scholarly journals Novel RNASEH2C mutation in multiple members of a large family: insights into phenotypic spectrum of Aicardi-Goutières Syndrome

2020 ◽  
Vol 2 (1) ◽  
pp. e000018
Author(s):  
Dema Lhamtsho ◽  
Uddandam Rajesh ◽  
Apoorv Saxena ◽  
Girish Bhardwaj ◽  
Vishal Sondhi
Keyword(s):  
Vegetative State ◽  
Family Members ◽  
Large Family ◽  
Periventricular White Matter ◽  
Inflammatory Disorder ◽  
Mri Findings ◽  
Exon 2 ◽  
Whole Exome ◽  
Unexplained Fever ◽  
Indel Variation

BackgroundAicardi-Goutières syndrome (AGS) is a genetic inflammatory disorder that presents with early infantile encephalopathy. We report the clinical and molecular details of multiple members of a family with AGS secondary to a novel RNASEH2C mutation, highlighting the evolution of phenotypic abnormalities in AGS.MethodsBetween February 2018 and June 2019, a pedigree tree was constructed for 141 members of a family. The clinical and radiological details of 14 symptomatic children were chronicled and compared with the asymptomatic family members. Genetic analysis was performed on 23 individuals (six symptomatic). This involved whole exome sequencing for one patient and confirmation of the identified indel variant in other family members.ResultsThe symptomatic children were diagnosed as AGS secondary to a novel indel variation in exon 2 of the RNASEH2C gene (chr11:65487843_65487846delinsGCCA). Clinically, between the ages of 2 and 6 months, the symptomatic children developed irritability (14/14), unexplained fever (9/14), chill blains (12/14), sleep irregularities (14/14) and developmental delay (14/14), with deterioration to vegetative state at a median (IQR) age of 10.5 months (9.25–11). In addition, chill blains were observed in 5/17 (29.4%) carrier individuals. Neuroimaging demonstrated a gradual progression of calcification involving basal ganglia, periventricular white matter and dentate nucleus. Three patients also demonstrated presence of subependymal germinolytic cysts.ConclusionThis report highlights a novel founder RNASEH2C mutation and the phenotypic evolution of AGS. In addition, we report chill blains in one-third of RNASEH2C mutation carriers. Neuroradiologically, the report illustrates novel MRI findings and demonstrates a progression pattern of disease. These findings will aid in earlier suspicion and diagnosis of AGS.

Abstract 484: Mir-19b-3p Regulates Autophagy by Targeting Raf-1 During Hypertrophic Cardiomyopathy

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Anupam Mittal ◽  
Perundurai S Dhandapany
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Novel Mutation ◽  
Family Members ◽  
Large Family ◽  
Untranslated Regions ◽  
Whole Exome ◽  
Signaling Axis ◽  
Functional Consequences ◽  
Sarcomeric Genes

Hypertrophic cardiomyopathy (HCM) is a heterogenous disease predominantly caused by sarcomeric genes. However, 40-50% cases etiology are not known. RAF1 mutations cause syndromic and isolated childhood cardiomyopathies. Functional mutations in untranslated regions (UTRs) of RAF-1 gene are rare, and their role in cardiomyopathy is unexplored. UTRs are important sites for interaction of epigenetic regulators such as microRNAs (miR). miRs have exhibited as crucial regulators of the cardiac remodeling process. We identified a novel mutation in RAF-1 3’-UTR (an important site for binding of miR-19a-3p/19b-3p) in large family members associated with HCM. Whole exome sequencing revealed that these family members are negative for mutations in known cardiomyopathy associated genes. miR-19a/b are known to play a crucial role in cardiac hypertrophy. The aim of this study is to determine the role of miR-19a-3p/19b-3p in regulating RAF-1 expression and delineating the molecular and functional consequences of identified RAF-1 3’-UTR mutation. Our results show that the overexpression of miR-19b-3p, leads to downregulation of RAF-1 expression and regulation. Notably, miR-19b-3p was found to be pro-hypertrophic as its overexpression resulted in increasing hypertrophic markers including ANP and β-MHC expression. Moreover, findings from experiments using RAF1 +/+ and RAF1 -/- mouse embryo fibroblasts (MEFs) confirms the role of miR-19b-3p interaction and regulation of RAF-1 signaling axis. Interestingly, we also observed many autophagy markers (Atg3, Atg 12-5 complex, and LC3 II) are dysregulated by miR-19-b-3p overexpression. Our study uncovers a novel mechanism through which miR-19b-3p regulates autophagy by targeting RAF-1.

SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family

2017 ◽  
Vol 55 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Benjamin Roeben ◽  
Rebecca Schüle ◽  
Susanne Ruf ◽  
Benjamin Bender ◽  
Bader Alhaddad ◽  
...  
Keyword(s):  
Large Family ◽  
Splice Mutation ◽  
Intermediate Phenotype ◽  
Common Disease ◽  
Juvenile Onset ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
Complex Lipid ◽  
Glutaconic Acid ◽  
Methylglutaconic Aciduria

ObjectiveTo demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes.MethodsCombined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family.Results5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10–20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype.ConclusionsOur findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum.

scholarly journals Contribution of Genetic and Environmental Risk Factors in a Juvenile Idiopathic Arthritis Large Family With SERPINA1 Gene Mutations

2021 ◽  
Author(s):  
Cyprian Popescu
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Gene Mutations ◽  
Large Family ◽  
Carrier Status ◽  
Multiplex Family ◽  
Serpina1 Gene ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genetic And Environmental Factors ◽  
Underlying Mechanisms

Abstract Objectives Although the underlying mechanisms and mediators of arthritis in juvenile idiopathic arthritis (JIA) are not well understood, accumulated evidence supports the mixt role of genetic and environmental factors. Few reports of multiplex families with JIA were published until now. The aim of this study was to identify new genetic or environmental associations concerning the patients of a kindred with juvenile idiopathic arthritis and psoriatic features (JIAPs). Methods Here, we characterized an extended multiplex family of 5 patients with juvenile idiopathic arthritis and psoriatic features (PsA) at the clinical and genetic level, using whole exome sequencing. Results We did not confirm in our family the linkage with the genetic factors already described that might be associated with increase susceptibility to JIA. We found a carrier status of siblings who inherited a pathogenic allele of the SERPINA1 gene from their mother who herself has two heterozygous pathogenic variants in the SERPINA1 gene. Conclusions Our data showed that JIA results from pleiotropic effects of environmental background with an only minor monogenic contribution. Even that a monogenetic factor could not be proved, some genetic factor as SERPINA1 mutations which can sensitize for psoriatic arthritis development seems to be involved. Further investigation must be done to prove whether SERPINA1 mutations may have a potential JIA causality.

scholarly journals Analysis of ACE2 Genetic Variants in 131 Italian SARS-CoV-2 Positive Patients

2020 ◽  
Author(s):  
Antonio Novelli ◽  
Michela Biancolella ◽  
Paola Borgiani ◽  
Dario Cocciadiferro ◽  
Vito Luigi Colona ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Dna Analysis ◽  
Large Family ◽  
Population Data ◽  
Host Susceptibility ◽  
University Hospital ◽  
Control Group ◽  
Allelic Association ◽  
Similar Frequency ◽  
Whole Exome

Abstract Background: Coronaviruses (CoV) are a large family of viruses that are common in humans and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East Respiratory Syndrome (MERS-CoV), the Severe Acute Respiratory Syndrome CoronaVirus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Several studies suggested that genetic variants in the ACE2 gene may influence the host susceptibility or resistance to SARS-CoV-2 infection according to the functional role of ACE2 in human pathophysiology. However, many of these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 131 Italian unrelated individuals clinically diagnosed with COVID-19 and in an Italian control population, to evaluate a possible allelic association with COVID-19, by direct DNA analysis.Methods: As a pilot study, we analyzed, by whole-exome sequencing, genetic variants of ACE2 gene in 131 DNA samples of COVID-19 patients hospitalized at Tor Vergata University Hospital and at Bambino Gesù Children’s Hospital, Rome. We used a large control group consisting of 1,000 individuals (500 males and 500 females).Results: We identified three different germline variants: one intronic c.439+4G>A and two missense c.1888G>C p.(Asp630His) and c.2158A>G p.(Asn720Asp) in a total of 131 patients with a similar frequency in male and female. Thus far, only the c.1888G>C p.(Asp630His) variant shows a statistically different frequency compared to the ethnically matched populations. Therefore, further studies are needed in larger cohorts, since it was found only in one heterozygous COVID-19 patient.Conclusions: Our results suggest that there is no strong evidence, in our cohort, of consistent association of ACE2 variants with COVID-19 severity. We might speculate that rare susceptibility/resistant alleles could be located in the non-coding regions of the ACE2 gene, known to play a role in regulation of the gene activity.

Innexin-3 forms connexin-like intercellular channels

1999 ◽  
Vol 112 (14) ◽  
pp. 2391-2396 ◽  
Author(s):  
Y. Landesman ◽  
T.W. White ◽  
T.A. Starich ◽  
J.E. Shaw ◽  
D.A. Goodenough ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Gap Junction ◽  
Functional Properties ◽  
Xenopus Oocytes ◽  
Family Members ◽  
Electrical Coupling ◽  
Large Family ◽  
Gap Junction Channel ◽  
Intercellular Channels

Innexins comprise a large family of genes that are believed to encode invertebrate gap junction channel-forming proteins. However, only two Drosophila innexins have been directly tested for the ability to form intercellular channels and only one of those was active. Here we tested the ability of Caenorhabditis elegans family members INX-3 and EAT-5 to form intercellular channels between paired Xenopus oocytes. We show that expression of INX-3 but not EAT-5, induces electrical coupling between the oocyte pairs. In addition, analysis of INX-3 voltage and pH gating reveals a striking degree of conservation in the functional properties of connexin and innnexin channels. These data strongly support the idea that innexin genes encode intercellular channels.

scholarly journals Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takaaki Hayashi ◽  
Shuhei Kameya ◽  
Kei Mizobuchi ◽  
Daiki Kubota ◽  
Sachiko Kikuchi ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Survival Curve ◽  
Japanese Patients ◽  
Outcome Data ◽  
High Rate ◽  
Exon 2 ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Whole Exome

Abstract Choroideremia (CHM) is an incurable progressive chorioretinal dystrophy. Little is known about the natural disease course of visual acuity in the Japanese population. We aimed to investigate the genetic spectrum of the CHM gene and visual acuity outcomes in 24 CHM patients from 16 Japanese families. We measured decimal best-corrected visual acuity (BCVA) at presentation and follow-up, converted to logMAR units for statistical analysis. Sanger and/or whole-exome sequencing were performed to identify pathogenic CHM variants/deletions. The median age at presentation was 37.0 years (range, 5–76 years). The mean follow-up interval was 8.2 years. BCVA of the better-seeing eye at presentation was significantly worsened with increasing age (r = 0.515, p < 0.01), with a high rate of BCVA decline in patients > 40 years old. A Kaplan–Meier survival curve suggested that a BCVA of Snellen equivalent 20/40 at follow-up remains until the fifties. Fourteen pathogenic variants, 6 of which were novel [c.49 + 5G > A, c.116 + 5G > A, p.(Gly176Glu, Glu177Ter), p.Tyr531Ter, an exon 2 deletion, and a 5.0-Mb deletion], were identified in 15 families. No variant was found in one family only. Our BCVA outcome data are useful for predicting visual prognosis and determining the timing of intervention in Japanese patients with CHM variants.

1265The results of whole exome sequencing in patients with bradyarrhythmias

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
E Polyakova ◽  
N Shcherbakova
Keyword(s):  
Family History ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heart Diseases ◽  
Stress Test ◽  
Family Members ◽  
Pacemaker Implantation ◽  
Structural Heart Disease ◽  
Clinical Prognosis ◽  
Whole Exome

Abstract Introduction. Sick sinus syndrome (SSS) and atrioventricular block (AVB) are life-threatening cardiac arrhythmias, that sometimes can manifest itself with syncope and needs a pacemaker implantation even in children. Sometimes, SSS and AVB are accompanied by structural heart diseases such as septal defects, cardiomyopathies, but often the heart is structurally normal. Some genes associated with bradyarrhythmias are well known. At the same time, the etiology of the SSS is unidentified and may be genetic caused in 50% of patients with SSS. There are no studies on the prevalence of with bradyarrhythmia-associated mutations in children. The purpose of our work is to identify and study the types of mutations associated with SSS and AVB in children. Methods. We included in the study 15 patients (27% boys) with severe SSS and AVB, from the database of the Russian Pediatric Arrhythmia Center. 11 were the probands and 4 - family members.  Personal and family history, physical examination, including ECG, stress test, Holter monitoring, ECHO and other tests, and whole exome sequencing were made. The average age was 14.1 ± 4.5 (from 2 to 17). Results.  In 30% (5 pts) there was the combination of with bradyarrhythmias and structural heart disease. 7 pts (47%) had syncope, 4 pacemakers were implanted. 10 children (67%) had the genetic variants of genes associated with SSS and AVB: SCN5A, TNNI3K, KCNA5, TRPM4, ANK2 and others. Family history of cardiac diseases was positive in 5 probands; 2 probands had family members with implanted pacemakers. In 3 pts were likely pathogenic variants and in 7 pts - variants of unknown significance found. Conclusion.  We found the genetic cause of bradyarrhythmias in 67% of children. Further research and larger patient samples are required to study the prevalence of genetic types of and show the correlation of the genotype with the clinical prognosis. In addition, our work will enable practitioners to identify children from families with family forms of SSS, AVB and sudden cardiac death. Further research can help us determine the criteria for selecting children for genetic testing.

scholarly journals Expression, purification, crystallization and preliminary crystallographic analysis of human myotubularin-related protein 3

2014 ◽  
Vol 70 (9) ◽  
pp. 1240-1243
Author(s):  
Ji Young Son ◽  
Jee Un Lee ◽  
Ki-Young Yoo ◽  
Woori Shin ◽  
Dong-Won Im ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Catalytic Domain ◽  
Family Members ◽  
Large Family ◽  
Crystallographic Analysis ◽  
Related Protein ◽  
Unit Cell Parameters ◽  
X Ray ◽  
Cell Parameters ◽  
Related Proteins

Myotubularin-related proteins are a large family of phosphatases that have the catalytic activity of dephosphorylating the phospholipid molecules phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Each of the 14 family members contains a phosphatase catalytic domain, which is inactive in six family members owing to amino-acid changes in a key motif for the activity. All of the members also bear PH-GRAM domains, which have low homologies between them and have roles that are not yet clear. Here, the cloning, expression, purification and crystallization of human myotubularin-related protein 3 encompassing the PH-GRAM and the phosphatase catalytic domain are reported. Preliminary X-ray crystallographic analysis shows that the crystals diffracted to 3.30 Å resolution at a synchrotron X-ray source. The crystals belonged to space groupC2, with unit-cell parametersa= 323.3,b= 263.3,c= 149.4 Å, β = 109.7°.

scholarly journals A Co-Occurrence of Familial Non-Medullary Thyroid Cancer and Lynch Syndrome

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A855-A855
Author(s):  
Kshama Aswath ◽  
James Welch ◽  
Sriram Gubbi ◽  
Mohammad Al Jundi ◽  
Padmasree Veeraraghavan ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Lymph Node ◽  
Medullary Thyroid Cancer ◽  
Family Members ◽  
Rare Event ◽  
Neck Lymph Node ◽  
Medullary Thyroid ◽  
Whole Exome ◽  
Node Metastases ◽  
Neck Lymph Node Metastases

Abstract Background: Lynch syndrome (LS) is an autosomal dominant disease caused by germline mutations in mismatch repair genes (MMR), leading to the early manifestation of tumors characterized by microsatellite instability (MSI) in &gt;3 family members across at least 2 generations. MSI is a rare event in thyroid cancer (TC), occurring in up to 2.5% of sporadic cases. There is limited data on germline MMR variants’ role in familial non-medullary thyroid cancer (FNMTC). The goal of this study was to analyze the potential clinical and molecular association between LS and FNMTC. Material and Methods: We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds with FNMTC. We performed a high-throughput whole exome sequencing (WES) of peripheral-blood DNA samples of 168 participants (54 affected by FNMTC and 140 unaffected). The GATK pipeline was used in variant analysis. The NIH Institutional Review Board approved the study. Results: The study included 383 family members (104 affected, 279 unaffected) aged 43.5 [7-99] years, with 2-9 members per family affected by FNMTC. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1 [0.2-5] cm, multifocal growth in 44%, gross extrathyroidal extension in 11.3%, central neck lymph node metastases in 40.3%, lateral neck lymph node metastases in 12.9% of patients, and no distant metastases. Family history screening revealed one family of Caucasian descent meeting the clinical criteria for FNMTC and LS diagnosis with 5 members affected by FNMTC and 8 individuals by Lynch-like tumors (3 with colorectal cancer/colon polyps, 2 with endometrial or ovarian tumors, 1 with kidney cancer, 1 with keratoacanthoma and 1 with unspecified Lynch-like tumors with detailed pathology report unavailable). We performed whole exome sequencing of 10 members from this family (3 affected and 7 unaffected) and remaining 158 study participants and detected exclusively in this family, a heterozygous missense variant rs373226409, in MSH2 gene c2120G&gt;A (pCys707Tyr) in three adults affected by LS-like manifestations and two unaffected children under the age of 18 with clear segregation across three generations. This variant appears to be relatively rare with a minor allele frequency (MAF) of 0.0006 in Caucasians; however, it is more common in the South Asian population at 0.003 MAF. Immunostaining performed on the TC tumor tissue of one of the affected family members revealed intact nuclear expression of MSH2, suggestive of no major effect of the variant on MSH2 expression. Five out of seven in-silico models predicted the variant to be functionally deleterious. Conclusion: The co-occurrence of LS and FNMTC is a rare event, presenting in 2% (1/43) of families in our cohort. A common genetic association between LS and FNMTC has not been identified, and the MSH2 variant observed in this family is unlikely to be an etiologic factor.

scholarly journals Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

2018 ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Aortic Disease ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

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