scholarly journals The dynamic mutation investigation and whole exome sequencing in a cohort of Chinese autosomal dominant cerebellar ataxia patients

2020 ◽  
Author(s):  
Fang Peng ◽  
Yue Zhang ◽  
Xin-Yue Zhou ◽  
Shuai-Qi Huang ◽  
Chen Chen ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Cerebellar Ataxia ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Autosomal Dominant Cerebellar Ataxia ◽  
Spinocerebellar Ataxias ◽  
Dynamic Mutation ◽  
Whole Exome ◽  
Dynamic Mutations

Abstract Background Spinocerebellar ataxias (SCAs) are the autosomal dominant cerebellar ataxia (ADCA) with great clinical and genetic heterogeneity. Genetic testing will contribute to the final diagnosis. Methods A total of 204 Chinese ADCA patients were recruited and 190 had genetic testing. Dynamic mutations of SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) were screened firstly. For the patients with negative results, the dynamic mutations of HTT of Huntington Disease (HD), SCA31, 36 and even the whole exome sequencing (WES) were further performed. We investigated the genetic results and clinical characteristics retrospectively. Results Among these 190 index cases, 177(93.16%) were identified SCA dynamic mutations. SCA3 was the commonest, accounting for 70.06%, followed by SCA1 (9.6%), 2 (9.05%), 12 (3.39%), 6 (2.26%), DRPLA (2.26%), 7(1.13%), 8 (1.13%) and 17(0.56%). One patient carried a compound dynamic mutation of SCA6 and SCA17 (SCA6/17). No SCA10 or SCA36 was found. Among the remaining 13 patients, three were diagnosed with HD (1.58%) and one with Episodic Ataxia 2 (EA2). WES did reveal several variants with uncertain significance (VUS) in the remaining nine patients, but failed to detect causative mutations. Conclusion We illustrated the approach and challenge of genetic testing in Chinese ADCA patients. Dynamic mutations of SCAs should be screened firstly. When the results were negative, dynamic mutation of HTT would better be screened consequently. In early-onset ADCA patients, WES might be effective to identify causative mutations, but in adult-onset cases, WES might be less effective.

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 Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Stephanie M Ware ◽  
Steven E Lipshultz ◽  
Steven D Colan ◽  
Ling Shi ◽  
Charles E Canter ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Whole Exome ◽  
Pediatric Cardiomyopathy ◽  
History Of

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.

scholarly journals Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ahra Cho ◽  
Jose Ronaldo Lima de Carvalho ◽  
Akemi J. Tanaka ◽  
Ruben Jauregui ◽  
Sarah R. Levi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome

P0066KIDNEYCODE: A GENETIC TESTING PROGRAM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Prasad Devarajan ◽  
Geoffrey Block ◽  
Keisha Gibson ◽  
Jim McKay ◽  
Colin Meyer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Genetic Testing ◽  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Alport Syndrome ◽  
Polycystic Kidney ◽  
Accuracy And Precision ◽  
Whole Exome

Abstract Background and Aims Knowledge about genetic causes of chronic kidney disease (CKD) is one of the key gaps in global kidney research and recent International Society of Nephrology recommendations encourage the adoption of genetic testing to enable a goal of providing precision medicine based on individual risk (1). A recent whole-exome sequencing study showed that genetic inheritance may be responsible for up to 10% of CKD diagnoses, many of which may be previously undiagnosed or mis-diagnosed (2). Continued advances in DNA sequencing technology have made genetic testing, even whole-exome sequencing, applicable to routine clinical diagnoses. In order to test the hypothesis that genetic testing can provide valuable information to increase the accuracy and precision of diagnosis in CKD, we designed a gene panel to prospectively provide genetic testing in a subset of patients with CKD defined by a specific set of inclusion criteria. Method Reata Pharmaceuticals is partnering with Invitae on a program called KidneyCode, which provides no-charge genetic testing to enable diagnosis of three specific rare monogenic causes of CKD: Alport syndrome (AS), autosomal dominant polycystic kidney disease (ADPKD) due to PKD2 mutations, and focal segmental glomerulosclerosis (FSGS), as well as detection of variants in one of the autosomal recessive polycystic kidney disease gene, PKHD1. Invitae’s renal disease panel includes 17 genes (ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, and TRPC6), and its assay includes both full-gene sequencing and intragenic deletion/duplication analysis using next-generation sequencing (NGS). The assay targets the coding exons and flanking 10bp of intronic sequences. Invitae’s method of variant classification uses a systematic process for assessing evidence based on guidelines published by the American College of Medical Genetics (3). Patients in the US at risk for hereditary CKD (eGFR ≤ 90 mL/min/1.73m2 plus hematuria or a family history of CKD) or with a known diagnosis of AS or FSGS are eligible. Family members of those with suspected or known AS or FSGS are also eligible. All participants in the KidneyCode program have access to genetic counseling follow-up at no additional charge. Results In the first five months of the KidneyCode program, 152 genetic tests have been completed. A genetic variant was reported in 87 patients. Of those 87 patients, 67 patients had 75 variants in COL4A3, 4, or 5 genes (34 Pathogenic/Likely Pathogenic (P/LP), 41 Variants of Uncertain Significance (VUS)), 20 patients had 24 variants in genes associated with FSGS (3 P/LP, 21 VUS), 15 patients had 20 variants in PKHD1 (1 P/LP, 19 VUS), and 2 patients had variants in PKD2 (1 P/LP, 1 VUS). Of the 34 patients with Pathogenic or Likely Pathogenic COL4A variants, 19 reported a previous diagnosis of Alport syndrome. Other diagnoses in patients with COL4A mutations included FSGS, thin basement membrane disease, and familial hematuria. Extra-renal manifestations such as hearing loss and eye disease were reported in 7 of the 34 patients with COL4A variants. Conclusion Initial results with the KidneyCode panel demonstrate the utility of NGS and support the hypothesis that combining genetic testing with clinical presentation and medical history can significantly improve accuracy and precision of diagnosis in patients with hereditary CKD.

Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness

2018 ◽  
Vol 94 (5) ◽  
pp. 419-428 ◽  
Author(s):  
X. Lu ◽  
Q. Wang ◽  
H. Gu ◽  
X. Zhang ◽  
Y. Qi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Pathogenic Variant ◽  
Whole Exome

scholarly journals Clinical and Molecular Characterization of Qatari Patients with Inherited Dysfibrinogenemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1037-1037
Author(s):  
Amna Gameil ◽  
Hajer Al-Mulla ◽  
Aliaa Amer ◽  
Tawfeg Ben-Omran ◽  
Mohamed A Yassin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Clinical Phenotype ◽  
Pathogenic Mutation ◽  
Functional Assay ◽  
Sequencing Analysis ◽  
Thrombin Time ◽  
Whole Exome ◽  
Antigen Assay

Abstract Background and Objectives: Inherited Dysfibrinogenemia is a rare functional fibrinogen disorder in which the fibrinogen protein is present but with a reduced function. Fibrinogen is a 340-kDa glycoprotein that is encoded by three genes namely: Fibrinogen Bb (FGB), Aa (FGA), and g (FGG). The disorder is characterized by a wide spectrum of clinical phenotypes, ranging from asymptomatic to mild- to-severe bleeding or thrombotic manifestations and recurrent miscarriages. The mode of inheritance is mostly autosomal dominant manner and frequently as a result of a point mutation in FGA (Arg35) and FGG (Arg301). The laboratory diagnosis is based on discrepancy between fibrinogen antigen (detected by immunoassay or by immuno-turbidimetric assay) and functional assay (detected by Clauss method or other clot-based assays). The disorder is often associated with prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT).Fibrinogen activity is reduced by Clauss method while the antigen assay remains normal. The management is directed towards prevention of bleeding with prophylactic fibrinogen concentrates or cryoprecipitate prior to invasive procedures, surgeries or delivery. Dysfibrinogenemia is a rare disorder yet it is very prevalent in Qatar as a result of high rate of consanguineous marriages. The aim of our study is to describe the clinical phenotype in relation to genotype in this cohort. Methods We conducted a retrospective analysis of 23 patients with Inherited Dysfibrinogenemia reported by our center from 2015 to 2020 . Patients with a positive family of history fibrinogen disorder and abnormal coagulation screen, low functional fibrinogen assay (by Clauss method) or normal antigen level by turbidimetry were included. Whole exome sequencing (WES) was performed on the proband case which detected a likely pathogenic mutation that was tested on subsequent cases. We diagnosed our patients with Inherited Dysfibrinogenemia based on both coagulation-based assays and molecular tests. Probable Inherited Dysfibrinogenemia was considered in patients where the molecular test or antigen assay were not performed. To assess the clinical phenotype, data was collected that included; age at diagnosis, gender, bleeding and thrombotic events as well as coagulation screening. (Table 1) Results 23 patients who were described in this cohort belong to the same tribe. 74% (17 o/23) were female and only 41% (7/17) reported an obstetric bleeding (postpartum or post abortion) and one reported mild bleeding that occurred in the postmenopausal period and no previous bleeding (case#19). The median age of diagnosis was 28.8 years (5-69) for the females. All male cases in the cohort were detected either during routine screening or prior to surgery with no previous history of bleeding. No thrombotic events were observed in this cohort. Genetic Analysis Following proper genetic counseling and informed consent, whole exome sequencing analysis (WES) was performed on the index case which included testing of the fibrinogen genes FGA, FGB and FGG. WES revealed a likely pathogenic mutation in the FGA gene (p. Arg35His (R35H) (CGT>CAT): c.104 G>A in exon 2)-Located within the cleavage site of fibrinopeptide A by thrombin (The UniProt Consortium, 2017), which is a mutational hotspot. This result is likely consistent with the diagnosis of Dysfibrinogenemia. Conclusion The FGA R35H mutation is considered a probable recurrent variant in a large tribe in the Qatari population and is associated with late onset mild bleeding manifestations in minority of cases . Despite the fact that the reported tribe is highly consanguineous, the R35H mutation behaved in an autosomal dominant manner rather than recessive in this cohort.Further studies to assess phenotype - genotype correlation of Dysfibrinogenemia is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals SAT-LB310 A Mysterious Multiple Endocrine Neoplasia (MEN) Like Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Myat Han Soe ◽  
cheng cheng ◽  
Chienying Liu
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Adrenal Mass ◽  
Multiple Endocrine Neoplasia ◽  
Hypertensive Crisis ◽  
Common Finding ◽  
Endocrine Tumors ◽  
Endocrine Neoplasia ◽  
Whole Exome

Abstract Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands in a single patient. Among the four MEN syndromes, MEN4 due to CDKN1B mutation is characterized by parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. We presented a patient with MEN 4 like syndrome without CDKN1B, menin or RET mutations. 74 year old male was diagnosed with acromegaly and primary hyperparathyroidism at age 63. Genetic testing revealed no mutations in menin and RET genes. At age 68, he was diagnosed with renal cell carcinoma (RCC) and at age 70, 2cm left adrenal mass was identified on surveillance computerized tomography (CT). No biochemical workup was pursued. Four years later, he developed hypertensive crisis during spine surgery at our institution. Workup revealed elevated plasma metanephrine (490 pg/ml, normal <57) and normetanephrine (1333 pg/ml, normal <148). CT showed the left adrenal mass increased in size to 4.5 cm. Family history is negative for any endocrine tumors. He underwent repeat genetic testing. Analyses of 133 gene panel reported no germline mutations in menin, RET, CDKN1B, NF12, VHL, SDH and other genes tested but there were variants of uncertain significance (VUS) identified in CHEK2 c.14C>T (p.Ser5Leu) and PTCH2 c.2812G>A (p.Gly938Ser). Patient successfully underwent left adrenalectomy after alpha blockage. Paired tumor-normal sequencing of the resected tumor detected a pathogenic deletion frameshift mutation in NF1 with loss of heterozygosity (LOH) along with copy number alterations with losses in 1p34.1-p11.2, 11p11.2-15.4, 11q14.1-q25 and 17q11.2 (including NF1). VUSs were also detected including CDKN1A C117Y variant, and CHD2P80L. Since germline and tumor testing failed to reveal any known pathogenic variants, whole exome sequencing (pending) will be pursued. The presentation with RCC, pheochromocytoma, pituitary adenoma and parathyroid adenoma is consistent with a MEN syndrome in this patient despite no known pathogenic MEN mutations detected. Somatic mutation in NF1 is a common finding in pheochromocytoma. The biochemical phenotype of pheochromocytoma (elevated metanephrines) is consistent with cluster 2 tumors of kinase signaling pathway as seen in tumors of MEN syndrome and neurofibromatosis. We hope to gain more insight via whole exome sequencing to evaluate for potential novel gene mutation(s).

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