scholarly journals Novel Variants in COL4A3 and COL4A4 are Causes of Alport Syndrome in Rio Grande do Norte, Brazil

2019 ◽  
Author(s):  
Washington Candeia de Araújo ◽  
Raul Maia Falcão ◽  
Raquel Uchoa ◽  
Carlos Alexandre Garcia ◽  
Jorge Estefano S. de Souza ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Alport Syndrome ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Chromosome 2 ◽  
Runs Of Homozygosity ◽  
Whole Exome ◽  
Novel Variants ◽  
Extrarenal Manifestations ◽  
Variant Analysis

AbstractBackgroundAlport syndrome is a progressive and hereditary nephropathy, characterized by hematuria and proteinuria, and extrarenal manifestations as hearing loss and eye abnormalities. The disease can be expressed as autosomal recessive or dominant, caused by variants in COL4A3 and COL4A4 loci, respectively, or X-linked caused by variants in COL4A5 locus.MethodsTwo unrelated families with Alport Syndrome from northeast of Brazil were studied and whole exome sequencing were performed. DNA sequences were mapped against the human genome (GRCh38/hg38 build) to identify associated mutations.ResultsVariant analysis showed deleterious variants in COL4A3 and COL4A4 loci in chromosome 2. Two variants were detected with alternative alleles in a homozygous state in the probands. One novel premature stop codon at position 481 of COL4A3 protein is present in one family and one frameshift mutation leading to a premature stop codon at position 786 of COL4A4 protein in the other family. Both Alport cases presented their variants surrounded by a broad runs of homozygosity (ROH).ConclusionsThe autosome recessive inheritance coupled with the runs of homozygosity in both families suggest inbreeding.

scholarly journals Attenuated Type of Asphyxiating Thoracic Dysplasia due to Mutations in DYNC2H1 Gene

2019 ◽  
Vol 120 (4) ◽  
pp. 124-130
Author(s):  
Anna Čechová ◽  
Alice Baxová ◽  
Jiří Zeman ◽  
Lukáš Lambert ◽  
Tomáš Honzík ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Chest Circumference ◽  
Anthropometric Parameters ◽  
Age Related ◽  
Whole Exome ◽  
Asphyxiating Thoracic Dysplasia ◽  
Health And Disease ◽  
Postnatal Adaptation

Asphyxiating thoracic dysplasia (ATD) represents a heterogeneous group of skeletal dysplasias with short ribs, narrow chest and reduced thoracic capacity. Mutations in several genes including IFT80, DYNC2H1, TTC21B and WDR19 have been found in patients with ATD. Both severe and milder course of the disease were described in correlation with secondary involvement of lung’s function. Two children with attenuated form of ATD are described. Their anthropometric parameters for birth weight, length and head circumference were normal but narrow thorax was observed in both of them in early infancy with chest circumference < –3 SD (standard deviation) in comparison to age related controls. The postnatal adaptation and development of both children was uneventful except for mild tachypnoea in one of them which persisted till the age of 6 months. In both children, radiographs revealed narrow upper half of the chest with shorter ribs and atypical configuration of pelvis with horizontally running acetabula and coarse internal edges typical for ATD. Molecular analyses using whole exome sequencing in one family revealed that the patient is compound heterozygote in DYNC2H1 gene for a frame-shift mutation c.4458delT resulting in premature stop-codon p.Phe1486Leufs*11 and a missense mutation c.9044A>G (p.Asp3015Gly). The second family refused the DNA analysis. Regular monitoring of anthropometric parameters during childhood is of big importance both in health and disease. In addition, measurement of the chest circumference should be included, at least at birth and during infancy.

scholarly journals AIMP1 Mutation Long-Term Follow-Up, With Decreased Brain N-Acetylaspartic Acid and Secondary Mitochondrial Abnormalities

2019 ◽  
Vol 6 ◽  
pp. 2329048X1982952 ◽  
Author(s):  
Aneal Khan ◽  
Jennifer Bennett ◽  
Morris H. Scantlebury ◽  
Xing-Chang Wei ◽  
Marina Kerr
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Monozygotic Twins ◽  
Trna Synthetase ◽  
Resonance Spectroscopy ◽  
Multifunctional Protein ◽  
Whole Exome ◽  
Long Term Follow Up

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N-acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N-acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

scholarly journals Identification of Main Genetic Causes Responsible for Non-Syndromic Hearing Loss in a Peruvian Population

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 581 ◽  
Author(s):  
Figueroa-Ildefonso ◽  
Bademci ◽  
Rajabli ◽  
Cornejo-Olivas ◽  
Villanueva ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genetic Factors ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Gjb2 Gene ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Different Populations ◽  
Global Population

: Hearing loss (HL) is a common sensory disorder affecting over 5% of the global population. The etiology underlying HL includes congenital and acquired causes; genetic factors are the main cause in over 50% of congenital cases. Pathogenic variants in the GJB2 gene are a major cause of congenital non-syndromic hearing loss (NSHL), while their distribution is highly heterogeneous in different populations. To the best of our knowledge, there is no data regarding the genetic etiologies of HL in Peru. In this study, we screened 133 Peruvian families with NSHL living in Lima. We sequenced both exons of the GJB2 gene for all probands. Seven probands with familial NSHL that remained negative for GJB2 variants underwent whole genome sequencing (WGS). We identified biallelic pathogenic variants in GJB2 in 43 probands; seven were heterozygous for only one allele. The c.427C>T variant was the most common pathogenic variant followed by the c.35delG variant. WGS revealed three novel variants in MYO15A in two probands, one of them was predicted to affect splicing and the others produce a premature stop codon. The Peruvian population showed a complex profile for genetic variants in the GJB2 gene, this particular profile might be a consequence of the admixture history in Peru.

scholarly journals Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome

2018 ◽  
Vol 29 (8) ◽  
pp. 2244-2254 ◽  
Author(s):  
Tomoko Horinouchi ◽  
Kandai Nozu ◽  
Tomohiko Yamamura ◽  
Shogo Minamikawa ◽  
Takashi Omori ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Alport Syndrome ◽  
Stop Codon ◽  
Consensus Sequence ◽  
Point Mutations ◽  
Premature Stop Codon ◽  
Transcript Level ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
Splicing Patterns

BackgroundX-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS.MethodsWe examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level.ResultsWe detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001).ConclusionsWe report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

scholarly journals Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas

2020 ◽  
Vol 4 (12) ◽  
Author(s):  
Sunita M C De Sousa ◽  
John Toubia ◽  
Tristan S E Hardy ◽  
Jinghua Feng ◽  
Paul Wang ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Transcriptome Analysis ◽  
Haplotype Analysis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Chromosome 1 ◽  
Sequencing Analysis ◽  
Kit Mutation ◽  
Whole Exome ◽  
Genetic Test Results

Abstract Context Germline mutations in the succinate dehydrogenase genes (SDHA/B/C/D, SDHAF2—collectively, “SDHx”) have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline SDHx mutation. However, approximately 20% of individuals with SDH-deficient tumors lack an identifiable germline SDHx mutation. Methods We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA. Results Germline WES revealed a novel SDHC intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant SDHC splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type SDHC in a PGL and a somatic gain-of-function KIT mutation in a GIST. The SDHC intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect. Conclusions This is the deepest intronic variant to be reported among the SDHx genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.

Hereditary vitamin D-resistant rickets: a report of four cases with two novel variants in the VDR gene and successful use of intermittent intravenous calcium via a peripheral route

2020 ◽  
Vol 33 (4) ◽  
pp. 557-562 ◽  
Author(s):  
Saygın Abalı ◽  
Mayuko Tamura ◽  
Serap Turan ◽  
Zeynep Atay ◽  
Pınar Isguven ◽  
...  
Keyword(s):  
Vitamin D ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Vdr Gene ◽  
Case Presentation ◽  
Novel Variants ◽  
Vitamin D Resistant Rickets ◽  
Resistant Rickets

AbstractBackgroundHereditary vitamin D-resistant rickets (HVDRR) is caused by vitamin D receptor (VDR) defects. Patients with HVDRR do not respond to standard doses of calcitriol and oral calcium (Ca) treatment and need to be treated with intravenous Ca (IV-Ca) via a central route. However, central catheter-related complications can cause significant morbidity.Case presentationFour unrelated patients with HVDRR presenting with rickets and alopecia totalis were administered intermittent IV-Ca treatment (2–5 times/week) through a peripheral route. No complications such as infection, extravasation or arrhythmias were detected upon peripheral infusion. Peripheral 1–22 months’ duration of IV-Ca normalized parathyroid hormone (PTH) and alkaline phosphatase (ALP) in all patients, after which, oral Ca of 200–400 mg/kg/day and calcitriol of 0.5 μg/kg/day were sufficient to maintain normal PTH levels. Molecular studies on the VDR gene showed a previously reported homozygous c.454C > T (p.Q152*) pathogenic variant in two patients. Two novel homozygous variants in the other two patients were detected: (1) c.756-2A > G, which affects the splice acceptor site, and (2) c.66dupG (p.I23Dfs*20) variant leading to a frameshift that results in a premature stop codon.ConclusionsPeripheral IV-Ca treatment is an effective and practical alternative treatment mode that provides dramatic clinical benefit in patients with HVDRR.

scholarly journals Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Francesco Saettini ◽  
Grazia Fazio ◽  
Daniele Moratto ◽  
Marta Galbiati ◽  
Nicola Zucchini ◽  
...  
Keyword(s):  
T Cells ◽  
Sclerosing Cholangitis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Recurrent Infections ◽  
Combined Immunodeficiency ◽  
Caucasian Girl ◽  
Novel Variants ◽  
Dock8 Deficiency ◽  
Somatic Reversion

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.

scholarly journals Neuroacanthocytosis diagnózisa új generációs exom-szekvenálással

2017 ◽  
Vol 158 (42) ◽  
pp. 1681-1684 ◽  
Author(s):  
Kinga Hadzsiev ◽  
Mónika Szőts ◽  
Anett Fekete ◽  
László Balikó ◽  
Kim Boycott ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
International Collaboration ◽  
Huntington Disease ◽  
Stop Codon ◽  
Neurological Diseases ◽  
Premature Stop Codon ◽  
Pathogenic Mutation ◽  
Normal Result ◽  
Whole Exome ◽  
Specific Symptoms

Abstract: In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms. Orv Hetil. 2017; 158(42): 1681–1684.

scholarly journals Highly multiplexed AmpliSeq technology identifies novel variation of flowering time-related genes in soybean (Glycine max)

DNA Research ◽  
2019 ◽  
Vol 26 (3) ◽  
pp. 243-260 ◽  
Author(s):  
Eri Ogiso-Tanaka ◽  
Takehiko Shimizu ◽  
Makita Hajika ◽  
Akito Kaga ◽  
Masao Ishimoto
Keyword(s):  
Flowering Time ◽  
Core Collection ◽  
Target Genes ◽  
Sequence Data ◽  
Stop Codon ◽  
Response Regulator ◽  
Premature Stop Codon ◽  
Mini Core Collection ◽  
Novel Variants ◽  
Two Component

Abstract Whole-genome re-sequencing is a powerful approach to detect gene variants, but it is expensive to analyse only the target genes. To circumvent this problem, we attempted to detect novel variants of flowering time-related genes and their homologues in soybean mini-core collection by target re-sequencing using AmpliSeq technology. The average depth of 382 amplicons targeting 29 genes was 1,237 with 99.85% of the sequence data mapped to the reference genome. Totally, 461 variants were detected, of which 150 sites were novel and not registered in dbSNP. Known and novel variants were detected in the classical maturity loci—E1, E2, E3, and E4. Additionally, large indel alleles, E1-nl and E3-tr, were successfully identified. Novel loss-of-function and missense variants were found in FT2a, MADS-box, WDR61, phytochromes, and two-component response regulators. The multiple regression analysis showed that four genes—E2, E3, Dt1, and two-component response regulator—can explain 51.1–52.3% of the variation in flowering time of the mini-core collection. Among them, the two-component response regulator with a premature stop codon is a novel gene that has not been reported as a soybean flowering time-related gene. These data suggest that the AmpliSeq technology is a powerful tool to identify novel alleles.

scholarly journals Novel genetic variant of HPS1 gene in Hermansky-Pudlak syndrome with fulminant progression of pulmonary fibrosis: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Martina Doubková ◽  
Jakub Trizuljak ◽  
Zuzana Vrzalová ◽  
Anna Hrazdirová ◽  
Ivona Blaháková ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Clinical Manifestation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Oculocutaneous Albinism ◽  
Differential Diagnostics ◽  
Compound Heterozygous ◽  
Carrier Status ◽  
Whole Exome ◽  
Hermansky Pudlak Syndrome

Abstract Background Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. Case presentation A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. Conclusions Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.

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