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Compound Heterozygosity (compound + heterozygosity)
Selected AbstractsCompound heterozygosity of Hb DIran (,22 Glu,Gln) and ,0 -thalassemia (619 bp-deletion) in IndiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2007Meenal G. Agrawal Abstract The present report describes the hematologic and molecular study of the second case of Hb DIran associated with ,0 -thalassemia (619 bp-deletion) found in India and the first case in which the mutations have been identified at molecular level. The patient showed hypochromic, microcytic red cell picture with reduced red cell indices. The characterization of the hemoglobinopathy was made by electrophoretic and chromatographic techniques and confirmed by sequencing of the beta-globin gene. Both the propositus and her father were found to be carriers of the gene for ,0 -thalassemia owing to the 619 bp-deletion mutation as seen by the polymerase chain reaction (PCR). Single base substitution GAA > CAA (indicative of Hb DIran) in the heterozygous form was seen in the propositus as well as the mother by sequencing. [source] Compound heterozygosity of two missense mutations in the NADH-cytochrome b5 reductase gene of a Polish patient with type I recessive congenital methaemoglobinaemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2003Dorota Grabowska Abstract: A case of type I methaemoglobinaemia observed in a Polish subject with compound heterozygosity for two mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) gene is described. One is a novel mutation 647T,C which leads to substitution of isoleucine by threonine at position 215 (I215T). This maternal mutation was found in several family members. A previously known mutation, 757G,A, leads to the replacement of valine by methionine at position 252 (V252M). The latter mutation was found also in the father and one of the two brothers. The effects of these mutations were analysed on a model of the human b5R protein obtained by homology modelling. Although both amino acid substitutions are located in the NADH-binding domain, the whole protein structure, especially the region between the flavin adenine dinucleotide and NADH-binding domains, is disturbed. The structural changes in the I215T mutant are less prominent than those in the V252M mutant. We presume that the 647T,C mutation is a type I mutation, however, it has not been observed in the homozygous state. [source] Compound heterozygosity in sibling patients with recessive dystrophic epidermolysis bullosa associated with a mild phenotypeINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 3 2006Y. Shibusawa MD We describe two cases of a 3-year-old Japanese boy and his 1-year-old sister presenting recessive dystrophic epidermolysis bullosa; a relatively mild phenotype. Blistering and scarring were limited to the acral region, and some fingernails and toenails were lost. PCR-RFLP and DNA sequencing analyses revealed compound heterozygotes for a splice-site mutation (6573 +1GtoC) and a nonsense mutation (E2857X) in the type VII collagen gene (COL7A1). Both mutations caused a premature termination codon (PTC). The mutation E2857X was located behind the candidate cleavage site within the NC-2 domain required for the assembly of anchoring fibrils. This PTC position may explain their mild phenotype. [source] Compound heterozygosity of non-deletional hereditary persistence of fetal hemoglobin and ,,-thalassemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2008Angelos Kalamaras No abstract is available for this article. [source] Prenatal diagnosis of oculocutaneous albinism type II and novel mutations in two Chinese familiesPRENATAL DIAGNOSIS, Issue 6 2007Li Hongyi Abstract Objective The prenatal genetic diagnosis and counseling of oculocutaneous albinism type II (OCA2) by detecting mutations in the OCA2 gene Methods DNA samples were extracted from peripheral whole blood and amniocentesis-derived cells. Polymerase chain reaction and automatic sequence analysis were used to screen the OCA2 gene. Results Case 1: Two novel heterozygous mutations (p.N476D and p.Y827H) in the P gene were detected in the proband. Molecular prenatal diagnosis on fetal DNA revealed N476D. The pregnancy progressed uneventfully to a normal outcome. Case 2: Mutation analysis of the DNA of family 2 revealed compound heterozygosities for two novel P gene mutations (p.N476D and p.G775R). The pregnant female and the fetus each presented with a single P gene mutation (p.V443I and G775R, respectively). The pregnancy was continued. Conclusion This is the first report of prenatal diagnosis performed in families with oculocutaneous albinism type II (OCA2). Also, this report reveals three novel mutations of the P gene. Copyright © 2007 John Wiley & Sons, Ltd. [source] Triose phosphate isomerase deficiency associated with two novel mutations in TPI geneEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2010Elisa Fermo Abstract We report the clinical, haematological and molecular characteristics of two triose phosphate isomerase deficient patients affected by haemolytic anaemia and neuromuscular impairment. The sequence of complete TPI gene showed the presence of two previously undescribed mutations: c.722 T>C (Phe240Ser) and c.28 insG; each of the two unrelated patients showed the new mutation in compound heterozygosity with the most common variant Glu104Asp. The association of Glu104Asp with c.28 insG resulted in a very severe clinical pattern. [source] ,-thalassaemia masked by , gene defects and a new polyadenylation site mutation on the ,2-globin geneEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Cornelis L. Harteveld Abstract We report three examples of chronic anaemia involving complex combinations of ,- and ,-globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [,26(B8)Glu,Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different ,2 polyadenylation site mutations masked by a ,-thalassaemia heterozygosity. The third had an intermediate ,-thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [,6(A3)Glu,Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed. [source] Compound heterozygosity of two missense mutations in the NADH-cytochrome b5 reductase gene of a Polish patient with type I recessive congenital methaemoglobinaemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2003Dorota Grabowska Abstract: A case of type I methaemoglobinaemia observed in a Polish subject with compound heterozygosity for two mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) gene is described. One is a novel mutation 647T,C which leads to substitution of isoleucine by threonine at position 215 (I215T). This maternal mutation was found in several family members. A previously known mutation, 757G,A, leads to the replacement of valine by methionine at position 252 (V252M). The latter mutation was found also in the father and one of the two brothers. The effects of these mutations were analysed on a model of the human b5R protein obtained by homology modelling. Although both amino acid substitutions are located in the NADH-binding domain, the whole protein structure, especially the region between the flavin adenine dinucleotide and NADH-binding domains, is disturbed. The structural changes in the I215T mutant are less prominent than those in the V252M mutant. We presume that the 647T,C mutation is a type I mutation, however, it has not been observed in the homozygous state. [source] Functional characterization of compound heterozygosity for GlyR,1 mutations in the startle disease hyperekplexiaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2002Ruth Rea Abstract The human disease hyperekplexia is characterized by excessive startle reactions to auditory and cutaneous stimuli. In its familial form, hyperekplexia has been associated with both dominant and recessive mutations of the GLRA1 gene encoding the glycine receptor ,1 subunit (GlyR,1), which mediates inhibitory transmission in the spinal cord and brainstem. Here we have examined the functional consequences of two amino acid substitutions found in a compound heterozygous family, R252H and R392H, to investigate the mechanisms determining this inheritance pattern. When expressed in Xenopus laevis oocytes, both mutations were non-functional. Neither mutant affected the electrophysiological properties of wild type GlyR,1 when co-expressed. We introduced a green fluorescent protein tag to mutant subunits and found that both mutant proteins were detectable. Evidence that subcellular localization differed from wild type was significant for one of the mutants. Thus, an effective loss of functional GlyR,1-mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic. [source] ALys amyloidosis caused by compound heterozygosity in Exon 2 (Thr70Asn) and Exon 4 (Trp112Arg) of the lysozyme gene,,HUMAN MUTATION, Issue 1 2006Christoph Röcken Abstract Hereditary amyloidoses are caused by germline mutations, which increase the propensity of a protein to form cross-, aggregates and deposit as amyloid. Hereditary amyloidoses are particularly interesting as they help to understand how changes in the primary structure of an otherwise non-amyloidogenic protein contribute to amyloidogenesis. Here we report on a novel form of systemic ALys amyloidosis, caused by compound heterozygosity in exon 2 (p.T70N) and exon 4 (p.W112R) of the lysozyme gene (LYZ), with both mutations being present on the same allele. This type of hereditary ALys amyloidosis is characterized by extended amyloid deposits in the upper gastrointestinal tract, entire colon, and kidney, leading to gastrointestinal bleeding. Both mutations are probably effective in disease manifestation. The novel mutation at position 112 in the mature protein is located within the ,-helical domain of the protein and therefore outside the cluster of residues that has so far been implicated in ALys amyloidosis. Taken together with the p.T70N mutation, this results in a lysozyme species where the correct folding of various protein domains is probably impaired and increases the propensity of amyloid fibril formation. Interestingly, this form of ALys amyloidosis is also characterized by the occurrence of proteolytic fragments of lysozyme in the amyloid deposits. © 2005 Wiley-Liss, Inc. [source] Unique epidermolytic bullous dermatosis with associated lethal cardiomyopathy related to novel desmoplakin mutationsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 5 2009Angeliki Asimaki Background:, Desmoplakin plays a vital role in cell adhesion, linking the transmembrane desmosomal complex to the cytoskeletal network. Clues to the biological significance of desmoplakin have emerged from the embryonic lethal phenotype of null mice and from naturally occurring human desmoplakin mutations, which cause cardiocutaneous phenotypes. Index case:, In this study, we describe a child who presented with the unique constellation of bullous dermatosis, profound plantar keratoderma, alopecia totalis and cardiomyopathy leading to sudden cardiac death at the age of 9 years. Results:, This complex cardiocutaneous phenotype is associated with compound heterozygosity for two novel nonsense desmoplakin mutations. Histological examination of a plantar skin biopsy showed full thickness epidermal acantholysis with superimposed spongiosis, hyperorthokeratosis and focal parakeratosis. Immunohistochemistry and quantitative confocal microscopy showed abnormal tissue distribution and reduced levels of expression for plakoglobin, desmoplakin and connexin 43 at epidermal junctional sites. Conclusions:, Interpretation of the changes in the context of the two mutations provides insight into the mechanism of clinical cell adhesion disease. [source] Analysis of haemochromatosis gene mutations in a population from the Mediterranean BasinLIVER INTERNATIONAL, Issue 4 2001Salvatore Campo Abstract:Background/Aims: The C282Y mutation in the haemochromatosis gene (HFE) located on chromosome 6 has been identified as the main genetic basis of hereditary haemochromatosis (HH). Two more mutations of that gene, H63D and S65C, appear to be associated with milder forms of HH. A high allele frequency for C282Y and H63D mutations was reported in populations from North Europe, while incomplete information is available for individuals from the Mediterranean Basin where C282Y homozygotes comprise a smaller percentage of HH cases. In this study we investigated the allele frequency of HFE mutations and the association between HFE mutations and cases of HH in a population from the South of Italy (Sicily and Calabria). In addition, we evaluated a possible association between HFE mutations and either chronic liver disease or type II diabetes. Patients and Methods: Three hundred and twenty-seven individuals (654 chromosomes) were tested for C282Y, H63D and S65C mutations of the HFE gene by restriction fragment length polymorphism. Four had HH, 23 had hepatocellular carcinoma, 100 had chronic liver disease, 100 had type II diabetes, and 100 were healthy controls. Results: Both C282Y and S65C mutations were each detected in one of the 654 chromosomes analysed (allele frequency=0.15%), while H63D change was found in 122 chromosomes (allele frequency=18.6%) and was equally distributed in all the categories examined. One healthy individual had compound heterozygosity for C282Y and H63D mutations. The frequency of C282Y in this Southern Italian sample was the lowest yet reported for a population of European origin. None of the four HH patients was either homozygous or heterozygous for C282Y. Conclusions: In Mediterranean populations from Southern Italy the C282Y mutation occurs sporadically and HFE polymorphisms seem to have little diagnostic relevance. [source] Tumor suppressor gene Co-operativity in compound Patched1 and suppressor of fused heterozygous mutant miceMOLECULAR CARCINOGENESIS, Issue 5 2009Jessica Svärd Abstract Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1+/, mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu+/, mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu+/,Ptch1+/, mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu+/,Ptch1+/, compared to Sufu+/, female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu+/,Ptch1+/, compared to Ptch1+/, female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu+/,Ptch1+/, mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in ,20% of the Ptch1+/, and Sufu+/,Ptch1+/, but not in Sufu+/, mice. Interestingly, most of the medulloblastomas from the Sufu+/,Ptch1+/, mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1+/, and Sufu+/,Ptch1+/, mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway. © 2008 Wiley-Liss, Inc. [source] Friedreich's ataxia with chorea and myoclonus caused by a compound heterozygosity for a novel deletion and the trinucleotide GAA expansionMOVEMENT DISORDERS, Issue 3 2002Danqing Zhu PhD Abstract Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting about 1 in 50,000 individuals. It is caused by mutations in the frataxin gene; 98% of cases have homozygous expansions of a GAA trinucleotide in intron 1 of the frataxin gene. The remaining 2% of patients are compound heterozygotes, who have a GAA repeat expansion in one allele and a point mutation in the other allele. FRDA patients with point mutation have been suggested to have atypical clinical features. We present a case of compound heterozygotes in a FRDA patient who has a deletion of one T in the start codon (ATG) of the frataxin gene and a GAA repeat expansion in the other allele. The patient presented with chorea and subsequently developed FRDA symptoms. The disease in this case is the result of both a failure of initiation of translation and the effect of the expansion. This novel mutation extends the range of point mutations seen in FRDA patients, and also broadens the spectrum of FRDA genotype associated with chorea. © 2002 Movement Disorder Society [source] Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemiaPRENATAL DIAGNOSIS, Issue 3 2006Wim J. Kleijer Abstract Background In the course of 25 years, we have experienced a high rate of affected fetuses in the prenatal diagnosis of citrullinemia. Methods and Results Ninety-one pregnancies at 1 in 4 risk were tested; 36 were diagnosed as affected (39.5%; P = 0.0015). The high rate of positive diagnoses was found both after chorionic villus sampling (24/68 = 35.3%) and amniocentesis (12/23 = 52.2%) despite the completely different and independent techniques used. Using exactly the same (indirect) enzyme assay for argininosuccinic aciduria on chorionic villi and a similar method on amniotic fluid, the expected rate of affected fetuses was found: 13/53 = 24.5%. Technical and genetic causes for the unexpected results were excluded by confirmatory studies performed on independent fetal material, which was available for 27 of the 36 fetuses affected with citrullinemia. Biochemical confirmation was obtained in the 27 cases, whereas in 18 fetuses homozygosity or compound heterozygosity for disease-causing mutations were retrospectively demonstrated in the stored fetal cells. Conclusion The results suggest the occurrence of preferential transmission of the mutant allele. An explanation for this phenomenon may be found in a protective role of argininosuccinic acid synthetase deficiency in mutant sperm cells against the possibly detrimental or apoptotic effect of nitric oxide produced normally from arginine by nitric oxide synthase. Copyright © 2006 John Wiley & Sons, Ltd. [source] Smith-Lemli-Opitz syndrome: New mutation with a mild phenotypeAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2002Chitra Prasad Abstract Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man, OMIMÔ, 2001, http://www.ncbi.nlm.nih.gov/omim/ for SLOS, MIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3,-hydroxysterol ,7 -reductase gene, DHCR7. We report on a female infant with an exceptionally mild phenotype of SLOS, in whom molecular studies identified a new mutation in DHCR7. The proposita initially presented with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2,3 syndactyly of her toes in both feet. The plasma cholesterol was borderline low at 2.88 mmol/L (normal 2.97,4.40 mmol/L). Elevated plasma 7-dehydrocholesterol level of 200.0 ,mol/L confirmed the clinical diagnosis of SLOS. Molecular analysis demonstrated compound heterozygosity for IVS8-1G ,C and Y280C, a new missense mutation in DHCR7. Since the other mutation in this patient is a known null mutation, this newly discovered mutation is presumably associated with significant residual enzyme activity and milder expression of clinical phenotype. © 2002 Wiley-Liss, Inc. [source] High-resolution Melting Facilitates Mutation Screening of PYGM in Patients with McArdle DiseaseANNALS OF HUMAN GENETICS, Issue 3 2009Morten Duno Summary Mutations in PYGM, encoding the muscle-specific glycogen phosphorylase (myophosphorylase), are responsible for McArdle disease. Among Caucasians, a large proportion of patients are homozygous for the R50X mutation, but other mutations can affect all the 20 exons of PYGM, making mutation detection laborious. We have developed a high-resolution melting (HRM) assay for mutation detection in PYGM. Twelve McArdle patients were investigated, in whom pre-screening had ruled out homozygosity or compound heterozygosity for the two common G205S and R50X mutations. In total, we identified 16 different variations. Thirteen of these are pathogenic, and three were classified as polymorphisms. Nine variations had not previously been described. One of the novel mutations, c.2430C > T, was initially predicted to result in a silent G810G change, but cDNA analysis demonstrated that the mutation led to abnormal mRNA processing. The HRM protocol reduced the need for direct sequencing by approximately 85%, and is a good approach to search for new mutations in PYGM. [source] Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith,Lemli,Opitz syndromeANNALS OF HUMAN GENETICS, Issue 3 2001P. E. JIRA Smith,Lemli,Opitz syndrome (SLOS) is caused by mutations in the DHCR7 gene leading to deficient activity of 7-dehydrocholesterol reductase (DHCR7; EC 1.3.1.21), the final enzyme of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursor 7-dehydrocholesterol in plasma and tissues. We here report mutations identified in the DHCR7 gene of 13 children diagnosed with SLOS by clinical and biochemical criteria. We found a high frequency of the previously described IVS8,1 G > C splice acceptor site mutation (two homozygotes, eight compound heterozygotes). In addition, 13 missense mutations and one splice acceptor mutation were detected in eleven patients with a mild to moderate SLOS-phenotype. The mutations include three novel missense mutations (W182L, C183Y, F255L) and one novel splice acceptor site mutation (IVS8,1 G > T). Two patients, homozygous for the IVS8,1 G > C mutation, presented with a severe clinical phenotype and died shortly after birth. Seven patients with a mild to moderate SLOS-phenotype disclosed compound heterozygosity of the IVS8,1 G > C mutation in combination with different novel and known missense mutations. [source] Combined factors V and VIII deficiency (F5F8D) in a Chinese family due to compound heterozygosity for nonsense mutations of the LMAN1 geneBRITISH JOURNAL OF HAEMATOLOGY, Issue 3 2007Edmond S. K. Ma No abstract is available for this article. [source] Compound heterozygous mutations in the , -glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factorsBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2004Simone Rost Summary Hereditary combined deficiency of the vitamin K-dependent coagulation factors II, VII, IX, X, protein C, S and protein Z (VKCFD) is a very rare autosomal recessive inherited bleeding disorder. The phenotype may result from functional deficiency of either the , -glutamyl carboxylase (GGCX) or the vitamin K epoxide reductase (VKOR) complex. We report on the third case of VKCFD1 with mutations in the , -glutamyl carboxylase gene, which is remarkable because of compound heterozygosity. Two mutations were identified: a splice site mutation of exon 3 and a point mutation in exon 11, resulting in the replacement of arginine 485 by proline. Screening of 100 unrelated normal chromosomes by restriction fragment length polymorphism and denaturing high-performance liquid chromatography analysis excluded either mutation as a frequent polymorphism. Substitution of vitamin K could only partially normalize the levels of coagulation factors. It is suggested that the missense mutation affects either the propeptide binding site or the vitamin K binding site of GGCX. [source] Acute inflammatory demyelinating polyradiculoneuropathy associated with perforin-deficient familial haemophagocytic lymphohistiocytosisACTA PAEDIATRICA, Issue 3 2003E Del Giudice This study reports the first paediatric case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) associated with a fatal haemophagocytic lymphohistiocytosis (HLH). The patient developed progressive weakness of the lower limbs in the context of a picture of infectious mononucleosis and Epstein-Barr virus (EBV) infection. After an apparent improvement, a fulminant hepatic failure and pancytopenia ensued, leading to death. Molecular genetic studies documented a compound heterozygosity for two mutations in the perforin (PRF1) gene as the background defect for a familial haemophagocytic lymphohistiocytosis (FHL). Conclusion: In this patient EBV infection triggered both AIDP and FHL. The latter condition was due to PRF1 deficiency. Two novel mutations in the PRF1 gene were concomitantly present in the patient. The first caused an amino acid change, while the second introduced a stop codon in the sequence which resulted in a truncated protein. [source] | |||||||||||||||||||||||||