scholarly journals Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with novel atypical phenotypes

2020 ◽  
Author(s):  
Marcin M. Machnicki ◽  
Valeria Guglielmi ◽  
Elia Pancheri ◽  
Francesca Gualandi ◽  
Lorenzo Verriello ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Degradation Products ◽  
Causative Role ◽  
Protein Aggregate ◽  
Causative Gene ◽  
Pathogenic Mutations ◽  
Whole Exome ◽  
Genes Encoding ◽  
Associated Proteins

Abstract Background Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype. Methods We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM. Results In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement. Conclusions Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations.

scholarly journals Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Sara Konstantin Nissen ◽  
Mette Christiansen ◽  
Marie Helleberg ◽  
Kathrine Kjær ◽  
Sofie Eg Jørgensen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Signaling Molecules ◽  
Innate Immune ◽  
Whole Exome ◽  
Genes Encoding ◽  
Hiv 1

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

2018 ◽  
Vol 55 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Wen-Bin He ◽  
Chao-Feng Tu ◽  
Qiang Liu ◽  
Lan-Lan Meng ◽  
Shi-Min Yuan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Male Patient ◽  
Histological Analysis ◽  
Pedigree Analysis ◽  
Obstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Causative Gene ◽  
Whole Exome

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

2016 ◽  
Vol 31 (14) ◽  
pp. 1534-1539 ◽  
Author(s):  
Maya Kuperberg ◽  
Dorit Lev ◽  
Lubov Blumkin ◽  
Ayelet Zerem ◽  
Mira Ginsberg ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Clinical Feature ◽  
Causative Gene ◽  
High Detection Rate ◽  
Whole Exome ◽  
Neurological Patients ◽  
Low Costs

Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of “Magen” neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.

scholarly journals Identification of two novel pathogenic variants of PIBF1 by whole exome sequencing in a 2-year-old boy with Joubert syndrome

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yue Shen ◽  
Hao Wang ◽  
Zhimin Liu ◽  
Minna Luo ◽  
Siyu Ma ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Autosomal Recessive Inheritance ◽  
Joubert Syndrome ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Syndrome Individual

Abstract Background Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. Case presentation A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. Conclusion In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.

Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness

2020 ◽  
Vol 63 (5) ◽  
pp. 103855 ◽  
Author(s):  
Xingxing Lu ◽  
Yanmei Zhang ◽  
Li Chen ◽  
Qi Wang ◽  
Zhen'gang Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Nonsyndromic Deafness ◽  
Causative Gene ◽  
Whole Exome

scholarly journals A Novel DES L115F Mutation Identified by Whole Exome Sequencing is Associated with Inherited Cardiac Conduction Disease

2019 ◽  
Vol 20 (24) ◽  
pp. 6227 ◽  
Author(s):  
Lung-An Hsu ◽  
Yu-Shien Ko ◽  
Yung-Hsin Yeh ◽  
Chi-Jen Chang ◽  
Yi-Hsin Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Structural Model ◽  
Coiled Coil ◽  
Cytoskeletal Proteins ◽  
Cardiac Conduction ◽  
Chinese Family ◽  
Cardiac Ion Channels ◽  
Whole Exome ◽  
Genes Encoding

Inherited cardiac conduction disease (CCD) is rare; it is caused by a large number of mutations in genes encoding cardiac ion channels and cytoskeletal proteins. Recently, whole-exome sequencing has been successfully used to identify causal mutations for rare monogenic Mendelian diseases. We used trio-based whole-exome sequencing to study a Chinese family with multiple family members affected by CCD, and identified a heterozygous missense mutation (c.343C>T, p.Leu115Phe) in the desmin (DES) gene as the most likely candidate causal mutation for the development of CCD in this family. The mutation is novel and is predicted to affect the conformation of the coiled-coil rod domain of DES according to structural model prediction. Its pathogenicity in desmin protein aggregation was further confirmed by expressing the mutation, both in a cellular model and a CRISPR/CAS9 knock-in mouse model. In conclusion, our results suggest that whole-exome sequencing is a feasible approach to identify candidate genes underlying inherited conduction diseases.

scholarly journals A combination of targeted enrichment methodologies for whole-exome sequencing reveals novel pathogenic mutations

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Fuyuki Miya ◽  
Mitsuhiro Kato ◽  
Tadashi Shiohama ◽  
Nobuhiko Okamoto ◽  
Shinji Saitoh ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pathogenic Mutations ◽  
Whole Exome ◽  
Targeted Enrichment
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