scholarly journals ACER3-Realted Leukoencephalopathy: Expanding The Clinical and Imaging Findings Spectrum Due to Novel Variants

2021 ◽  
Author(s):  
Ali Zare Dehnavi ◽  
Erfan Heidari ◽  
Maryam Rasulinezhad ◽  
Morteza Heidari ◽  
Mahmoud Reza Ashrafi ◽  
...  
Keyword(s):  
Early Years ◽  
Cellular Growth ◽  
Clinical Context ◽  
Causative Gene ◽  
Mortality And Morbidity ◽  
Developmental Regression ◽  
Molecular Events ◽  
Whole Exome ◽  
Novel Variants ◽  
Significant Mortality

Abstract Background: Leukodystrophies are the main subgroup of inherited CNS white matter disorders which cause significant mortality and morbidity in early years of life. Diagnosis is mostly based on clinical context and neuroimaging findings, however, genetic tools, particularly whole-exome sequencing (WES) have led to comprehending the causative gene and molecular events contributing to these disorders. Mutation in Alkaline Ceramidase 3 (ACER3) gene which encodes alkaline ceramidase enzyme that plays a crucial role in cellular growth and viability, has been stated as an uncommon reason for inherited leukoencephalopathies. Merely only two ACER3 mutations in cases of progressive leukodystrophies have been reported thus far. Results: In the current study, we have identified three novel variants in ACER3 gene in cases with new neurological manifestations including developmental regression, dystonia, and spasticity. The detected variants were segregated into family members.Conclusion: Our study expands the clinical, neuroimaging, electroencephalographic and genetic spectrum of ACER3 mutations. Furthermore, we reviewed and compared the findings of all the previously reported cases and the cases identified here in order to facilitate their diagnosis and management.

scholarly journals ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ali Zare Dehnavi ◽  
Erfan Heidari ◽  
Maryam Rasulinezhad ◽  
Morteza Heidari ◽  
Mahmoud Reza Ashrafi ◽  
...  
Keyword(s):  
Early Years ◽  
Cellular Growth ◽  
Clinical Context ◽  
Causative Gene ◽  
Mortality And Morbidity ◽  
Developmental Regression ◽  
Molecular Events ◽  
Whole Exome ◽  
Novel Variants ◽  
Significant Mortality

Abstract Background Leukodystrophies are the main subgroup of inherited CNS white matter disorders which cause significant mortality and morbidity in early years of life. Diagnosis is mostly based on clinical context and neuroimaging findings; however, genetic tools, particularly whole-exome sequencing (WES), have led to comprehending the causative gene and molecular events contributing to these disorders. Mutation in Alkaline Ceramidase 3 (ACER3) gene which encodes alkaline ceramidase enzyme that plays a crucial role in cellular growth and viability has been stated as an uncommon reason for inherited leukoencephalopathies. Merely only two ACER3 mutations in cases of progressive leukodystrophies have been reported thus far. Results In the current study, we have identified three novel variants in ACER3 gene in cases with new neurological manifestations including developmental regression, dystonia, and spasticity. The detected variants were segregated into family members. Conclusion Our study expands the clinical, neuroimaging, electroencephalographic, and genetic spectrum of ACER3 mutations. Furthermore, we reviewed and compared the findings of all the previously reported cases and the cases identified here in order to facilitate their diagnosis and management.

Identification of novel exonic variants responsible for hereditary breast and ovarian cancer in West Indian population

2021 ◽  
Author(s):  
Bhargav N. Waghela ◽  
Ramesh J. Pandit ◽  
Apurvasinh Puvar ◽  
Franky D. Shah ◽  
Prabhudas S. Patel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Early Diagnosis ◽  
West Indian ◽  
Disease Association ◽  
Dna Integrity ◽  
Degree Relative ◽  
Mortality And Morbidity ◽  
Whole Exome ◽  
Novel Variants ◽  
Next Generation Sequencing Ngs

Abstract Background Breast and ovarian cancers are the most common cancer types in females in India which pertain to higher mortality and morbidity due to late diagnosis and poor prognosis. Early diagnosis for better prognosis improve the patient’s treatment and survival. The next-generation sequencing (NGS)-based screening has accelerated molecular diagnosis of various cancers. Methods We performed whole exome sequencing (WES) of 30 patients who had a first or second degree relative with breast or ovarian cancer. Further, all these patients are tested negative for BRCA1/2 or other high and moderate risk genes reported for HBOC. WES data from 30 patients were analyzed and variants were called using bcftools. Functional annotation of variants and variant prioritization was performed by Exomiser. The clinical significance of variants was determined by Varsome tool. The functional analysis of genes was determined by STRING analysis and disease association was determined by open target tool. Results We examined the variants based on the prevalence of variants among 30 patients i.e. frequency and disease association determined by the phenotype score of exomiser. From both the approaches, we found novel variants and novel gene candidates associated with HBOC conditions. The variants in HYDIN, AVIL, IWS1, PLA2G6, PRDM4, ST3GAL2, and ZNF717 were predicted highly oncogenic. Moreover, we also found 59 genes having higher phenotype score (phenotype score >0.75) and which are associated with various biological processes such as DNA integrity maintenance, transcriptional regulation, cell cycle and apoptosis. Conclusion The gene variants associated with HBOC condition in West Indian cohort have been revisited. Our findings provide novel as well as highly prevalent variants in the population which could be further studied in detail for their use in early diagnosis and better prognosis of HBOC patients.

scholarly journals Whole Exome Sequencing Confirms Molecular Diagnostics of Three Pakhtun Families With Autosomal Recessive Epidermolysis Bullosa

2021 ◽  
Vol 9 ◽  
Author(s):  
Fozia Fozia ◽  
Rubina Nazli ◽  
Nousheen Bibi ◽  
Sher Alam Khan ◽  
Noor Muhammad ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epidermolysis Bullosa ◽  
Vital Role ◽  
Early Years ◽  
Khyber Pakhtunkhwa ◽  
Whole Exome ◽  
Novel Variants ◽  
Epithelial Junctions ◽  
Khyber Pakhtunkhwa Province

Epidermolysis bullosa (EB) is a genetic skin disorder that shows heterogeneous clinical fragility. The patients develop skin blisters congenitally or in the early years of life at the dermo-epithelial junctions, including erosions, hyperkeratosis over the palms and soles. The other associated features are hypotrichosis on the scalp, absent or dystrophic nails, and dental anomalies. Molecular diagnosis through whole-exome sequencing (WES) has become one of the successful tool in clinical setups. In this study, three Pakhtun families from the Khyber Pakhtunkhwa province of Pakistan were ascertained. WES analysis of a proband in each family revealed two novel variants (COL17A1: NM_000494.4: c.4041T>G: p.Y1347* and PLEC: NM_201380.3: c.1283_1285delGCT: p.L426del) and one previously known COL17A1: NM_000494.4:c.3067C>T: p.Q1023*) variant in homozygous forms. Sanger sequencing of the identified variants confirmed that the heterozygous genotypes of the obligate carriers. The identified variants have not only increased the mutation spectrum of the COL17A1 and PLEC but also confirms their vital role in the morphogenesis of skin and its associated appendages. WES can be used as a first-line diagnostic tool in genetic testing and counselling families from Khyber Pakhtunkhwa, Pakistan.

scholarly journals Defence Medical Rehabilitation Centre (DMRC) COVID-19 Recovery Service

2021 ◽  
pp. e001681
Author(s):  
Oliver O'Sullivan ◽  
R Barker-Davies ◽  
R Chamley ◽  
E Sellon ◽  
D Jenkins ◽  
...  
Keyword(s):  
Occupational Medicine ◽  
Armed Forces ◽  
Acute Illness ◽  
Medical Rehabilitation ◽  
Rehabilitation Centre ◽  
Operational Effectiveness ◽  
Mortality And Morbidity ◽  
Recovery Service ◽  
Significant Mortality

Coronavirus disease 2019 (COVID-19) causes significant mortality and morbidity, with an unknown impact in the medium to long term. Evidence from previous coronavirus epidemics indicates that there is likely to be a substantial burden of disease, potentially even in those with a mild acute illness. The clinical and occupational effects of COVID-19 are likely to impact on the operational effectiveness of the Armed Forces. Collaboration between Defence Primary Healthcare, Defence Secondary Healthcare, Defence Rehabilitation and Defence Occupational Medicine resulted in the Defence Medical Rehabilitation Centre COVID-19 Recovery Service (DCRS). This integrated clinical and occupational pathway uses cardiopulmonary assessment as a cornerstone to identify, diagnose and manage post-COVID-19 pathology.

scholarly journals Genotype-Phenotype Correlations in RP1-Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN

2021 ◽  
Vol 10 (11) ◽  
pp. 2265
Author(s):  
Kei Mizobuchi ◽  
Takaaki Hayashi ◽  
Noriko Oishi ◽  
Daiki Kubota ◽  
Shuhei Kameya ◽  
...  
Keyword(s):  
Age At Onset ◽  
Japanese Patients ◽  
Clinical Findings ◽  
Cone Dystrophy ◽  
Element Insertion ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Novel Variants ◽  
Alu Element ◽  
Frequent Variant

Background: Little is known about genotype–phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. Results: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. Conclusions: Our results suggest a genotype–phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.

scholarly journals Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dongdong Tang ◽  
Yanwei Sha ◽  
Yang Gao ◽  
Jingjing Zhang ◽  
Huiru Cheng ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Sperm Morphology ◽  
Immunofluorescence Staining ◽  
Compound Heterozygous ◽  
Sperm Tail ◽  
Transmission Electron ◽  
Whole Exome ◽  
Detailed Medical History ◽  
Novel Variants ◽  
Common Causes

Abstract Background Asthenozoospermia is one of the most common causes of male infertility, and its genetic etiology is poorly understood. DNAH9 is a core component of outer dynein arms in cilia and flagellum. It was reported that variants of DNAH9 (OMIM: 603330) might cause primary ciliary dyskinesia (PCD). However, variants in DNAH9 lead to nonsyndromic severe asthenozoospermia have yet to be reported. Methods Whole exome sequencing (WES) was performed for two individuals with nonsyndromic severe asthenozoospermia from two non-consanguineous families, and Sanger sequencing was performed to verify the identified variants and parental origins. Sperm routine analysis, sperm vitality rate and sperm morphology analysis were performed according the WHO guidelines 2010 (5th edition). Transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail. Quantitative realtime-PCR and immunofluorescence staining were performed to detect the expression of DNAH9-mRNA and location of DNAH9-protein. Furthermore, assisted reproductive procedures were applied. Results By WES and Sanger sequencing, compound heterozygous DNAH9 (NM_001372.4) variants were identified in the two individuals with nonsyndromic severe asthenozoospermia (F1 II-1: c.302dupT, p.Leu101fs*47 / c.6956A > G, p.Asp2319Gly; F2 II-1: c.6294 T > A, p.Phe2098Leu / c.10571 T > A, p.Leu3524Gln). Progressive rates less than 1% with normal sperm morphology rates and normal vitality rates were found in both of the two subjects. No respiratory phenotypes, situs inversus or other malformations were found by detailed medical history, physical examination and lung CT scans etc. Moreover, the expression of DNAH9-mRNA was significantly decreased in sperm from F1 II-1. And expression of DNAH9 is lower in sperm tail by immunofluorescence staining in F1 II-1 compared with normal control. Notably, by intracytoplasmic sperm injection (ICSI), F1 II-1 and his partner successfully achieved clinical pregnancy. Conclusions We identified DNAH9 as a novel pathogenic gene for nonsyndromic severe asthenospermia, and ICSI can contribute to favorable pregnancy outcomes for these patients.

scholarly journals Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Somayeh Khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh-Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

Postvaricella Acute Transverse Myelitis: A Case Presentation and Review of the Literature

PEDIATRICS ◽  
1978 ◽  
Vol 62 (2) ◽  
pp. 202-204
Author(s):  
John T. McCarthy ◽  
Jules Amer
Keyword(s):  
Transverse Myelitis ◽  
Sensory Loss ◽  
Review Of The Literature ◽  
Case Presentation ◽  
Mortality And Morbidity ◽  
Acute Transverse Myelitis ◽  
Significant Mortality

Although the complications and sequelae of varicella are rare, they can cause significant mortality and morbidity in both the normal and compromised patient. Eight cases of "pure" acute transverse myelitis (ATM) following varicella have previously been reported in the literature. We report the ninth case of postvaricella ATM in a 9-year-old girl. Her course was characterized by paraplegia, sensory Loss, hvperesthesia, and incontinence of urine and feces. All patients, except ours, recovered fully from ATM.

scholarly journals Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

2017 ◽  
Vol 97 (1) ◽  
pp. 49-59 ◽  
Author(s):  
N. Dinckan ◽  
R. Du ◽  
L.E. Petty ◽  
Z. Coban-Akdemir ◽  
S.N. Jhangiani ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Permanent Teeth ◽  
Tooth Agenesis ◽  
Disease Genes ◽  
Nonsense Mediated Decay ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Complex Inheritance

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

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