scholarly journals Whole-Exome Sequencing Identified a Novel Compound Heterozygous Mutation of LRRC6 in a Chinese Primary Ciliary Dyskinesia Patient

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Lv Liu ◽  
Hong Luo
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Ciliary Dyskinesia ◽  
Premature Stop Codon ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Mrna Levels ◽  
Whole Exome ◽  
Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a clinical rare peculiar disorder, mainly featured by respiratory infection, tympanitis, nasosinusitis, and male infertility. Previous study demonstrated it is an autosomal recessive disease and by 2017 almost 40 pathologic genes have been identified. Among them are the leucine-rich repeat- (LRR-) containing 6 (LRRC6) codes for a 463-amino-acid cytoplasmic protein, expressed distinctively in motile cilia cells, including the testis cells and the respiratory epithelial cells. In this study, we applied whole-exome sequencing combined with PCD-known genes filtering to explore the genetic lesion of a PCD patient. A novel compound heterozygous mutation in LRRC6 (c.183T>G/p.N61K; c.179-1G>A) was identified and coseparated in this family. The missense mutation (c.183T>G/p.N61K) may lead to a substitution of asparagine by lysine at position 61 in exon 3 of LRRC6. The splice site mutation (c.179-1G>A) may cause a premature stop codon in exon 4 and decrease the mRNA levels of LRRC6. Both mutations were not present in our 200 local controls, dbSNP, and 1000 genomes. Three bioinformatics programs also predicted that both mutations are deleterious. Our study not only further supported the importance of LRRC6 in PCD, but also expanded the spectrum of LRRC6 mutations and will contribute to the genetic diagnosis and counseling of PCD patients.

scholarly journals Identification of Novel ADGRV1 and KCNC2 Variants Using Whole-Exome Sequencing in Two Colombian Patients with Usher and Encephalopathy Syndromes

2021 ◽  
Author(s):  
Estephania Candelo ◽  
Lorena Diaz-Ordoñez ◽  
Rafael Pacheco ◽  
Emelina Ruiz ◽  
Harry Pachajoa
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Usher Syndrome ◽  
Epileptic Encephalopathy ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Epilepsy Syndrome ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Excellent Method

Abstract Introduction: Usher syndrome has a broad phenotypic and genotypic spectrum. Developmental and epileptic encephalopathy-52 (DEE52) is a sever autosomal recessive seizure disorder that is characterized by infantile onset of refractory seizures, consequently resulting in delayed global development. This study aimed to describe the clinical features and to investigate the four variants identified in a Colombian family with Usher syndrome and KCNC2 encephalopathy syndrome.Methods and Results: We present a case of a family with two clinically relevant phenotypes: a mother with a compound heterozygous mutation causing Usher Syndrome, type IIC (USH2C) and her 15-year-old son who carried one heterozygous variant in the KCNC2 gene (p.P470S) and two cis mutations (p.V2927I and p.Q4955EfsTer10) in the ADGRV1 gene segregated from his mother, and a second non-disrupted allele. Owing to this, the boy did not present with USH2C but presented a developmental epilepsy syndrome. His younger sibling was unaffected, although he did inherit the trans mutation in a single pathogenic allele from his mother.Discussion and Conclusion: Whole-exome sequencing helps detect genes related to known and novel hearing loss and seizure syndrome. However, familiar segregation studies are an excellent method to clarify genotype-phenotype correlation in families, where multiple genes of clinically relevant have been identified. This method helps determine the genotype-phenotype relationship of a disease, which is associated with the clinical presentation and determines the pathogenicity of variants that are classified as variants of uncertain clinical significance.

scholarly journals Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia

2020 ◽  
Vol 6 (4) ◽  
pp. 00213-2020
Author(s):  
Alex Gileles-Hillel ◽  
Hagar Mor-Shaked ◽  
David Shoseyov ◽  
Joel Reiter ◽  
Reuven Tsabari ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Ciliary Dyskinesia ◽  
Diagnostic Yield ◽  
Characteristic Curve ◽  
Transmission Electron Microscopy Analysis ◽  
Alternative Diagnosis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Ciliary Dyskinesia

The diagnosis of primary ciliary dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified.To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene.Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0–37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in 11 known PCD-causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the receiver operating characteristic curve (AUC) 0.75, 95% CI 0.60–0.90). Consecutive WES considerably improved the diagnostic accuracy of nNO in young children (AUC 0.97, 95% CI 0.93–1). Finally, WES established an alternative diagnosis in four patients.In patients with clinically suspected PCD and low nNO levels, WES is a simple, beneficial and accurate next step to confirm the diagnosis of PCD or suggest an alternative diagnosis, especially in preschool-aged children in whom nNO is less specific.

Three Cases of Primary Ciliary Dyskinesia Combined With Reduced Exhaled Nitric Oxide

2019 ◽  
Vol 128 (11) ◽  
pp. 1081-1085
Author(s):  
Sung Min Han ◽  
Chi Sang Hwang ◽  
Hyun Jong Jeon ◽  
Ho Young Lee ◽  
Hyung-Ju Cho ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Primary Ciliary Dyskinesia ◽  
Exhaled Nitric Oxide ◽  
Diagnostic Tools ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Causative Gene ◽  
Tem Analysis ◽  
Ciliary Dyskinesia

Objectives: The diagnosis of primary ciliary dyskinesia (PCD) is often delayed in part related to the limitations of the available diagnostic tests. We present 3 cases of PCD diagnosed using an exhaled nitric oxide (eNO) measurement. Methods: Three cases with a clinical phenotype consistent with PCD were evaluated using an eNO assay with additional transmission electron microscopy (TEM) and/or genetic panel testing. Results: One male and 2 female patients presented with common symptoms included recurrent respiratory infection from early childhood and a history of neonatal respiratory distress as term newborn. Two of them had situs inversus totalis. Fractional eNO measurement revealed extremely low NO levels, and subsequently, TEM analysis confirmed ciliary ultrastructural defects in all patients. One patient had compound heterozygous mutation of the PCD-causative gene ( DNAH5) identified using next generation sequencing. Conclusion: Our report stresses the reliability of eNO measurement in the diagnosis of PCD, accompanied by clinical phenotypes and additional diagnostic tools, such as TEM analysis and genetic testing.

scholarly journals Whole-exome sequencing identification of novel DNAH5 mutations in a young patient with primary ciliary dyskinesia

2016 ◽  
Vol 14 (6) ◽  
pp. 5077-5083 ◽  
Author(s):  
Gen Kano ◽  
Hisashi Tsujii ◽  
Kazuhiko Takeuchi ◽  
Kaname Nakatani ◽  
Makoto Ikejiri ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Young Patient ◽  
Whole Exome Sequencing ◽  
Primary Ciliary Dyskinesia ◽  
Whole Exome ◽  
Ciliary Dyskinesia
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