Identification of TTN as a novel candidate gene for atrioventricular block in a Chinese pedigree by whole-exome sequencing

PurposeCardiovascular diseases are the most common cause of death globally. In which atrioventricular block (AVB) is a common disorder with genetic causes, but the responsible genes have not been fully identified yet. To determine the underlying causative genes involved in cardiac AVB, here we report a three-generation Chinese family with severe autosomal dominant cardiac AVB that has been ruled out as being caused by known genes mutations.MethodsWhole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.ResultsWhole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C>A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members, but not in the unaffected family members. The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.ConclusionBased on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.

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A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

Journal of Ophthalmology ◽

10.1155/2016/4353957 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Yu Zhou ◽

Yaru Zhai ◽

Lulin Huang ◽

Bo Gong ◽

Jie Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Congenital Cataract ◽

Autosomal Dominant ◽

Family Members ◽

Chinese Family ◽

Heterozygous Mutation ◽

Whole Exome ◽

Causal Mutation ◽

Control Samples

Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T<G (p.E167X) in CRYBB2 gene was found. And the results showed that the mutation cosegregated with the disease phenotype in the family and was absolutely absent in 1000 ethnicity-matched control samples. Thus, the heterozygous mutation c.499T<G (p.E167X) in CRYBB2 was the causal mutation responsible for this ADCC family. In conclusion, our findings revealed a novel stopgain mutation c.499T<G (p.E167X) in the exon 6 of CRYBB2 which expanded the mutation spectrum of CRYBB2 in Chinese congenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract.

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Novel SOX2 Mutation in Autosomal Dominant Cataract-Microcornea Syndrome

10.21203/rs.3.rs-1085640/v1 ◽

2021 ◽

Author(s):

Zhi-Bo Lin ◽

Jin Li ◽

Hai-Sen Sun ◽

A-Yong Yu ◽

Shi-Hao Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Congenital Cataract ◽

Autosomal Dominant ◽

Family Members ◽

High Mobility ◽

Chinese Family ◽

Whole Exome

Abstract Background: Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although several causative genes have been reported in patients with CCMC, the genetic etiology of CCMC is yet to be clearly understood. Purpose: To unravel the genetic cause of autosomal dominant family with CCMC.Methods: All patients and available family members underwent a comprehensive ophthalmologic clinical examination in the hospital by expert ophthalmologists and carried out to clinically diagnosis. All the patients were screened by whole-exome sequencing and then validated using co-segregation by Sanger sequencing. Results: Four CCMC patients from a Chinese family, and five unaffected family members were enrolled in this study. Using whole-exome sequencing, missense mutation c.295G>T (p.a99s, NM_003106.4) in the SOX2 gene was identified and validated by segregation analysis. In addition, this missense mutation was predicted to be damaging by multiple predictive tools. Variant p.Ala99Ser was located in a conservation high mobility group (HMG)-box domain in SOX2 protein, with a potential pathogenic impact of p.Ala99Ser on protein level.Conclusions: A novel missense mutation (c.295G>T, p.Ala99Ser) in the SOX2 gene was found in this Han Chinese family with congenital cataract and microcornea. Our study firstly determined that mutations in SOX2 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder. This result expands the mutation spectrum of SOX2 and provides useful information to study the molecular pathogenesis of CCMC.

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A Novel Heterozygous Pathogenic Variation in CYCS Gene Cause Autosomal Dominant Non-Syndromic Thrombocytopenia 4 in a Large Chinese Family

Frontiers in Genetics ◽

10.3389/fgene.2021.783455 ◽

2022 ◽

Vol 12 ◽

Author(s):

Fengyu Che ◽

Jiangang Zhao ◽

Yujuan Zhao ◽

Zhi Wang ◽

Liyu Zhang ◽

...

Keyword(s):

Genetic Variation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Family Members ◽

Clinical Signs ◽

Missense Variant ◽

Chinese Family ◽

Whole Exome ◽

The Family

Aim: To determine the etiology of a Chinese family with thrombocytopenia by analyzing the clinical features and genetic variation.Methods: Clinical profiles and genomic DNA extracts of the family members were collected for the study. Whole exome sequencing and Sanger sequencing was used to detect the associated genetic variation and verify the family co-segregation respectively. Bioinformatics analysis assessed the pathogenicity of missense mutations.Results: The study reported a 3-generation pedigree including eight family members with thrombocytopenia. The platelet counts of the patients were varied, ranging from 38 to 110 × 109/L (reference range: 150–450 x 109/L). The mean volumes and morphology of the sampled platelet were both normal. The bleeding abnormality and mitochondriopathy were not observed in all the patients. Clinical signs of thrombocytopenia were mild. A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in CYCS gene associated with autosomal dominant thrombocytopenia.Conclusion: We report the first large family with autosomal dominant non-syndromic thrombocytopenia 4 in a Chinese family, a novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified. The whole exome sequencing is an efficient tool for screening the variants specifically associated with the disease. The finding enriches the mutation spectrum of CYCS gene and laid a foundation for future studies on the correlation between genotype and phenotype.

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A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Translational Stroke Research ◽

10.1007/s12975-021-00926-0 ◽

2021 ◽

Author(s):

Qing Li ◽

Chengfeng Wang ◽

Wei Li ◽

Zaiqiang Zhang ◽

Shanshan Wang ◽

...

Keyword(s):

Basement Membrane ◽

Skin Biopsy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Heterozygous Mutation ◽

Collagen Type Iv ◽

Lacunar Infarcts ◽

Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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Whole-Exome Sequencing Identifies a Novel TRPM4 Mutation in a Chinese Family with Atrioventricular Block

BioMed Research International ◽

10.1155/2021/9247541 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Yi Dong ◽

Ran Du ◽

Liang-liang Fan ◽

Jie-yuan Jin ◽

Hao Huang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Atrioventricular Block ◽

Transient Receptor Potential ◽

Novel Mutation ◽

Receptor Potential ◽

Cardiac Conduction ◽

Chinese Family ◽

Transient Receptor Potential Melastatin ◽

Whole Exome

Atrioventricular block (AVB) is a leading cause of sudden cardiac death, and most of AVB cases are presented as autosomal dominant. The electrocardiogram of AVB patients presents an abnormal progressive cardiac conduction disorder between atria and ventricles. Transient receptor potential melastatin 4 (TRPM4) is a nonselective Ca2+-activated cation channel gene defined as a novel disease-causing gene of AVB. So far, 47 mutations of TRPM4 have been recorded in Human Gene Mutation Database. The aim of this study was to explore the relationship between TRPM4 mutation and pathogenesis of AVB. We investigated a Chinese family with AVB by whole-exome sequencing. An arrhythmia-related gene filtering strategy was used to analyze the disease-causing mutations. Three different bioinformatics programs were used to predict the effects of the mutation result. A novel mutation of TRPM4 was identified (c.2455C>T/p.R819C) and cosegregated in the affected family members. The three bioinformatics programs predicted that the novel mutation may lead to damage. Our study will contribute to expand the spectrum of TRPM4 mutations and supply accurate genetic testing information for further research and the clinical therapy of AVB.

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Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family

PLoS ONE ◽

10.1371/journal.pone.0133522 ◽

2015 ◽

Vol 10 (7) ◽

pp. e0133522 ◽

Cited By ~ 8

Author(s):

Juanjuan Gao ◽

Qi Wang ◽

Cheng Dong ◽

Siqi Chen ◽

Yu Qi ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Nonsyndromic Deafness ◽

Causative Gene ◽

Whole Exome

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Analysis of the Genetic Characteristics of a Chinese Family With Otosclerosis

Ear Nose & Throat Journal ◽

10.1177/0145561320910627 ◽

2020 ◽

pp. 014556132091062

Author(s):

Yongli Zhang ◽

Qi Tang ◽

Ruoyan Xue ◽

Xiaohui Zhu ◽

Hua Yang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Autosomal Dominant ◽

Family Members ◽

Autosomal Dominant Inheritance ◽

Dominant Inheritance ◽

Genetic Characteristics ◽

Whole Exome ◽

The Family

Background: Otosclerosis is a focal lesion of the inner ear. The role of genetic factors in the pathogenesis of otosclerosis has received increasing attention. We analyzed the clinical manifestations, inheritance pattern, and pathogenic genes in a family with otosclerosis. Methods: We collected clinical data and generated a family pedigree. High-throughput second-generation sequencing technology was used to identify candidate genes by performing whole-exome sequencing of 7 members of the family, and Sanger sequencing was performed to validate candidate gene mutations in the 7 family members. Results: Otosclerosis was characterized by autosomal dominant inheritance in this family. Whole-exome sequencing did not reveal mutation sites in known deafness-related genes. However, a c.2209A > G (p.T737A) mutation was detected in exon 6 of the SP1 gene, which is associated with the COL1A1 gene. This mutation was a pathogenic mutation, and Sanger sequencing confirmed that this mutation cosegregated with the clinical phenotype among the family members. Conclusions: The pattern of otosclerosis in this family is consistent with autosomal dominant inheritance, and the SP1 gene, harboring the c.2209A > G (p.T737A) mutation in exon 6, may be the causative gene of otosclerosis in this family.

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A Cohesin Subunit Variant Identified from a Peripheral Sclerocornea Pedigree

Disease Markers ◽

10.1155/2019/8781524 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Bi Ning Zhang ◽

Tommy Chung Yan Chan ◽

Pancy Oi Sin Tam ◽

Yu Liu ◽

Chi Pui Pang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Cell Lines ◽

Family Members ◽

Case Series ◽

Genetic Alterations ◽

Chinese Family ◽

Retrospective Case ◽

Whole Exome ◽

Rare Congenital Disorder

Background. Sclerocornea is a rare congenital disorder characterized with the opacification of the cornea. Here, we report a nonconsanguineous Chinese family with multiple peripheral sclerocornea patients spanning across three generations inherited in an autosomal dominant manner. Methods. This is a retrospective case series of a peripheral sclerocornea pedigree. Comprehensive ophthalmic examinations were conducted and assessed on 14 pedigree members. Whole-exome sequencing was used to identify the genetic alterations in the affected pedigree members. Lymphoblastoid cell lines (LCLs) were established using blood samples from the family members. Functional tests were performed with these cell lines. Results. Six affected and eight unaffected members of a family with peripheral sclerocornea were examined. All affected individuals showed features of scleralization over the peripheral cornea of both eyes. Mean horizontal and vertical corneal diameter were found significantly decreased in the affected members. Significant differences were also observed on the mean apex pachymetry between affected and unaffected subjects. These ophthalmic parameters did not resemble that of cornea plana. A RAD21C1348T variant was identified by whole-exome sequencing. Although this variant causes RAD21 R450C substitution at the separase cleavage site, cells from peripheral sclerocornea family members had no mitosis and ploidy defects. Conclusion. We report a family of peripheral sclerocornea with no association with cornea plana. A RAD21 variant was found cosegregating with peripheral sclerocornea. Our results suggest that RAD21 functions, other than its cell cycle and chromosome segregation regulations, could underline the pathogenesis of peripheral sclerocornea.

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Whole exome sequencing of a family revealed a novel variant in the CHM gene, c.22delG p.(Glu8Serfs*4), which co-segregated with choroideremia

Bioscience Reports ◽

10.1042/bsr20200067 ◽

2020 ◽

Vol 40 (5) ◽

Author(s):

Handong Dan ◽

Tuo Li ◽

Xinlan Lei ◽

Xin Huang ◽

Yiqiao Xing ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Family Members ◽

Clinical Manifestations ◽

Complex Form ◽

Chinese Family ◽

Sequencing Data ◽

Whole Exome ◽

Novel Variant

Abstract Choroideremia is a complex form of blindness-causing retinal degeneration. The aim of the present study was to investigate the pathogenic variant and molecular etiology associated with choroideremia in a Chinese family. All available family members underwent detailed ophthalmological examinations. Whole exome sequencing, bioinformatics analysis, Sanger sequencing, and co-segregation analysis of family members were used to validate sequencing data and confirm the presence of the disease-causing gene variant. The proband was diagnosed with choroideremia on the basis of clinical manifestations. Whole exome sequencing showed that the proband had a hemizygous variant in the CHM gene, c.22delG p. (Glu8Serfs*4), which was confirmed by Sanger sequencing and found to co-segregate with choroideremia. The variant was classified as likely pathogenic and has not previously been described. These results expand the spectrum of variants in the CHM gene, thus potentially enriching the understanding of the molecular basis of choroideremia. Moreover, they may provide insight for future choroideremia diagnosis and gene therapy.

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