scholarly journals An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing

2016 ◽  
Vol 170 (4) ◽  
pp. 1080-1085 ◽  
Author(s):  
Luisa Mackenroth ◽  
Björn Fischer-Zirnsak ◽  
Johannes Egerer ◽  
Jochen Hecht ◽  
Tilmann Kallinich ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heterozygous Mutation ◽  
Ehlers Danlos Syndrome ◽  
Missense Variants ◽  
Whole Exome ◽  
Danlos Syndrome

scholarly journals AB0008 APPLYING WHOLE EXOME SEQUENCING TO FAMILIAL ANTIPHOSPHOLIPID SYNDROME: NEW PLAYERS IN A RARE DISEASE?

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1039.1-1039
Author(s):  
A. Barinotti ◽  
M. Radin ◽  
I. Cecchi ◽  
S. G. Foddai ◽  
E. Rubini ◽  
...  
Keyword(s):  
Immune Response ◽  
Ischemic Stroke ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Antiphospholipid Syndrome ◽  
Missense Mutations ◽  
Literature Research ◽  
Missense Variants ◽  
Vein Thrombosis ◽  
Whole Exome

Background:Antiphospholipid Syndrome (APS) is an autoimmune disease whose precise aetiology is still unknown, but the high heterogeneity of its manifestations and clinical course is presumably due to the occurrence of different mechanisms and alterations at different levels and pathways [1]. The first genetic studies in APS focused primarily on the human leukocytes antigen system region, but more recent data highlighted a role of other genes in APS susceptibility, primarily those involved in the immune response and in the haemostatic process.Objectives:We aimed to deepen the investigation of APS genetic background starting from a case of familial APS, analysing two siblings with thrombotic APS (Table 1), both triple positive for antiphospholipid antibodies (aPL).Table 1.Main clinical and laboratory characteristics of the patients included in the study.PatientAgeaPL ProfileRelevant Clinical History1 (F)51Triple positive (LA, aCL IgG, aβ2GPI IgG)Two episodes of ischemic stroke, one episode of CAPS (renal thrombotic microangiopathy, visual impairment, ischemic stroke)2 (M)47Triple positive (LA, aCL IgG, aβ2GPI IgG)Three episodes of deep vein thrombosis, regardless ongoing well conducted therapy vitamin k antagonist and additional retinal vein thrombosisLA: lupus anticoagulant; aCL: anti-cardiolipin antibodies; aβ2GPI: anti- β2 glycoprotein I antibodies; CAPS: catastrophic APS.Methods:Genomic DNA was extracted from peripheral blood and the samples underwent Whole Exome Sequencing (WES). Sequencing was done on a 100X coverage, and reads have been aligned to the human reference genome (GRCh37/hg19 assembly) using the Burrows–Wheeler Alignment tool (BWA). The mean sequencing depth on target regions was 170X for patient 1, 205X for patient 2, moreover, 99.50% of the targeted bases had at least 10X coverage for all the three donors. The resulting single nucleotide polymorphisms (SNPs) have been analysed through a step-by-step process based on their frequency population (using Genome Aggregation Database), their predicted effects on the protein (using VarSome) and a literature research about the genes carrying them. Moreover, genes previously associated with a pro-thrombotic tendency and with APS have been analysed in the two patients.Results:Starting from more than 120000 SNPs for each patients, the analysis led to reduce the list of SNPs of interest to 27 missense mutations. The complete literature research regarding the genes carrying these mutations allowed to further reduce the number of selected genes, focusing on those that exert a role potentially involved in APS pathogenesis and development. In particular, these genes (PLA2G6, HSPG2, BCL3, ZFAT, ATP2B2, CRTC3 and ADCY3) take part in the immune response and the vascular homeostasis. The list of the DNA missense variants of interest found in our cases of familial APS is resumed in Figure 2.Figure 2.List of DNA missense variants of interest found in patient 1 and 2. Genes potentially involved in APS pathogenesis and development are highlighted in bold.No mutations on genes known to be associated with a pro-thrombotic state (F5, F2, MTHFR, F13A1, PROC, PROS1, FGB and SERPINE1), or on genes previously associated with APS (B2GPI, PF4V1, SELP, TLR2, TLR4, GP Ia, GP1BA, F2R, F2RL1, TFPI, F3, VEGFA, FLT1, and TNF) have been found in the WES analysis.Conclusion:To some extent, this can be seen as a proof of concept of the complexity of APS. Efforts to interpret the genetic risk factors involved in the heterogeneous clinical features of the syndrome, for instance, the integration of WES and network-based approaches might help to identify and stratify patients at risk of developing APS.References:[1]Iuliano A, Galeazzi M, Sebastiani GD. Antiphospholipid syndrome’s genetic and epigenetic aspects. Autoimmun Rev. 2019;18(9).Disclosure of Interests:None declared

scholarly journals A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

2021 ◽  
Author(s):  
Qing Li ◽  
Chengfeng Wang ◽  
Wei Li ◽  
Zaiqiang Zhang ◽  
Shanshan Wang ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Skin Biopsy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Collagen Type Iv ◽  
Lacunar Infarcts ◽  
Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

scholarly journals Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yahya Benbouchta ◽  
Imane Cherkaoui Jaouad ◽  
Habiba Tazi ◽  
Hamza Elorch ◽  
Mouna Ouhenach ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Symptoms ◽  
Age Of Onset ◽  
Novel Mutation ◽  
Corneal Dystrophy ◽  
Heterozygous Mutation ◽  
Large Variability ◽  
Whole Exome ◽  
Moroccan Family

Abstract Background Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, noninflammatory bilateral corneal diseases that are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths in the cornea. Clinical symptoms revealed bilateral multiple superficial, epithelial, and stromal anterior granular opacities in different stages of severity among three patients of this family. A total of 99 genes are involved in CDs. The aim of this study was to identify pathogenic variants causing atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with severely different stages of evolution. Case presentation In this study, we report a large Moroccan family with CD. Whole-exome sequencing (WES) was performed in the three affected members who shared a phenotype of corneal dystrophy in different stages of severity. Variant validation and familial segregation were performed by Sanger sequencing in affected sisters and mothers and in two unaffected brothers. Whole-exome sequencing showed a novel heterozygous mutation (c.1772C > A; p.Ser591Tyr) in the TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities in different stages of severity among three patients in this family. Conclusions This report describes a novel mutation in the TGFBI gene found in three family members affected by different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy; therefore, it could be considered a novel phenotype genotype correlation, which will help in genetic counselling for this family.

scholarly journals Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Qin Xiang ◽  
Lamei Yuan ◽  
Yanna Cao ◽  
Hongbo Xu ◽  
Yunfeiyang Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Transforming Growth Factor ◽  
Corneal Dystrophy ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Type I ◽  
Whole Exome ◽  
The Family

Background/Aims. Corneal dystrophies (CDs) belong to a group of hereditary heterogeneous corneal diseases which result in visual impairment due to the progressive accumulation of deposits in different corneal layers. So far, mutations in several genes have been responsible for various CDs. The purpose of this study is to identify gene mutations in a three-generation Hui-Chinese family associated with granular corneal dystrophy type I (GCD1). Methods. A three-generation Hui-Chinese pedigree with GCD1 was recruited for this study. Slit-lamp biomicroscopy, optical coherence tomography, and confocal microscopy were performed to determine the clinical features of available members. Whole exome sequencing was performed on two patients to screen for potential disease-causing variants in the family. Sanger sequencing was used to test the variant in the family members. Results. Clinical examinations demonstrated bilaterally abundant multiple grayish-white opacities in the basal epithelial and superficial stroma layers of corneas of the two patients. Whole exome sequencing revealed that a heterozygous missense mutation (c.1663C > T, p.Arg555Trp) in the transforming growth factor beta-induced gene (TGFBI) was shared by the two patients, and it cosegregated with this disease in the family confirmed by Sanger sequencing. Conclusions. The results suggested that the heterozygous TGFBI c.1663C > T (p.Arg555Trp) mutation was responsible for GCD1 in the Hui-Chinese family, which should be of great help in genetic counseling for this family.

scholarly journals Whole-Exome Sequencing Identifies an Intronic Cryptic Splice Site in SERPINF1 Causing Osteogenesis Imperfecta Type VI

JBMR Plus ◽  
2018 ◽  
Vol 2 (4) ◽  
pp. 235-239 ◽  
Author(s):  
Zixue Jin ◽  
Lindsay C Burrage ◽  
Ming-Ming Jiang ◽  
Yi-Chien Lee ◽  
Terry Bertin ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Site ◽  
Osteogenesis Imperfecta Type ◽  
Cryptic Splice Site ◽  
Whole Exome

scholarly journals Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei

2019 ◽  
Author(s):  
Mei Sim Lung ◽  
Catherine A. Mitchell ◽  
Maria A. Doyle ◽  
Andrew C. Lynch ◽  
Kylie L. Gorringe ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Site ◽  
Pseudomyxoma Peritonei ◽  
Loss Of Function ◽  
Site Mutation ◽  
Germline Variants ◽  
Missense Variants ◽  
Whole Exome ◽  
Mucinous Tumours

Abstract Background Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. Materials and Methods Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. Results Seventeen novel variants in 17 genes were shared by the father and daughter: a nonsense mutation in REEP5 , an essential splice site mutation in THOP1 , and 15 missense variants. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes ( EXOG , RANBP2, RANBP6 and TNFRSF1B ) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic PMP; no LoF or rare missense germline variants were identified. Conclusion Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.

scholarly journals Identification of Novel ADGRV1 and KCNC2 Variants Using Whole-Exome Sequencing in Two Colombian Patients with Usher and Encephalopathy Syndromes

2021 ◽  
Author(s):  
Estephania Candelo ◽  
Lorena Diaz-Ordoñez ◽  
Rafael Pacheco ◽  
Emelina Ruiz ◽  
Harry Pachajoa
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Usher Syndrome ◽  
Epileptic Encephalopathy ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Epilepsy Syndrome ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Excellent Method

Abstract Introduction: Usher syndrome has a broad phenotypic and genotypic spectrum. Developmental and epileptic encephalopathy-52 (DEE52) is a sever autosomal recessive seizure disorder that is characterized by infantile onset of refractory seizures, consequently resulting in delayed global development. This study aimed to describe the clinical features and to investigate the four variants identified in a Colombian family with Usher syndrome and KCNC2 encephalopathy syndrome.Methods and Results: We present a case of a family with two clinically relevant phenotypes: a mother with a compound heterozygous mutation causing Usher Syndrome, type IIC (USH2C) and her 15-year-old son who carried one heterozygous variant in the KCNC2 gene (p.P470S) and two cis mutations (p.V2927I and p.Q4955EfsTer10) in the ADGRV1 gene segregated from his mother, and a second non-disrupted allele. Owing to this, the boy did not present with USH2C but presented a developmental epilepsy syndrome. His younger sibling was unaffected, although he did inherit the trans mutation in a single pathogenic allele from his mother.Discussion and Conclusion: Whole-exome sequencing helps detect genes related to known and novel hearing loss and seizure syndrome. However, familiar segregation studies are an excellent method to clarify genotype-phenotype correlation in families, where multiple genes of clinically relevant have been identified. This method helps determine the genotype-phenotype relationship of a disease, which is associated with the clinical presentation and determines the pathogenicity of variants that are classified as variants of uncertain clinical significance.

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