Identification of a Novel VPS13B Mutation in a Chinese Patient with Cohen Syndrome by Whole-Exome Sequencing

Abstract Background The mutations of thiamine pyrophosphokinase-1 (TPK1) gene have been frequently studied in some patients with thiamine metabolism dysfunction syndrome-5 (THMD5), while TPK1 mutations in Chinese patients have been investigated by only homozygous. A search of the literature on the mutations in the Chinese population currently published revealed that no reports of compound heterozygous mutations were reported. Here, we report a Chinese patient with compound heterozygous TPK1 mutations who underwent magnetic resonance imaging (MRI), whole exome sequencing (WES), molecular diagnosis, bioinformatics analysis, and three-dimensional (3D) protein structure analysis. Case presentation A Chinese boy was born after an uneventful pregnancy to non-consanguineous and healthy parents. On the sixth day after his birth, the lactate level of the patient was between 8.6 mmol/L and 14.59 mmol/L in plasma (the normal level is in the range of 0.5–2.2 mmol/L). Lactate was reduced to the normal level after rehydration, acid correction, expansion, and other treatments. After 4 months, the patient presented with an acute, 3-h-long, non-induced convulsions, and was admitted to our hospital for weakness, decreased oral intake, and lethargy. Results achieved by electroencephalography (EEG), cerebrospinal fluid, and other biochemical findings were normal. A visible hemorrhagic lesion was also observed in the brain. Seizures increased significantly during infection, which was accompanied by higher lactic acid levels. MRI of the brain showed an obvious signal shadow, in which bilateral frontal and temporal parietal subarachnoid cavities were widened, and more abnormal signals were observed; therefore, further consideration of hypoxic-ischemic encephalopathy and genetic metabolic disease was taken into account. Conclusions The results of WES revealed that the patient was associated with compound heterozygous mutations NM_022445.3:c.[263G>A]; [226A>G] of TPK1. His parents were non-consanguineous; while his father was found to be a heterozygous carrier with the mutation c.[263G>A], his mother was identified as a heterozygous carrier with the mutation c.[226A>G]. The results indicated that the patient had a compound heterozygous TPK1 mutation, and this is the first reported case in China.

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Whole-Exome Sequencing Identified a De Novo Mutation of Junction Plakoglobin (p.R577C) in a Chinese Patient with Arrhythmogenic Right Ventricular Cardiomyopathy

BioMed Research International ◽

10.1155/2019/9103860 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6

Author(s):

Lv Liu ◽

Chan Chen ◽

YaLi Li ◽

Rong Yu

Keyword(s):

Right Ventricular ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Connexin 43 ◽

De Novo ◽

Arrhythmogenic Right Ventricular Cardiomyopathy ◽

Chinese Patient ◽

De Novo Mutation ◽

Ventricular Cardiomyopathy ◽

Whole Exome

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare and potentially life-threatening disorder of the heart. The clinical spectrum of ARVC includes myocyte loss and fibro-fatty tissue replacement. With the progress of ARVC, the patient can present serious ventricular arrhythmias, heart failure, and even sudden cardiac death. Previous studies have demonstrated that desmosomes and intermediate junctions play a crucial role in the generation and development of ARVC. In this study, we enrolled a Chinese patient with suspicious ARVC. The patient suffered from right ventricular enlargement and less thickening of right ventricular wall. ECG record showed an epsilon wave. However, there was no obvious symptom in his parents. After whole-exome sequencing and data filtering, we identified a de novo mutation (c.1729C>T/p.R577C) of junction plakoglobin (JUP) in this patient. Bioinformatics programs predicted that this mutation was deleterious. Western blot revealed that, compared to cells transfected with WT plasmids, the expressions of desmoglein 2 (DSG2) and Connexin 43 were decreased overtly in cells transfected with the mutant plasmid. Previous studies have proven that the reduction of DSG2 and Connexin 43 may disturb the stability of desmosomes. In this research, we reported a novel de novo mutation (c.1729C>T/p.R577C) of JUP in a Chinese patient with suspicious ARVC. Functional research further confirmed the pathogenicity of this novel mutation. Our study expanded the spectrum of JUP mutations and may contribute to the genetic diagnosis and counseling of patients with ARVC.

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Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy

Mitochondrion ◽

10.1016/j.mito.2020.12.014 ◽

2021 ◽

Author(s):

Zhimei Liu ◽

Masaru Shimura ◽

Li Zhang ◽

Weihua Zhang ◽

Jianing Wang ◽

...

Keyword(s):

Basal Ganglia ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Optic Atrophy ◽

Chinese Patient ◽

Childhood Onset ◽

Whole Exome

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A novel PAX9 mutation found in a Chinese patient with hypodontia via whole exome sequencing

Oral Diseases ◽

10.1111/odi.12982 ◽

2018 ◽

Vol 25 (1) ◽

pp. 234-241 ◽

Cited By ~ 4

Author(s):

Tingting Zhang ◽

Xiaoxue Zhao ◽

Feifei Hou ◽

Yanwei Sun ◽

Jing Wu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Patient ◽

Whole Exome

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A de novo mutation of SMYD1 (p.F272L) is responsible for hypertrophic cardiomyopathy in a Chinese patient

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-0578 ◽

2019 ◽

Vol 57 (4) ◽

pp. 532-539 ◽

Cited By ~ 6

Author(s):

Liang-Liang Fan ◽

Dong-Bo Ding ◽

Hao Huang ◽

Ya-Qin Chen ◽

Jie-Yuan Jin ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Western Blot ◽

Exome Sequencing ◽

Real Time ◽

Whole Exome Sequencing ◽

De Novo ◽

Left Ventricular ◽

Chinese Patient ◽

De Novo Mutation ◽

Whole Exome

Abstract Background Hypertrophic cardiomyopathy (HCM) is a serious disorder and one of the leading causes of mortality worldwide. HCM is characterized as left ventricular hypertrophy in the absence of any other loading conditions. In previous studies, mutations in at least 50 genes have been identified in HCM patients. Methods In this research, the genetic lesion of an HCM patient was identified by whole exome sequencing. Real-time polymerase chain reaction (PCR), immunofluorescence and Western blot were used to analyze the effects of the identified mutation. Results According to whole exome sequencing, we identified a de novo mutation (c.814T>C/p.F272L) of SET and MYND domain containing histone methyltransferase 1 (SMYD1) in a Chinese patient with HCM exhibiting syncope. We then generated HIS-SMYD1-pcDNA3.1+ (WT and c.814T>C/p.F272L) plasmids for transfection into AC16 cells to functionalize the mutation. The immunofluorescence experiments indicated that this mutation may block the SMYD1 protein from entering the nucleus. Both Western blot and real-time PCR revealed that, compared with cells transfected with WT plasmids, the expression of HCM-associated genes such as β-myosin heavy chains, SMYD1 chaperones (HSP90) and downstream targets including TGF-β were all disrupted in cells transfected with the mutant plasmid. Previous studies have demonstrated that SMYD1 plays a crucial role in sarcomere organization and heart development. Conclusions This novel mutation (c.814T>C/p.F272L) may be the first identified disease-causing mutation of SMYD1 in HCM patients worldwide. Our research expands the spectrum of HCM-causing genes and contributes to genetic counseling for HCM patients.

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