RNA sequencing combining with whole exome sequencing reveals a compound heterozygous variant in ATM in a girl with atypical ataxia-telangiectasia

2021 ◽  
Vol 523 ◽  
pp. 6-9
Author(s):  
Chunyu Gu ◽  
Hong Wang ◽  
Jianbo Shu ◽  
Jie Zheng ◽  
Dong Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rna Sequencing ◽  
Whole Exome Sequencing ◽  
Ataxia Telangiectasia ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Heterozygous Variant

scholarly journals Identification and Splicing Characterization of Novel TMC6 and TMC8 Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongrong Wang ◽  
Jiawei Liu ◽  
Xueting Yang ◽  
Xiaerbati Habulieti ◽  
Xue Yu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epidermodysplasia Verruciformis ◽  
Compound Heterozygous ◽  
Chinese Families ◽  
Qrt Pcr ◽  
Skin Cancers ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
Nonsense Mediated Mrna Decay

Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in TMC6, TMC8, and CIB1. This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis.Methods: Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant TMC6 and TMC8.Results: Whole-exome sequencing identified two novel homozygous variants (c.2278-2A > G in TMC6 and c.559G > A in TMC8) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G > A and c.1389G > A, in TMC8. The c.2278-2A > G TMC6 variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the TMC8 c.559G > A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded via nonsense-mediated mRNA decay (NMD).Conclusion: We identified three novel disease-causing variants in TMC6 or TMC8 in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.

Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica

2017 ◽  
Vol 60 (12) ◽  
pp. 635-638 ◽  
Author(s):  
Ryojun Takeda ◽  
Masaki Takagi ◽  
Hiroyuki Shinohara ◽  
Hiroshi Futagawa ◽  
Satoshi Narumi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Japanese Patient ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Compound Heterozygous Mutations

scholarly journals Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency

2020 ◽  
Vol 8 ◽  
pp. 205031212092265
Author(s):  
Adiratna Mat Ripen ◽  
Hamidah Ghani ◽  
Chai Teng Chear ◽  
Mei Yee Chiow ◽  
Sharifah Nurul Husna Syed Yahya ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Complex Disease ◽  
Monozygotic Twins ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Missense Mutations ◽  
Upper Respiratory Tract ◽  
Whole Exome ◽  
Tract Infections

Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients. Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed. Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing. Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.

A novel heterozygous variant p.(Trp538Arg) of SYNM is identified by whole‐exome sequencing in a Chinese family with dilated cardiomyopathy

2018 ◽  
Vol 83 (2) ◽  
pp. 95-99 ◽  
Author(s):  
Shu‐Bing Zhang ◽  
Yu‐Xing Liu ◽  
Liang‐Liang Fan ◽  
Hao Huang ◽  
Jing‐Jing Li ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Family ◽  
Whole Exome ◽  
Heterozygous Variant

Novel NGS-Based Platforms For Molecular Diagnosis Of Severe Congenital Neutropenia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1034-1034
Author(s):  
Tomas Racek ◽  
Jacek Puchalka ◽  
Naschla Kohistani ◽  
Christoph Klein
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnostic ◽  
Compound Heterozygous ◽  
Neutrophil Granulocytes ◽  
Diagnostic Strategy ◽  
Congenital Neutropenia ◽  
Coding Regions ◽  
Whole Exome ◽  
Custom Made

Abstract Congenital neutropenia (CN) is a heterogeneous disorder. More than 30 distinct genetic defects have been discovered in patients with genetic diseases associated with decreased numbers of peripheral neutrophil granulocytes. Currently, most molecular diagnostic laboratories use Sanger-based sequencing techniques to define disease-causing mutations in patients with CN. In approximately 50% of patients no known genetic disorder can be found. To identify novel genes that can be causative for unexplained CN cases we embarked on next-generation whole-exome sequencing using SOLiD 5500™ and Ion Proton™ sequencers. Up to date we sequenced whole exomes of 49 families, in which children were diagnosed with CN. The fragment libraries were constructed using the SureSelect™ V4+UTRs System (Agilent) allowing us to target whole coding sequence and the majority of UTRs of human genome (approx. 71 Mb). The vast majority of the families were analysed in the “Trio” approach and suitable homozygous or compound heterozygous rare variations (frequency below 1%) in protein coding regions or in splice sites were chosen for further validations. In seven cases mutations previously described as causative for neutropenia were identified including G6PC3, HAX1, and ELANE. Four other rare variants are currently being analysed for their potential to cause CN. In 35 patients, no plausible candidate could be identified so far. When we assessed variants within the genes related to CN, our data revealed unequal coverage pattern over these genes. Around 10% of the exons were insufficiently covered (coverage of less than 10) to allow for reliable variant and genotype call. These facts limit the power of whole exome sequencing as a diagnostic tool, as mutations at the non-covered positions cannot be ruled out, and demonstrate the need of an alternative comprehensive approach. We are currently assessing sensitivity and specificity of a robust, rapid, and cost-effective approach that comprehensively analyses the sequence of 34 CN-relevant genes. Our approach is based on enrichment of specific exon regions by amplification using custom made AmpliSeq™ (Life Technologies) panel. For 25 genes we are able to sequence coding region as well as both UTR sequences, for 9 genes sequencing is limited to coding regions. This approach will provide a reliable, quick, and inexpensive diagnostic strategy for CN patients which will be offered free-of-charge to patients worldwide, independent of ethnic, national, or financial considerations. Disclosures: No relevant conflicts of interest to declare.

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