scholarly journals Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5927 ◽  
Author(s):  
Zhening Pu ◽  
Haoliang Sun ◽  
Junjie Du ◽  
Yue Cheng ◽  
Keshuai He ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Connective Tissue Disorder ◽  
Pedigree Analysis ◽  
Vital Role ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Background Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. Methods We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. Results Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.

scholarly journals A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yanyan Nie ◽  
Yu Mu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mental Disorders ◽  
De Novo ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Whole Exome ◽  
De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications

2001 ◽  
Vol 3 (29) ◽  
pp. 1-10 ◽  
Author(s):  
Tahir Tellioglu ◽  
David Robertson
Keyword(s):  
Orthostatic Intolerance ◽  
Clinical Manifestations ◽  
Synaptic Cleft ◽  
Norepinephrine Transporter ◽  
Genetic Mutation ◽  
Clinical Syndrome ◽  
Loss Of Function ◽  
Direct Association ◽  
Type Gene

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.

scholarly journals Abnormal fibrillin assembly by dermal fibroblasts from two patients with Marfan syndrome

1994 ◽  
Vol 124 (6) ◽  
pp. 997-1004 ◽  
Author(s):  
CM Kielty ◽  
CA Shuttleworth
Keyword(s):  
Marfan Syndrome ◽  
Time Course ◽  
De Novo ◽  
Dermal Fibroblast ◽  
Clinical Manifestations ◽  
Connective Tissue Disorder ◽  
Dermal Fibroblasts ◽  
Relative Molecular Mass ◽  
Cell Layers ◽  
The Relationship

The microfibrillar glycoprotein fibrillin is linked to the Marfan syndrome, an autosomal dominant connective tissue disorder. In this study, fibrillin synthesis, deposition and assembly has been investigated in Marfan dermal fibroblast lines from two unrelated patients for whom distinct mutations in the fibrillin gene FBN1 have been identified. In patient NB, a point mutation has occurred which causes an amino acid substitution and the other patient (GK) has a deletion in one allele. The two cell lines were broadly comparable with respect to de novo fibrillin synthesis and its distribution between medium and cell layer compartments. Electrophoresis of fibrillin immunoprecipitates confirmed the presence of fibrillin in medium and cell layers. GK cells secreted an additional higher relative molecular mass fibrillin-immunoreactive component. The time-course of fibrillin secretion was similar for the two lines, but differences in fibrillin aggregation were apparent. Rotary shadowing electron microscopy of extracted cell layers demonstrated the presence of abundant and extensive microfibrils in NB cell layers. These were abnormal in their gross morphology in comparison to microfibrils isolated from control cultures. No periodic microfibrillar structures were isolated from GK cell layers. These studies underline the need to classify fibrillin defects in terms of biochemical and ultrastructural criteria. Examination of the effects of individual mutations on microfibril organization will be particularly informative in elucidating the relationship between microfibril dysfunction and the complex clinical manifestations of Marfan patients.

scholarly journals Genetic diagnosis of Mendelian disorders via RNA sequencing

2016 ◽  
Author(s):  
Laura S Kremer ◽  
Daniel M Bader ◽  
Christian Mertes ◽  
Robert Kopajtich ◽  
Garwin Pichler ◽  
...  
Keyword(s):  
Rare Variants ◽  
Genetic Diagnosis ◽  
Underlying Disease ◽  
Diagnostic Tools ◽  
Loss Of Function ◽  
Mendelian Disorders ◽  
Whole Exome ◽  
Established Disease ◽  
Assembly Factor ◽  
Strong Candidate

AbstractAcross a large variety of Mendelian disorders, ~50-75% of patients do not receive a genetic diagnosis by whole exome sequencing indicative of underlying disease-causing variants in non-coding regions. In contrast, whole genome sequencing facilitates the discovery of all genetic variants, but their sizeable number, coupled with a poor understanding of the non-coding genome, makes their prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to provide a confirmed genetic diagnosis for 10% (5 of 48) of undiagnosed mitochondrial disease patients and identify strong candidate genes for patients remaining without diagnosis. We found a median of 1 aberrantly expressed gene, 5 aberrant splicing events, and 6 mono-allelically expressed rare variants in patient-derived fibroblasts and established disease-causing roles for each kind. Private exons often arose from sites that are weakly spliced in other individuals, providing an important clue for future variant prioritization. One such intronic exon-creating variant was found in three unrelated families in the complex I assembly factor TIMMDC1, which we consequently established as a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants of Mendelian disorders and provides examples of intronic loss-of-function variants with pathological relevance.

scholarly journals Gli3 regulates vomeronasal neurogenesis, olfactory ensheathing cell formation and GnRH-1 neuronal migration

2019 ◽  
Author(s):  
Ed Zandro M. Taroc ◽  
Ankana Naik ◽  
Jennifer M. Lin ◽  
Nicolas B. Peterson ◽  
David L. Keefe ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nasal Mucosa ◽  
Neuronal Migration ◽  
Neuronal Development ◽  
Olfactory Ensheathing Cells ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome ◽  
Ensheathing Cells ◽  
Whole Exome Sequencing Data

AbstractDuring mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1) positive vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xt mice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1null mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the non-overlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Since Kallmann syndrome (KS) is characterized by abnormal GnRH migration, we examined whole exome sequencing data from KS subjects. We identified and validated a GLI3 loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that human GLI3 mutations contribute to KS etiology.Significance statementThe transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl1 null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl1 is necessary for GnRH-1 ontogeny. Analyzing human whole exome sequencing data, we identified a GLI3 loss-of-function variant in a KS individual. Our data suggest that GLI3 is a candidate gene contributing to KS etiology.

scholarly journals Characterization and genetic diversity of Helicobacter pylori type IV secretion system components, CagI and CagN and its association with clinical outcomes among Iranian patients

2020 ◽  
Author(s):  
Yasaman Azizimoghaddam ◽  
Sadaf Kermanpour ◽  
Nasrin Mirzaei ◽  
Hamidreza Houri ◽  
Abbas Yadegar ◽  
...  
Keyword(s):  
Codon Usage ◽  
Clinical Outcomes ◽  
Reference Strain ◽  
Clinical Manifestations ◽  
Pcr Analysis ◽  
Sequencing Data ◽  
Type Iv ◽  
High Prevalence ◽  
H Pylori

Abstract Background A number of cagPAI genes in H. pylori genome was proposed to be the most probably evolved under a diversifying selection and evolutionary pressure. Among them, CagI and CagN are described as a part of the two different-operon of cagPAI that are involved in the T4SS, but the definite association of these factors with clinical manifestations is unclear. Methods A total of 70 H. pylori isolates were obtained from different gastroduodenal pateints. All isolates were examined for the presence of primary H. pylori virulence genes by PCR analysis. Direct DNA sequence analysis was performed for the cagI and cagN genes. The results were compared with reference strain. Results The cagI, cagN, cagA, cagL, vacA s1m1, vacA s1m2, vacA s2m2, babA2, sabA and dupA genotypes were detected in 80%, 91.4%, 84%, 91.4%, 32.8%, 42.8%, 24.4%, 97.1%, 84.3%, and 84.3% of the total isolates, respectively. The most variable codon usage in cagI was observed at residues 20 to 25, 55 to 60, 94, 181 to 199, 213 to 221, 241 to 268, and 319 to 320, while the most variable codon usage in CagN hypervariable motif (CagNHM) was observed at residues 53 to 63. This CagNHM region is postulated to contain GDEEITEEEKK sequence in the P12 reference strain. Sequencing data analysis of cagN revealed a conserved hypothetical hexapeptide repeat (EAKDEN/K) in residues of 278–283 among six H. pylori isolates, which needs further studies to evaluate its putative function. Conclusion The present study demonstrated a high prevalence of cagI and cagN genes among Iranian H. pylori isolates with gastroduodenal diseases. Furthermore, no significant correlation between cagI and cagN variants and clinical outcomes was observed. However, all patients had high prevalence of cagPAI genes including cagI, cagN, cagA and cagL that indicates more potential role of these genes in disease outcome.

scholarly journals RIPK1-Associated Inborn Errors of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Zhang ◽  
Taijie Jin ◽  
Ivona Aksentijevich ◽  
Qing Zhou
Keyword(s):  
Immune Deficiency ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

102 Exome Sequencing Identifies Novel Molecular Determinants of Human Congenital Hydrocephalus

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 220-220
Author(s):  
Charuta Gavankar Furey ◽  
Jungmin Choi ◽  
Daniel Duran ◽  
Andrew T Timberlake ◽  
Xue Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Statistical Significance ◽  
The United States ◽  
Congenital Hydrocephalus ◽  
Common Disease ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Abstract INTRODUCTION Congenital hydrocephalus (CH), with an estimated prevalence of 1 in 1000 births, is the most common disease treated by pediatric neurosurgeons, and exerts a tremendous burden on the United States health care budget, consuming over $2 billion annually. Paradoxically, CH treatments remain inadequate, crude, and primarily symptomatic, comprised largely of surgical shunts riddled with infectious and mechanical complications. Despite evidence that genetic factors play a major role in the pathogenesis of CH an estimated 40% of human CH has a genetic etiology our knowledge of specific CH-causing mutations and their pathogenic mechanisms remains primitive. Understanding critical genetic drivers underlying human CH holds promise for the development of targeted therapies. However, traditional genetic approaches have been limited in their ability to identify causative CH genes because kindreds are rare, small in size, or appear to have sporadic inheritance patterns. Next-generation sequencing, and specifically whole exome sequencing (WES), can overcome these barriers to gene discovery. METHODS We performed whole-exome sequencing on DNA isolated from 130 patient-parent trios (affected patient and unaffected parents) and an additional 57 probands for a total of 187 CH patients with non-L1CAM primary CH. Exome-sequencing data from these 447 individuals was then analyzed to identify rare, de novo and transmitted mutations contributing to CH, and candidate mutations were subsequently confirmed by Sanger sequencing. RESULTS >Exome sequencing identified multiple novel and recurrent de novo and transmitted loss-of function gene mutations enriched in neurodevelopmental and ciliogenesis pathways. Binomial and case-control analyses confirmed exome-wide statistical significance of candidate genes, and functional modeling in Xenopus established gene causality. CONCLUSION These findings reveal novel disease-causing mutations in human CH, thereby providing new opportunities for improved prognostic assessment and non-invasive therapies.

scholarly journals Exome-Wide Analysis of the DiscovEHR Cohort Reveals Novel Candidate Pharmacogenomic Variants for Clinical Pharmacogenomics

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 561
Author(s):  
Maria-Theodora Pandi ◽  
Marc S. Williams ◽  
Peter van der Spek ◽  
Maria Koromina ◽  
George P. Patrinos
Keyword(s):  
Genetic Variation ◽  
Sequence Data ◽  
Sequencing Data ◽  
Sequencing Technology ◽  
Next Generation Sequencing Technology ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Generation Sequencing

Recent advances in next-generation sequencing technology have led to the production of an unprecedented volume of genomic data, thus further advancing our understanding of the role of genetic variation in clinical pharmacogenomics. In the present study, we used whole exome sequencing data from 50,726 participants, as derived from the DiscovEHR cohort, to identify pharmacogenomic variants of potential clinical relevance, according to their occurrence within the PharmGKB database. We further assessed the distribution of the identified rare and common pharmacogenomics variants amongst different GnomAD subpopulations. Overall, our findings show that the use of publicly available sequence data, such as the DiscovEHR dataset and GnomAD, provides an opportunity for a deeper understanding of genetic variation in pharmacogenes with direct implications in clinical pharmacogenomics.

scholarly journals Ssc-miR-21-5p regulates endometrial epithelial cell proliferation, apoptosis and migration via the PDCD4/AKT pathway

2020 ◽  
Vol 133 (23) ◽  
pp. jcs248898
Author(s):  
Renwu Hua ◽  
Xiuling Zhang ◽  
Wenchao Li ◽  
Weisi Lian ◽  
Qiaorui Liu ◽  
...  
Keyword(s):  
Embryo Implantation ◽  
Vital Role ◽  
Endometrial Receptivity ◽  
Akt Pathway ◽  
Loss Of Function ◽  
Endometrial Epithelial Cell ◽  
Programmed Cell Death 4 ◽  
And Migration

ABSTRACTEndometrial receptivity plays a vital role in successful embryo implantation in pigs. MicroRNAs (miRNAs), known as regulators of gene expression, have been implicated in the regulation of embryo implantation. However, the role of miRNAs in endometrial receptivity during the pre-implantation period remains elusive. In this study, we report that the expression level of Sus scrofa (ssc)-miR-21-5p in porcine endometrium tissues was significantly increased from day 9 to day 12 of pregnancy. Knockdown of ssc-miR-21-5p inhibited proliferation and migration of endometrial epithelial cells (EECs), and induced their apoptosis. We verified that programmed cell death 4 (PDCD4) was a target gene of ssc-miR-21-5p. Inhibition of PDCD4 rescued the effect of ssc-miR-21-5p repression on EECs. Our results also revealed that knockdown of ssc-miR-21-5p impeded the phosphorylation of AKT (herein referring to AKT1) by targeting PDCD4, which further upregulated the expression of Bax, and downregulated the levels of Bcl2 and Mmp9. Furthermore, loss of function of Mus musculus (mmu)-miR-21-5p in vivo resulted in a decreased number of implanted mouse embryos. Taken together, knockdown of ssc-miR-21-5p hampers endometrial receptivity by modulating the PDCD4/AKT pathway.

Sign in / Sign up

Export Citation Format

Share Document