Molecular characterization of 11 novel mutations in patients with heterozygous and homozygous FV deficiency
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Abstract:
Summary. Coagulation factor V (FV) has an important role in the blood coagulation cascade, in both the pro‐ and anticoagulant pathways. FV deficiency is a rare bleeding disorder with variable phenotypic expression. We report a cohort of 10 patients with mild‐severe FV deficiency in whom a total of 11 novel mutations were identified. Three patients were compound heterozygous for two mutations, whereas each of the remaining patients had a single heterozygous variant. FV levels did not correlate with either the type of mutation identified or the bleeding diathesis exhibited by the patients. Although considered to have an autosomal recessive mode of inheritance, patients with a single missense mutation may present with a significant bleeding history. The addition of a significant number of previously unidentified mutations to the public domain will contribute to the knowledge and understanding of the molecular pathology of this rare disorder.Keywords:
Bleeding diathesis
Compound heterozygosity
Heterozygote advantage
Nonsense mutation
Coagulation cascade
Friedreich's ataxia is a neurodegenerative disorder associated with a GAA trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene. It is the most common autosomal recessive cerebellar ataxia, with a mean age of onset at 16 years. Nearly 95-98% of patients are homozygous for a 90-1300 GAA repeat expansion with only 2-5% demonstrating compound heterozygosity. Compound heterozygous individuals have a repeat expansion in one allele and a point mutation/deletion/insertion in the other. Compound heterozygosity and point mutations are very rare causes of Friedreich's ataxia and nonsense mutations are a further rarity among point mutations. We report a rare compound heterozygous Friedrich's ataxia patient who was found to have one expanded GAA FXN allele and a nonsense point mutation in the other. We summarize the four previously published cases of nonsense mutations and compare the phenotype to that of our patient. We compared clinical information from our patient with other nonsense FXN mutations reported in the literature. This nonsense mutation, to our knowledge, has only been described once previously; interestingly the individual was also of Cuban ancestry. A comparison with previously published cases of nonsense mutations demonstrates some common clinical characteristics.
Nonsense mutation
Compound heterozygosity
Nonsense
Frataxin
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Objective: To investigate the prevalence and analyze the clinical hematological data of β-thalassemia(β-thal) CD41-42 (-TCTT) heterozygote(β41-42 heterozygote) compound deletional α-thal in this area. Methods: α-thal genes and β-thal genes were detected by single-tube complex PCR and reverse dot blotting(RDB), respectively. The analysis of blood corpuscle and the other thal screening tests were generally used. Results : 8 cases were identified to compound with α-thal in 144 β 41-42 heterozygote cases, including 7 cases (4.9%) compound α-thal-1(αα/-- SEA ) and 1 case(0.69%) compound deletional HbH gene(-α 3.7 /-- SEA ). The MCV of the 7 cases compoundα-thal-1 were all higher than the average MCV (63.53fl) of the 136 β 41-42 heterozygote cases. The HbH section couldn't be found in the case which compounds the HbH gene by the pH8.6 and the pH 6.5 Hemoglobin electrophoresis method. Conclusions: We can't only depend on the clinical symptoms and the routine lab examination results on diagnosing the β 41-42 heterozygote compound α-thal patients.
Compound heterozygosity
Heterozygote advantage
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Fibrillin
Compound heterozygosity
Heterozygote advantage
Ectopia lentis
Dominance (genetics)
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Abstract Homozygosity for the C282Y mutation in the HFE gene is strongly associated with hereditary hemochromatosis. More than one subject out of 10 in the general population is a heterozygote for the C282Y mutation. In this study, we address whether or not conclusions drawn from HLA‐based family studies regarding the expression of heterozygous hemochromatosis are applicable to C282Y heterozygotes. The correlation between HLA‐inferred and HFE genotypes and the variation of serum iron tests according to HFE genotype and other factors were studied in persons from well‐characterized hemochromatosis pedigrees. Subjects were tested for both C282Y and H63D mutations. The following factors were studied: age, sex, alcohol consumption, body mass index, liver function tests, serum lipids and glucose, serum iron, transferrin saturation, and ferritin. HLA‐inferred heterozygotes were C282Y heterozygotes in only 70% and compound heterozygotes (i.e., heterozygotes for both C282Y and H63D) in 20%. C282Y heterozygotes did not differ from wild type homozygotes in terms of serum iron tests. Only compound heterozygotes presented with slightly increased transferrin saturation. On the other hand, increased serum ferritin was strongly associated with overweight or lipidic or glucose abnormalities. C282Y heterozygotes selected from family studies do not have greater serum iron tests than wild type homozygotes, except for compound heterozygotes, and therefore should not require special followup. The discovery of abnormal iron tests in a C282Y heterozygote should lead to workup for other causes of iron overload. © 2002 Wiley‐Liss, Inc.
Heterozygote advantage
Compound heterozygosity
Transferrin saturation
Hereditary hemochromatosis
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Nonsense mutation
Compound heterozygosity
Heterozygote advantage
Nonsense
Congenital muscular dystrophy
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The −50 (G>A) (HBB: c.-100G>A) mutation was first reported as a β-thalassemia (β-thal) allele in a Chinese family. However, the hematological features of carriers with this variant are not available. In this study, we present the hematological data associated with −50 (G>A) to determine its phenotype. During a 4-year period, eight simple heterozygotes and three double heterozygotes for the −50 mutation and α-thalassemia (α-thal) were included. The simple heterozygotes had normal hematological parameters. The double heterozygotes had the hematological findings of simple α-thal heterozygotes. Two subjects with a compound heterozygosity for −50 and β-thal were also found, and both had typical hematological parameters of β-thal trait. Therefore, we present evidence that −50 (G>A) is likely a silent β-thal allele. Compound heterozygotes for −50/β-thal had no phenotype of severe β-thal. This information might be helpful in genetic counseling for couples in thalassemia high-prevalence areas.
Heterozygote advantage
Compound heterozygosity
Hemoglobinopathy
Beta thalassemia
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Abstract Objective Mutations of the gap junction beta 2 (GJB2) gene coding for the protein connexin 26 account for up to 50% of nonsyndromic sensorineural hearing loss (NSHL), with specific mutations associated with distinct ethnic groups. A biracial family with nonsyndromic sensorineural deafness consistent with autosomal recessive inheritance was examined for connexin 26 (Cx26) mutations. Study Design Prospective observational study. Methods A family consisting of a Caucasian mother and a Chinese father with two of six children affected by NSHL was examined for Cx26 mutations. Peripheral blood lymphocyte DNA was used to amplify by polymerase chain reaction the Cx26 coding region, followed by mutation detection enhancement gel screening and complete sequencing. Phenotypic characterization using audiometric testing was completed for all children and both parents. Results The two affected children were found to be compound heterozygotes for Cx26 mutations, displaying a previously unreported combination of 35delG and 235delC. The parents were each unaffected heterozygotes consistent with their ethnic heritage, specifically, the Caucasian mother a 35delG heterozygote and the Chinese father a 235delC heterozygote. Conclusions Connexin 26 mutations account for a significant proportion of NSHL worldwide, with specific mutations linked to distinct ethnic groups. Genetic analysis of a biracial family with NSHL revealed a novel 35delG/235delC compound heterozygous state in phenotypically affected children. These results highlight the usefulness of Cx26 mutation screening for genetic counseling and suggest that the 235delC mutation is present in China as it is in Japan and Korea.
Compound heterozygosity
Heterozygote advantage
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Objective:To perform prenatal diagnosis in a pregnancy with a fetus at-risk for SEA HPFH deletion and β-thalassemia.Methods:PCR-reverse dot blot and long-range PCR methods were used to determine the genotype in the at-risk fetus.Results:The father was revealed to be a heterozygote for the codons 41-42(-TTCT) mutation,the mother a heterozygote for SEA HPFH deletion and the fetus a heterozygote for the codons 41-42(-TTCT) mutation.Conclusions:For pregnant women whose fetuses are at-risk for a compound heterozygote of SEA HPFH deletion and β-thalassemia,prenatal diagnosis should be done.
Compound heterozygosity
Heterozygote advantage
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Compound heterozygosity
Heterozygote advantage
Transferrin saturation
Hereditary hemochromatosis
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Objective:To examine clinical characteristics of heterozygote and double heterozygote of three rare mutations [Hb Constants Spring(Hb CS),Hb Westmead(Hb WS) and Hb Quong Sze(Hb QS)] among alpha-thalassemia patients in Guangxi province, China. Methods:135 alpha-thalassemia patients, and 40 controls, were included in this study. Routine examination of blood and hemoglobin electrophoresis were performed. The alpha-thalassemia mutations were detected using Gap-PCR and reverse dot-blotting. Results: There were no clinical symptoms in three heterozygote groups and the double heterozygote group of αCSα/αWSα. MCV and MCH in the heterozygote group of Hb QS were significantly lower than those in other heterozygote groups(Hb CS and Hb WS)(P0.05). However,there was mild clinical symptoms in the double heterozygote group of αCSα/αQSα, while MCV and MCH were also significantly lower than those in other heterozygote groups(Hb CS and Hb WS)(P 0.05). Conclusions: The heterozygote Hb CS,heterozygote Hb WS and double heterozygote αCSα/αWSα are the silent carrier in clinical manifestations, the heterozygote Hb QS is the thalassemia trait, and the double heterozygote αCSα/αQSα is similar to the HbH disease. It is important to note this variability of clinical manifestations of those double heterozygotes in genetic consultation.
Heterozygote advantage
Compound heterozygosity
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