Clinical features and genetic defect in six index patients with congenital fibrinogen disorders: Three novel mutations with one common mutation in Taiwan's population

Abstract Abstract 1047 Hereditary hemochromatosis (HH) is a genetic disorder in which hyperabsorption of dietary iron leads to accumulation of iron in multiple tissues including liver and heart. A common clinical manifestation in HH patients is cirrhosis and hepatocellular carcinoma as a result of iron-mediated injury in liver. The most prevalent genetic defect for HH is the failure to up-regulate hepcidin, a peptide hormone that inhibits the absorption of iron in duodenum and the release of iron from intracellular iron storage such as macrophages. Mutations in a number of genes have been identified as the cause for HH, including hepcidin itself. However, the most common mutation is C282Y mutation in HFE, which is a positive regulator for hepcidin expression. C282Y mutation represents about 85% of the HH population. HFE C282Y HH is an autosomal recessive disease with a ∼50% penetrance. Currently, the only treatment available for iron overload is phlebotomy which will continue throughout the patient's life. Hepcidin is mainly expressed and secreted by the liver and its expression is regulated predominantly at the transcription level. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor for hepcidin expression. It's been demonstrated that hepcidin expression is significantly elevated in Tmprss6−/− mice and reduction of TMPRSS6 in Hfe−/− mice could ameliorate the iron overload phenotype (Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg KE et al., Blood, 2011). Using second generation antisense technology, we identified antisense oligonucleotides (ASOs) targeting mouse TMPRSS6 for the treatment of HH. These compounds were first identified through in vitro screens in mouse primary hepatocytes. After 4 weeks of treatment in C57BL/6 mice on normal chow, we observed an 80% to 90% reduction of liver TMPRSS6 mRNA with a subsequent 2–3 fold induction of liver hepcidin mRNA. Serum iron and transferrin saturation levels were reduced by ∼50%. These ASOs are currently being evaluated in a diet-induced iron overload model and an Hfe−/− iron overload model. Our preliminary results demonstrate that targeting TMPRSS6 is a viable approach for the treatment of hereditary hemochromatosis and possibly other iron-loading diseases associated with suppressed hepcidin levels. Disclosures: Booten: Isis Pharmaceuticals: Employment. Knox:Isis Pharmaceuticals: Summer Intern. Alvarado:Isis Pharmaceuticals: Employment. Guo:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment.

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Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations

Clinical Endocrinology ◽

10.1111/j.1365-2265.2006.02635.x ◽

2006 ◽

Vol 65 (5) ◽

pp. 606-610 ◽

Cited By ~ 84

Author(s):

Alberto Ferlin ◽

Cinzia Vinanzi ◽

Andrea Garolla ◽

Riccardo Selice ◽

Daniela Zuccarello ◽

...

Keyword(s):

Androgen Receptor ◽

Male Infertility ◽

Clinical Features ◽

Receptor Gene ◽

Gene Mutations ◽

Androgen Receptor Gene ◽

Novel Mutations

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Malonyl-CoA decarboxylase deficiency: Long-term follow-up of a patient new clinical features and novel mutations

Brain and Development ◽

10.1016/j.braindev.2014.02.001 ◽

2015 ◽

Vol 37 (1) ◽

pp. 107-113 ◽

Cited By ~ 8

Author(s):

Padmini P. Polinati ◽

Leena Valanne ◽

Tiina Tyni

Keyword(s):

Clinical Features ◽

Novel Mutations ◽

Malonyl Coa ◽

Long Term Follow Up ◽

Decarboxylase Deficiency

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The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients

Frontiers in Endocrinology ◽

10.3389/fendo.2021.728043 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mengge Yang ◽

Lusi Xu ◽

Chunmei Xu ◽

Yuying Cui ◽

Shan Jiang ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Features ◽

Peripheral Blood ◽

Common Mutation ◽

Mitochondrial Mutations ◽

China National Knowledge Infrastructure ◽

Mitochondrial Diabetes ◽

Onset Of Diabetes ◽

Spearman Test ◽

Inherited Diabetes

AimsTo investigate the clinical features and mitochondrial mutations for maternally inherited diabetes and deafness.MethodsPubMed, Embase, Medline, Web of Science, the China National Knowledge Infrastructure, and Wanfang were searched with the following search terms: “Maternally inherited diabetes and deafness” OR “MIDD” OR “Mitochondrial diabetes”. The mutations and clinical features were analyzed. Correlation between the heteroplasmy levels of the m.3243A>G mutation in the peripheral blood and age at the onset of diabetes was conducted by Spearman test. The significance level was set as p < 0.05. Statistical analysis was performed using the Statistical Package for the Social Sciences version 26 for Windows.ResultsTotally 161 patients with 21 different mitochondrial mutations were enrolled. The most common mutation was the m.3243A>G mutation in 136 cases. Of 142 patients, 120 (84.51%) had family histories of diabetes or hearing loss. Hearing loss presented in 85.71% of the patients with mitochondrial mutations. Central nervous system diseases were found in 29.19%, myopathy in 22.98%, oculopathy in 23.60%, cardiac disease in 23.60%, and nephropathy in 13.66% of the patients. Forty-two of 101 (41.58%) patients were underweight. A significant negative correlation was found between the heteroplasmy levels of the m.3243A>G mutation in the peripheral blood and age at the onset of diabetes.ConclusionsThe young onset of diabetes with low or normal BMI, maternal inheritance, and presence of impairments of multiple systems should prompt a genetic testing in order to differentiate MIDD from other types of diabetes earlier.

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Whole Exome Sequencing Identifies Three Novel Mutations in the ASPM Gene From Saudi Families Leading to Primary Microcephaly

Frontiers in Pediatrics ◽

10.3389/fped.2020.627122 ◽

2021 ◽

Vol 8 ◽

Author(s):

Muhammad Imran Naseer ◽

Angham Abdulrahman Abdulkareem ◽

Osama Yousef Muthaffar ◽

Sameera Sogaty ◽

Hiba Alkhatabi ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Frameshift Mutation ◽

Genetic Defect ◽

Deletion Mutation ◽

Primary Microcephaly ◽

Novel Mutations ◽

Whole Exome ◽

Novel Variants ◽

Healthy Control

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental defect that is characterized by reduced head circumference at birth along with non-progressive intellectual disability. Till date, 25 genes related to MCPH have been reported so far in humans. The ASPM (abnormal spindle-like, microcephaly-associated) gene is among the most frequently mutated MCPH gene. We studied three different families having primary microcephaly from different regions of Saudi Arabia. Whole exome sequencing (WES) and Sanger sequencing were done to identify the genetic defect. Collectively, three novel variants were identified in the ASPM gene from three different primary microcephaly families. Family 1, showed a deletion mutation leading to a frameshift mutation c.1003del. (p.Val335*) in exon 3 of the ASPM gene and family 2, also showed deletion mutation leading to frameshift mutation c.1047del (p.Gln349Hisfs*18), while in family 3, we identified a missense mutation c.5623A>G leading to a change in protein (p.Lys1875Glu) in exon 18 of the ASPM gene underlying the disorder. The identified respective mutations were ruled out in 100 healthy control samples. In conclusion, we found three novel mutations in the ASPM gene in Saudi families that will help to establish a disease database for specified mutations in Saudi population and will further help to identify strategies to tackle primary microcephaly in the kingdom.

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Abstract 2249: Overlap Between LQT3 and Brugada Syndrome: Clinical Features in a Common Mutation and Underlying Biophysical Mechanisms

Circulation ◽

10.1161/circ.116.suppl_16.ii_490-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Naomasa Makita ◽

Elijah Behr ◽

Wataru Shimizu ◽

Minoru Horie ◽

Lia Crotti ◽

...

Keyword(s):

Clinical Features ◽

Brugada Syndrome ◽

Sinus Node ◽

Sinus Node Dysfunction ◽

Common Mutation ◽

Wild Type ◽

Biophysical Properties ◽

Long Qt ◽

Negative Shift ◽

Mutation Carriers

Introduction: Features of the Brugada syndrome (BrS) have been sporadically reported in type-3 long QT syndrome (LQT3). However, it is not clear whether such phenotypic overlap is determined by the biophysical properties of the mutant channel, or by other factors such as co-inherited genetic variations, gender, or ethnicity. To address this question, we report here the clinical features and biophysical properties of a single SCN5A mutation, E1784K, identified in multiple families of diverse ethnicities. Methods and Results: Among 37 LQT3 families (Asian 20, Caucasian 17) enrolled in 6 referral centers, 11 (30%) were carriers of E1784K, with a total of 33 mutation carriers (15 men, 18 women, 26±20 years; mean±SD). Two probands were the victims of sudden cardiac death. The LQT3 phenotype was highly penetrant: 30/33 (90.9%) mutation carriers had abnormally long QT intervals (carriers: QTc= 484±32 ms, n=33; non-carriers: QTc= 402±31 ms, n=21; p<0.001; mean±SD). In addition, 13/33 carriers (39%) showed sinus node dysfunction, and a diagnosis of BrS was established in 7/33. Four of five carriers exhibited coved-type ST elevation after class IC drug challenge. E1784K channels heterologously expressed in tsA201 cells in the presence of β 1 subunit showed late Na current characteristic of LQT3. In addition, E1784K displayed properties seen with other mutations sporadically reported to generate a mixed clinical phenotype (1795insD, ΔKPQ, ΔK1500): a large (−15.0 mV) negative shift in the voltage-dependence of inactivation (V 1/2 : wild type= −86.8±1.1 mV, n=25; E1784K= −101.8±1.3 mV, n=17; p<0.001, mean±SE), and a marked (7.5-fold) increase in flecainide affinity for rested channels (IC 50 : wild type= 150.3 μM, E1784K= 20.4 μM). These properties are not reported with T1304M, an LQT3 mutation that has not been associated with BrS. Conclusions: E1784K is a highly prevalent SCN5A mutation in different ethnicities, producing LQT3 as well as BrS and sinus node dysfunction. In vitro studies suggest that a negative shift of steady-state inactivation and enhanced channel inhibition at rest by class IC drugs identify LQT3 mutations that can generate such a mixed phenotype. Class IC drugs should be avoided in patients with LQT3 mutations displaying these behaviors.

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Beta Thalassemia In Different Tribal Population In West Bengal, India

Blood ◽

10.1182/blood.v116.21.5170.5170 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5170-5170

Author(s):

Deboshree Majumdar ◽

Jayasri Basak ◽

Abhijit Chakraborty ◽

Soma Mukhopadhyay ◽

Nabamita Pal ◽

...

Keyword(s):

West Bengal ◽

Conflicts Of Interest ◽

Globin Gene ◽

Genetic Defect ◽

Beta Thalassemia ◽

Dihydrogen Phosphate ◽

Common Mutation ◽

Beta Globin ◽

Beta Globin Gene ◽

North Bengal

Abstract Abstract 5170 Background: The Thalassemias are a group of anemia that results from a genetic defect whch reduces the rate of synthesis of normal globin chains. Beta Thalassemia results in severe microcytic, hypochromic, haemolytic anaemia among affected patients. It has emerged as one of the most common health problems among the tribal populations in West Bengal. A project entitled, “Status of Prevalence and Awarness Among Thalassaemia Population: Special reference to various tribes belonging in different Districts of West Bengal” has been sanctioned by the Department of Biotechnology, Govt. of India(BT/PR10336/SPD/24/293/2007). This study is aimed to observe the spectrum of various beta mutations among the tribes. In the screening schedule thalassemia awarness programme was conducted in various rural areas of West Bengal. We mainly confronted with the Sardar tribes in extreme south of West Bengal. In North Bengal there were Toto, Rabha, Oraon, Munda, Toppo, Baraik, Nagbanshi, Khalko, Kheria, Kerketta and Soren. Method: In the year 2009–2010, 1289 tribes were screened. Mass awarness programme were followed by collection of peripheral blood samples in EDTA vials and transported to the laboratory in ice packs. NESTROFT was done on spot using 0.36% Saline Buffer solution (Sodium chloride, Sodium dihydrogen phosphate, Disodium hydrogen Phosphate). Complete Blood Count was performed within 24 hours of collection. HPLC (High Performance Liquid Chromatography) was done to identify the beta samples. DNA was extracted from the blood of beta carrier and beta major and subjected to ARMS (Amplification Refractory Mutation System) PCR (Polymerase Chain Reaction) to detect the point mutations. Result: Conclusion: Molecular Characterization of Beta globin gene mutations among these tribes have confirmed the presence of the following mutations: IVS-1 nt5 (G>C), IVS-1 nt1(G>T), codon 15 (G>A), codon 26 (G>A), the mutation which leads to HbE, codon 19 (A>G), codon 17 (A>T), -28 (A>G). The most common mutation observed among Totos and Rabhas were codon 26 (G>A) of North Bengal. The prevalence of Beta carrier among them is negligible. The mutation IVS-1 nt5 (G>C) is prevalent among the Oraon, Nagbanshi and Sardar tribes of Bengal. The other mutations which are present among them are codon 15 (G>A) and codon 30 (G>C). There are two codon 17 (A>T) and one -28 (A>G) mutations which are present among Mundas. The rest of them are mutation IVS-1 nt5 (G>C). In few cases presence of sickle cell anemia was observed. Our results have added to the existing data on the common beta globin gene defects which are prevalent among the general population of West Bengal, India. Disclosures: No relevant conflicts of interest to declare.

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Facioscapulohumeral Dystrophy

Physical Therapy ◽

10.2522/ptj.20070104 ◽

2008 ◽

Vol 88 (1) ◽

pp. 105-113 ◽

Cited By ~ 41

Author(s):

Shree Pandya ◽

Wendy M King ◽

Rabi Tawil

Keyword(s):

Muscular Dystrophy ◽

Natural History ◽

Myotonic Dystrophy ◽

Clinical Features ◽

Genetic Defect ◽

Duchenne Dystrophy ◽

Current Management ◽

Facioscapulohumeral Dystrophy ◽

The Third

Facioscapulohumeral dystrophy (FSHD) is the third most common inherited muscular dystrophy after Duchenne dystrophy and myotonic dystrophy. Over the last decade, major advances have occurred in the understanding of the genetics of this disorder. Despite these advances, the exact mechanisms that lead to atrophy and weakness secondary to the genetic defect are still not understood. The purposes of this article are to increase awareness of FSHD among clinicians; to provide an update regarding the genetics, clinical features, natural history, and current management of FSHD; and to discuss opportunities for research.

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