scholarly journals Compound Heterozygous Splicing Variants In KIAA0586 Cause Fetal Short-Rib Thoracic Dysplasia And Cerebellar Malformation: The Use of Whole Exome Sequencing In Prenatal Diagnosis

2021 ◽  
Author(s):  
Qianying Zhao ◽  
Bocheng Xu ◽  
Qinqin Xiang ◽  
Yu Tan ◽  
Hanbin Xie ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Fetal Monitoring ◽  
Joubert Syndrome ◽  
Compound Heterozygous ◽  
Thoracic Cage ◽  
Cerebellar Malformation ◽  
Dna And Rna ◽  
Whole Exome ◽  
Splicing Variants

Abstract Background: Short-rib thoracic dysplasia (SRTD) and Joubert syndrome (JS) are rare genetic ciliopathies, both patients can manifest cerebellar malformation and variable developmental delays. However, neither could be easily diagnosed during pregnancy due to limited fetal phenotype. Here, we investigated a fetus with short limbs, polydactyly initially and uncovered a compound heterozygous pathogenesis through whole exome sequencing (WES).Results: Merely short limbs and polydactyly of the fetus were detected during second trimester of gestation. Two variants (c.3940+1G>A and c.3303G>A), affecting splicing of KIAA0586 gene, were identified from amniocytes through WES. The presence and effect of these mutations were further validated on DNA and RNA level through Sanger sequencing. More intensive fetal monitoring was applied; deformed cerebellar malformation and restricted thoracic cage of the fetus were additionally uncovered. Conclusion: Herein, we discovered a genetic pathogenesis of KIAA0586 gene associated with SRTD and/or JS in a fetus with mild ultrasound anomalies initially. With the information of prenatal WES and distinct phenotypes of the fetus uncovered by imaging examination, we could reach more accurate clinical diagnosis and provide valuable prognosis information for parents.

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

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing

2021 ◽  
Author(s):  
Fulvio D’Abrusco ◽  
Filippo Arrigoni ◽  
Valentina Serpieri ◽  
Romina Romaniello ◽  
Caterina Caputi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Joubert Syndrome ◽  
Molar Tooth ◽  
Whole Exome

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.

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family

2020 ◽  
Author(s):  
Muhammad Ismail Khan ◽  
Muhammad Latif ◽  
Maria Saif ◽  
Hilal Ahmad ◽  
Atta Ullah Khan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Joubert Syndrome ◽  
Whole Exome ◽  
Missense Alteration

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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