scholarly journals Case Report: Infantile Urticaria as a Herald of Neonatal Onset Multisystem Inflammatory Disease With a Novel Mutation in NLRP3

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna E. Patrick ◽  
Eden M. Lyons ◽  
Lisa Ishii ◽  
Alan S. Boyd ◽  
Joseph M. Choi ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Early Recognition ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Inflammatory Disorder ◽  
Laboratory Findings ◽  
Genetic Sequencing ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
The Impact

Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1β. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant’s diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.

Abstract 193: Hemophagocytic lymphohistiocytosis following kawasaki disease:Differential Diagnosis in IVIG Refractory Kawasaki Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Hyun Ok Jun ◽  
Eun Kyung Cho ◽  
Jeong Jin Yu ◽  
So Yeon Kang ◽  
Chang Deok Seo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Coronary Artery ◽  
Kawasaki Disease ◽  
Skin Rash ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Clinical Symptoms ◽  
Early Recognition ◽  
Cervical Lymphadenopathy ◽  
Inflammatory Disorder ◽  
Laboratory Findings

Introduction: Hemophagocytic lymphohistiocytosis(HLH) is a systemic inflammatory disorder characterized by uncontrolled histiocytic proliferation, hemophagocytosis and up-regulation of inflammatory cytokines. Thus, both HLH and Kawasaki disease(KD) are characterized by prolonged fever, and are diagnosed by a clinical and laboratory scoring system, concurrent manifestation of HLH and KD has been described in the literature. We describe two cases of children who diagnosed as KD initially, but after intravenous gamma globulin(IVIG) failed to produce clinical response, were found to have HLH. Case report: A 3-year-old boy who had previous KD history 5 months ago was admitted for 9day fever and skin rash. His symptoms were fulfilled KD criteria, and echocardiography showed dilated right coronary artery of 4.2mm. He was treated with 2 cycles of IVIG until fever subsided. However, 2 days later, he got fever again and cytopenia(Hb<9.0), hypertriglyceridemia, high level of ferritin was shown and had splenomegaly on physical examination. In the suspicion of HLH, bone marrow biopsy was done and revealed hemophagocytosis, consistent with HLH. A second case of 11-month-old boy admitted for 8-day fever with Kawasaki feature. Although, he showed incomplete feature(fever, skin rash, conjunctival injection, cervical lymphadenopathy), echocardiography showed dilated left main coronary artery(3.5mm) and treated with IVIG. However, 2days after IVIG administration, he was still pyrexial. The laboratory findings fulfilled 5 diagnostic criteria of HLH; bicytopenia(anemia, thrombocytopenia), hypofibrinogenemia, hyperferritinemia, hemophagocytosis in bone marrow, raised level of soluble IL-2 receptor. In both cases, the patients treated according to the HLH protocol 2004, and after that clinical symptoms and laboratory findings were improved. Several causes of febrile illness, EBV, CMV, rubella, parvo-viral infection, for example, were excluded. Comment: There is considerable overlap between the clinical syndromes of KD and HLH and early recognition and treatment of these two disease entity is imperative to avoid fatal outcomes in severe cases. Thus, these should both be considered and excluded in any child with unremitting fever and rash.

scholarly journals Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

2019 ◽  
Author(s):  
Sathiya N. Manivannan ◽  
Sihem Darouich ◽  
Aida Masmoudi ◽  
David Gordon ◽  
Gloria Zender ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exome Sequencing ◽  
Rapid Screening ◽  
Functional Study ◽  
Ventricular Muscle ◽  
Loss Of Function ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
The Impact

AbstractHypertrophic cardiomyopathy (HCM) is characterized by enlargement of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the C-terminal EF-hand (CEF) domain. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stopgain variants that lead to loss of the CEF domain are stably expressed. However, stopgain variants show impaired localization suggesting a functional role for the CEF domain. The degradation of the MYL2-fs can be rescued by inhibiting the cell’s proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither MYL2-fs nor MYL2:p.Gly162Arg supports regular cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathies.Author SummaryWe report a novel frameshift variant in MYL2 that is associated with a severe form of infantile-onset hypertrophic cardiomyopathy. The impact of the variant is only observed in the recessive form of the disease in the proband and not in the parents who are carriers of the variant. This is in contrast to other dominant variants in MYL2 that are associated with cardiomyopathies. We compared the stability of this variant to that of other cardiomyopathy associated MYL2 variants and found molecular differences in the disease pathology. We also show different protein domain requirement for stability and localization of MYL2 in cardiomyocytes. Further, we used a fly model to demonstrate functional deficits due to the variant in the developing heart. Overall, our study shows a molecular mechanism by which loss-of-function variants in MYL2 are recessive while missense variants are dominant. We highlight the use of exome sequencing and functional testing to assist in the diagnosis of rare forms of diseases where pathogenicity of the variant is not obvious. The new tools we developed for in vitro functional study and the fly fluorescent reporter analysis will permit rapid analysis of MYL2 variants of unknown significance.

scholarly journals A segregating human allele ofSPO11modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve

2019 ◽  
Author(s):  
Tina N. Tran ◽  
John C. Schimenti
Keyword(s):  
Variants Of Unknown Significance ◽  
Y Chromosomes ◽  
Sperm Counts ◽  
Meiotic Dsbs ◽  
Unknown Significance ◽  
Causes Of Disease ◽  
Underlying Causes ◽  
Timely Fashion ◽  
Difficult Challenge ◽  
The Impact

ABSTRACTA major challenge in medical genetics is to characterize variants of unknown significance (VUS), so as to better understand underlying causes of disease and design customized treatments. Infertility has presented an especially difficult challenge with respect to not only determining if a given patient has a genetic basis, but also to identify the causative genetic factor(s). Though genome sequencing can identify candidate variants, in silico predictions of causation are not always sufficiently reliable so as to be actionable. Thus, experimental validation is crucial. Here, we describe the phenotype of mice containing a nonsynonymous (proline-to-threonine at position 306) change inSpo11, corresponding to human SNP rs185545661. SPO11 is a topoisomerase-like protein that is essential for meiosis because it induces DNA double stranded breaks (DSBs) that stimulate pairing and recombination of homologous chromosomes.Although both male and femaleSpo11P306T/P306Tmice were fertile, they had reduced sperm and oocytes, respectively. Spermatocyte chromosomes exhibited synapsis defects (especially between the X and Y chromosomes), elevated apoptotic cells, persistent markers of DSBs, and most importantly, fewer Type 1 crossovers that causes some chromosomes to have none.Spo11P306T/−mice were sterile and made fewer meiotic DSBs thanSpo11+/−animals, suggesting that theSpo11P306Tallele is a hypomorph and likely is delayed in making sufficient DSBs in a timely fashion. If the consequences are recapitulated in humans, it would predict phenotypes of premature ovarian failure, reduced sperm counts, and possible increased number of aneuploid gametes. These results emphasize the importance of deep phenotyping in order to accurately assess the impact of VUSs in reproduction genes.

Non-ocular Stickler Syndrome With a Novel Mutation in COL11A2 Diagnosed by Massively Parallel Sequencing in Japanese Hearing Loss Patients

2015 ◽  
Vol 124 (1_suppl) ◽  
pp. 111S-117S ◽  
Author(s):  
Yoh-ichiro Iwasa ◽  
Hideaki Moteki ◽  
Mitsuru Hattori ◽  
Ririko Sato ◽  
Shin-ya Nishio ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Clinical Symptoms ◽  
Massively Parallel Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Analysis Data ◽  
Massively Parallel ◽  
Stickler Syndrome ◽  
Parallel Sequencing ◽  
First Case

Objectives: This study aims to document the clinical features of patients with COL11A2 mutations and to describe the usefulness of massively parallel sequencing. Methods: One thousand one hundred twenty (1120) Japanese hearing loss patients from 53 ENT departments nationwide participated in this study. Massively parallel sequencing of 63 genes implicated in hearing loss was performed to identify the genetic causes in the Japanese hearing loss patients. Results: A novel mutation in COL11A2 (c.3937_3948delCCCCCAGGGCCA) was detected in an affected family, and it was segregated in all hearing loss individuals. The clinical findings of this family were compatible with non-ocular Stickler syndrome. Orofacial features of mid-facial hypoplasia and slowly progressive mild to moderate hearing loss were also presented. Audiological examinations showed favorable auditory performance with hearing aid(s). Conclusion: This is the first case report of the genetic diagnosis of a non-ocular Stickler syndrome family in the Japanese population. We suggest that it is important to take both genetic analysis data and clinical symptoms into consideration to make an accurate diagnosis.

Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

2020 ◽  
pp. jmedgenet-2020-106867
Author(s):  
Mathilde Lefebvre ◽  
Ange-Line Bruel ◽  
Emilie Tisserant ◽  
Nicolas Bourgon ◽  
Yannis Duffourd ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Congenital Abnormalities ◽  
Diagnostic Yield ◽  
Causal Variant ◽  
Developmental Abnormalities ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Bibliographic Search ◽  
The Impact ◽  
Multiple Congenital Abnormalities

PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

scholarly journals Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

2019 ◽  
Vol 22 (2) ◽  
pp. 5-16
Author(s):  
M Staninova-Stojovska ◽  
N Matevska-Geskovska ◽  
M Panovski ◽  
B Angelovska ◽  
N Mitrevski ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genetic Diagnosis ◽  
Promoter Regions ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Predisposition Genes ◽  
Hereditary Factors ◽  
Polyposis Syndromes ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs

AbstractHereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.

Web-Based Bioinformatics Predictors: Recommendations to Assess Lysosomal Cholesterol Trafficking Diseases-Related Genes

2019 ◽  
Vol 58 (01) ◽  
pp. 050-059 ◽  
Author(s):  
Laura López de Frutos ◽  
Jorge J. Cebolla ◽  
Pilar Irún ◽  
Ralf Köhler ◽  
Pilar Giraldo
Keyword(s):  
Genetic Variants ◽  
Lysosomal Storage ◽  
Cholesterol Trafficking ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Deleterious Gene ◽  
The One ◽  
Matthew’S Correlation Coefficient ◽  
Sensitivity Specificity ◽  
The Impact

Introduction The growing number of genetic variants of unknown significance (VUS) and availability of several in silico prediction tools make the evaluation of potentially deleterious gene variants challenging. Materials and Methods We evaluated several programs and software to determine the one that can predict the impact of genetic variants found in lysosomal storage disorders (LSDs) caused by defects in cholesterol trafficking best. We evaluated the sensitivity, specificity, accuracy, precision, and Matthew's correlation coefficient of the most common software. Results Our findings showed that for exonic variants, only MutPred1 reached 100% accuracy and generated the best predictions (sensitivity and accuracy = 1.00), whereas intronic variants, SROOGLE or Human Splicing Finder (HSF) generated the best predictions (sensitivity = 1.00, and accuracy = 1.00). Discussion Next-generation sequencing substantially increased the number of detected genetic variants, most of which were considered to be VUS, creating a need for accurate pathogenicity prediction. The focus of the present study is the importance of accurately predicting LSDs, with majority of previously unreported specific mutations. Conclusion We found that the best prediction tool for the NPC1, NPC2, and LIPA variants was MutPred1 for exonic regions and HSF and SROOGLE for intronic regions and splice sites.

scholarly journals Cell Painting predicts impact of lung cancer variants

2021 ◽  
Author(s):  
Juan C Caicedo ◽  
John Arevalo ◽  
Federica Piccioni ◽  
Mark-Anthony Bray ◽  
Cathy L Hartland ◽  
...  
Keyword(s):  
Single Cell ◽  
Low Cost ◽  
Transcriptional Profiling ◽  
Patient Specific ◽  
Cell Level ◽  
Functional Impact ◽  
Variants Of Unknown Significance ◽  
Online Portal ◽  
Unknown Significance ◽  
The Impact

Most variants in most genes across most organisms have an unknown impact on the function of the corresponding gene. This gap in knowledge is especially acute in cancer, where clinical sequencing of tumors now routinely reveals patient-specific variants whose functional impact on the corresponding gene is unknown, impeding clinical utility. Transcriptional profiling was able to systematically distinguish these variants of unknown significance (VUS) as impactful vs. neutral in an approach called expression-based variant-impact phenotyping (eVIP). We profiled a set of lung adenocarcinoma-associated somatic variants using Cell Painting, a morphological profiling assay that captures features of cells based on microscopy using six stains of cell and organelle components. Using deep-learning-extracted features from each cell's image, we found that cell morphological profiling (cmVIP) can predict variants' functional impact and, particularly at the single-cell level, reveals biological insights into variants which can be explored in our public online portal. Given its low cost, convenient implementation, and single-cell resolution, cmVIP profiling therefore seems promising as an avenue for using non-gene-specific assays to systematically assess the impact of variants, including disease-associated alleles, on gene function.

scholarly journals A segregating human allele of SPO11 modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve†

2019 ◽  
Vol 101 (2) ◽  
pp. 347-359 ◽  
Author(s):  
Tina N Tran ◽  
John C Schimenti
Keyword(s):  
Variants Of Unknown Significance ◽  
Y Chromosomes ◽  
Sperm Counts ◽  
Meiotic Dsbs ◽  
Unknown Significance ◽  
Causes Of Disease ◽  
Underlying Causes ◽  
Timely Fashion ◽  
Difficult Challenge ◽  
The Impact

Abstract A major challenge in medical genetics is to characterize variants of unknown significance (VUS). Doing so would help delineate underlying causes of disease and the design of customized treatments. Infertility has presented an especially difficult challenge with respect to not only determining if a given patient has a genetic basis, but also to identify the causative genetic factor(s). Though genome sequencing can identify candidate variants, in silico predictions of causation are not always sufficiently reliable so as to be actionable. Thus, experimental validation is crucial. Here, we describe the phenotype of mice containing a non-synonymous (proline-to-threonine at position 306) change in Spo11, corresponding to human SNP rs185545661. SPO11 is a topoisomerase-like protein that is essential for meiosis because it induces DNA double stranded breaks (DSBs) that stimulate pairing and recombination of homologous chromosomes. Although both male and female Spo11P306T/P306T mice were fertile, they had reduced sperm and oocytes, respectively. Spermatocyte chromosomes exhibited synapsis defects (especially between the X and Y chromosomes), elevated apoptotic cells, persistent markers of DSBs, and most importantly, fewer Type 1 crossovers that causes some chromosomes to have none. Spo11P306T/− mice were sterile and made fewer meiotic DSBs than Spo11+/- animals, suggesting that the Spo11P306T allele is a hypomorph and likely is delayed in making sufficient DSBs in a timely fashion. If the consequences are recapitulated in humans, it would predict phenotypes of premature ovarian failure, reduced sperm counts, and possible increased number of aneuploid gametes. These results emphasize the importance of deep phenotyping in order to accurately assess the impact of VUSs in reproduction genes.

scholarly journals Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics

2020 ◽  
pp. jmedgenet-2020-106901 ◽  
Author(s):  
Gina Ravenscroft ◽  
Joshua S Clayton ◽  
Fathimath Faiz ◽  
Padma Sivadorai ◽  
Di Milnes ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Research Collaboration ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Arthrogryposis Multiplex Congenita ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Diagnostic Research ◽  
Gene Panels ◽  
Neurogenetic Disease

BackgroundFetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions.MethodsWe performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required.ResultsOf the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with CACNA1S, CHRNB1, GMPPB and STAC3. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations—SMPD4.ConclusionsComprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.

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