.

Keywords： neurodevelopmental disorder autosomal recessive intellectual disability consanguinity spastic paraplegia