Dataset Information

A novel frameshift variant in SON causes Zhu-Tokita-Takenouchi-Kim Syndrome.

ABSTRACT: BACKGROUND:Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem developmental disorder characterized by intellectual disability, developmental delay, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. This syndrome is caused by heterozygous pathogenic variants in the SON gene at chromosome 21q22.1. OBJECTIVES:The aim of this study was to investigate the pathogenesis of a 4-year-old Chinese child who displayed severe intellectual disability, delayed psychomotor development, and facial dysmorphism. METHODS:A sequential detection including chromosome karyotyping, chromosome microarray analysis (CMA), and whole-exome sequencing (WES) was performed on this child. The familial verification of WES result was conducted by Sanger sequencing. RESULTS:A de novo frameshift variant SON: c.5230delC (p.Arg1744ValfsTer29) was identified in the proband. The identical variant was not found in his family members. The frequencies of this variant in gnomAD/gnomAD_EAS databases were both none. CONCLUSIONS:This study substantiates that SON: c.5230delC (p.Arg1744ValfsTer29) is a pathogenic variant of Zhu-Tokita-Takenouchi-Kim syndrome and it is the first time to report Zhu-Tokita-Takenouchi-Kim syndrome in China.

SUBMITTER: Tan Y

PROVIDER: S-EPMC7439338 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A novel frameshift variant in SON causes Zhu-Tokita-Takenouchi-Kim Syndrome.

Tan Ya Y Duan Ling L Yang Kai K Liu Qian Q Wang Jing J Dong Zhe Z Li Zhi Z He Yiwen Y Yan Yousheng Y Lin Li L

Journal of clinical laboratory analysis 20200414 8

<h4>Background</h4>Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem developmental disorder characterized by intellectual disability, developmental delay, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. This syndrome is caused by heterozygous pathogenic variants in the SON gene at chromosome 21q22.1.<h4>Objectives</h4>The aim of this study was to investigate the pathogenesis of a 4-year-old Chinese child who d ...[more]

PMID: 32291808

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Project description:Background and objectivesZhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship between SON LoF in ZTTK syndrome and hemiplegic migraine remains unknown.MethodsWe identified a patient with a pathogenic variant in SON who shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediated SON knockdown on mRNA expression of the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of PRRT2 on SON knockdown was further examined by RT-PCR using primers targeting specific exons.ResultsRecurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed that SON knockdown significantly reduces PRRT2 mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in CACNA1A, ATP1A2, and SCN1A mRNA expression was not observed. We further identified that SON knockdown leads to failure in intron 2 removal from PRRT2 pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2.DiscussionThis report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation of PRRT2 caused by SON LoF as a mechanism causing hemiplegic migraine. Examination of the SON gene may be indicated in individuals with recurrent hemiplegic migraine.

Project description:Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/−) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/− mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. To obtain a more comprehensive understanding of the changes within HSPCs at the molecular level, we employed single-cell RNA-sequencing (scRNAseq) using both WT and Son+/− bone marrow HSPCs isolated and sorted based on their Lin− cKit+ (LK) cell markers (24,355 total LK cells from 2 WT mice; 31,232 total LK cells from 2 Son+/− mice. The linage-marker-negative (Lin-) c-kit+ population containing hematopoietic stem and progenitor cells was sorted from dissociated mouse bone marrow cells by flow cytometry. Sorted single-cell suspension, 10x barcoded gel beads and oil (10xGenomics Chromium Next GEM Single Cell 3' Kit v3.1 PN 1000268) were loaded into 10x Chromium™ Single Cell Chip to capture single cells into nanoliter-scale oil droplets by 10xChromium X Controller and generate Gel Bead-In-EMulsions (GEMs). cDNA from single cells were synthesized and barcoded by incubation of the GEMs in a thermocycler machine and then purified from GEMs by DynaBeads (10xGenomics PN 2000048). cDNA was pre-amplified by PCR to generate sufficient mass for sequencing library construction. The single-cell cDNA libraries were constructed by following 10xGenomics 3’ NextGem 3.1 version kit instructions. The final constructed 3’-biased single-cell libraries were sequenced by the Illumina Novaseq6000 machine, targeting 50,000 read pairs/cell. We identified hematopoietic abnormalities in Son+/− mice, including leukocytopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency inclines cell fate toward the myeloid lineage but compromises lymphoid lineage development by reducing genes required for lymphoid and B-cell lineage specification. Additionally, Son haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythroid maturation. These findings highlight the importance of the full gene dosage of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

Dataset Information

A novel frameshift variant in SON causes Zhu-Tokita-Takenouchi-Kim Syndrome.

Publications

A novel frameshift variant in SON causes Zhu-Tokita-Takenouchi-Kim Syndrome.

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