Vip Viprakasit | Mahidol University (original) (raw)

Papers by Vip Viprakasit

Research paper thumbnail of Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

Research paper thumbnail of Haemoglobin Hope in a northern Thai family: first identification of homozygous haemoglobin Hope associated with haemoglobin H disease

European Journal of Haematology, 2007

Haemoglobin (Hb) Hope [beta136(H14)Gly--&... more Haemoglobin (Hb) Hope [beta136(H14)Gly-->Asp(GGT-->GAT)] is one of the unstable haemoglobin variants of the beta-globin chain, which is demonstrated in people of various ethnic backgrounds. Here we report a Thai female patient with clinical thalassaemia intermedia since childhood. This patient had experienced neither blood transfusion nor hospitalisation. Hb Bart's-H and a large amount of Hb Hope were identified by high-performance liquid chromatography (HPLC) assay and the diagnosis of homozygous Hb Hope was definitely achieved by direct sequencing of exon 3 of beta-globin gene. Furthermore, we could identify that her brother carried the mutation of homozygous Hb Hope without abnormal alpha globin chain involvement, and another family member had heterozygous Hb Hope in association with -alpha(3.7) mutation, and both of them were clinically silent.

Research paper thumbnail of De novo deletion within the telomeric region flanking the human alpha globin locus as a cause of alpha thalassaemia

British journal of haematology, 2003

We have identified and characterized a Scottish individual with alpha thalassaemia, resulting fro... more We have identified and characterized a Scottish individual with alpha thalassaemia, resulting from a de novo 48 kilobase (kb) deletion from the telomeric flanking region of the alpha globin cluster which occurred as a result of recombination between two misaligned repetitive elements that normally lie approximately 83 kb and 131 kb from the 16p telomere. The deletion removes two previously described putative regulatory elements (HS-40 and HS-33) but leaves two other elements (HS-10 and HS-8) intact. Analysis of this deletion, together with eight other published deletions of the telomeric region, showed that they all severely downregulated alpha globin expression. Together they defined a 20.4-kb region of the human alpha cluster, which contains all of the positive cis-acting elements required to regulate alpha globin expression. Comparative analysis of this region with the corresponding segment of the mouse alpha globin cluster demonstrated conserved non-coding sequences correspondin...

Research paper thumbnail of Hemophagocytic lymphohistiocytosis following dengue hemorrhagic fever in Hb H/Hb Constant Spring patient

Pediatrics International, 2015

Infection-associated hemophagocytic syndrome (IAHS), a secondary form of hemophagocytic lymphohis... more Infection-associated hemophagocytic syndrome (IAHS), a secondary form of hemophagocytic lymphohistiocytosis (HLH), has been found following several types of infections and can be fatal. We report herein a case of IAHS following dengue infection in a 14-year-old patient with underlying α-thalassemia syndrome (non-deletional Hb H/Hb Constant Spring disease). He developed prolonged fever, thrombocytopenia, and progressive splenomegaly. Further investigations indicated hyperferritinemia, and increased reactive histiocytes with hemophagocytic activity in the bone marrow. He responded promptly to dexamethasone and i.v. immune globulin. Physicians should be aware of this condition, especially in countries where both dengue hemorrhagic fever and thalassemia are prevalent. The fatal outcome of IAHS can be prevented with prompt appropriate treatment.

Research paper thumbnail of Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

Research paper thumbnail of A normal reference of bone mineral density (BMD) measured by dual energy X-ray absorptiometry in healthy thai children and adolescents aged 5-18 years: a new reference for Southeast Asian Populations

PloS one, 2014

Ethnic-specific normative data of bone mineral density (BMD) is essential for the accurate interp... more Ethnic-specific normative data of bone mineral density (BMD) is essential for the accurate interpretation of BMD measurement. There have been previous reports of normative BMD data for Caucasian and Asian children including Japanese, Chinese, Korean and Indian. However, the normative BMD data for Southeast Asian including Thai children and adolescents are not currently available. The goals of our study were 1) to establish normative data of BMD, bone mineral content (BMC), bone area (BA) and lean body mass (LBM) for healthy Thai children and adolescents; aged 5-18 years measured by dual energy X-ray absorptiometry (DXA, Lunar Prodigy) and 2) to evaluate the relationships between BMD vs. age, sex, puberty, weight, height, calcium intake and the age of menarche in our population. Gender and age-specific BMD (L2-4; LS and total body; TB), BMADLS (apparent BMD of the lumbar spine), BMC (L2-4 and total body), BA (L2-4 and total body) and LBM were evaluated in 367 children (174 boys and 1...

Research paper thumbnail of Prevalence of HFE mutations among the Thai population and correlation with iron loading in haemoglobin E disorder

Co-inheritance of HFE mutations has a substantial role in iron overload in beta-thalassaemia carr... more Co-inheritance of HFE mutations has a substantial role in iron overload in beta-thalassaemia carriers in north European populations where two HFE mutations, C282Y and H63D, are prevalent. In Thailand, there was little information about the allele frequency of HFE mutations. It is of interest to determine whether such determinants represent a potential risk in developing iron overload as nearly 40% of the Thai population carry either one of thalassaemia or haemoglobinpathy alleles. A total of 380 normal controls from five different regions including Bangkok were screened for the HFE C282Y, H63D and IVS5+1 G-->A alleles. In addition, 70 individuals with homozygous haemoglobin E (Hb EE) were also tested and their genotypes were correlated with levels of serum ferritin. H63D is the major HFE mutation found in the Thai population with an average allele frequency of 3% (range 1-5%). One individual was heterozygous for the splice site mutation IVS5 + 1 G --> A, and the C282Y allele was not detected. In the Hb EE group, five individuals had iron deficiency (ferritin <12 microg/L) and the remaining 65 individuals had a wide range of serum ferritin levels of 16-700 microg/L. Four individuals with Hb EE were heterozygous for the H63D allele. No significant difference in serum ferritin level was detected in this group with or without the HFE mutation (137.2 +/- 78 vs. 116.3 +/- 128 microg/L). HFE mutations are relatively uncommon among the Thai population, and the average allele frequency of the ancient H63D mutation is similar to that of other countries in this region. Because of their paucity, it appears that these alleles are less likely to be responsible for high ferritin levels and iron loading in individuals with Hb E related disorders.

Research paper thumbnail of Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

Blood, Jan 6, 2014

In this study, we report on 8 compound heterozygotes for mutations in the key erythroid transcrip... more In this study, we report on 8 compound heterozygotes for mutations in the key erythroid transcription factor Krüppel-like factor 1 in patients who presented with severe, transfusion-dependent hemolytic anemia. In most cases, the red cells were hypochromic and microcytic, consistent with abnormalities in hemoglobin synthesis. In addition, in many cases, the red cells resembled those seen in patients with membrane defects or enzymopathies, known as chronic nonspherocytic hemolytic anemia (CNSHA). Analysis of RNA and protein in primary erythroid cells from these individuals provided evidence of abnormal globin synthesis, with persistent expression of fetal hemoglobin and, most remarkably, expression of large quantities of embryonic globins in postnatal life. The red cell membranes were abnormal, most notably expressing reduced amounts of CD44 and, consequently, manifesting the rare In(Lu) blood group. Finally, all tested patients showed abnormally low levels of the red cell enzyme pyru...

Research paper thumbnail of Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment

European journal of haematology, Jan 18, 2015

Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overlo... more Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade(®) ) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), pre-dose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n=1114), myelodysplastic syndromes (MDS, n=336) and sickle cell disease (SCD, n=80). Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in SCD patients, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised ...

Research paper thumbnail of Iron chelation therapy for non-transfusion-dependent thalassemia (NTDT): a status quo

Blood cells, molecules & diseases

Research paper thumbnail of A Regulatory SNP Causes a Human Genetic Disease by Creating a New Transcriptional Promoter

Research paper thumbnail of Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition

Proceedings of the National Academy of Sciences, 2009

Research paper thumbnail of IRON CHELATION THERAPY WITH DEFERASIROX (EXJADE®) IN REDUCING CARDIAC SIDEROSIS IN β-THALASSEMIA PATIENTS: 2-YEAR RESULTS FROM THE EPIC CARDIAC SUBSTUDY

Journal of the American College of Cardiology, 2010

Research paper thumbnail of Iron chelation therapy in the management of thalassemia: the Asian perspectives

International Journal of Hematology, 2009

Research paper thumbnail of Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox

International Journal of Hematology, 2011

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy a... more Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

Research paper thumbnail of Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis

Human Molecular Genetics, 2003

Research paper thumbnail of Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias

Research paper thumbnail of What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1?

Epidemiology and Infection, 2010

Research paper thumbnail of Molecular analysis of unknown β-globin gene mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique and its application in Thai families with β-thalassemias and β-globin variants

Clinical Biochemistry, 2005

Research paper thumbnail of ATR-X Syndrome Protein Targets Tandem Repeats and Influences Allele-Specific Expression in a Size-Dependent Manner

Cell, 2010

ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retarda... more ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRX mutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated.

Research paper thumbnail of Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

Research paper thumbnail of Haemoglobin Hope in a northern Thai family: first identification of homozygous haemoglobin Hope associated with haemoglobin H disease

European Journal of Haematology, 2007

Haemoglobin (Hb) Hope [beta136(H14)Gly--&... more Haemoglobin (Hb) Hope [beta136(H14)Gly-->Asp(GGT-->GAT)] is one of the unstable haemoglobin variants of the beta-globin chain, which is demonstrated in people of various ethnic backgrounds. Here we report a Thai female patient with clinical thalassaemia intermedia since childhood. This patient had experienced neither blood transfusion nor hospitalisation. Hb Bart's-H and a large amount of Hb Hope were identified by high-performance liquid chromatography (HPLC) assay and the diagnosis of homozygous Hb Hope was definitely achieved by direct sequencing of exon 3 of beta-globin gene. Furthermore, we could identify that her brother carried the mutation of homozygous Hb Hope without abnormal alpha globin chain involvement, and another family member had heterozygous Hb Hope in association with -alpha(3.7) mutation, and both of them were clinically silent.

Research paper thumbnail of De novo deletion within the telomeric region flanking the human alpha globin locus as a cause of alpha thalassaemia

British journal of haematology, 2003

We have identified and characterized a Scottish individual with alpha thalassaemia, resulting fro... more We have identified and characterized a Scottish individual with alpha thalassaemia, resulting from a de novo 48 kilobase (kb) deletion from the telomeric flanking region of the alpha globin cluster which occurred as a result of recombination between two misaligned repetitive elements that normally lie approximately 83 kb and 131 kb from the 16p telomere. The deletion removes two previously described putative regulatory elements (HS-40 and HS-33) but leaves two other elements (HS-10 and HS-8) intact. Analysis of this deletion, together with eight other published deletions of the telomeric region, showed that they all severely downregulated alpha globin expression. Together they defined a 20.4-kb region of the human alpha cluster, which contains all of the positive cis-acting elements required to regulate alpha globin expression. Comparative analysis of this region with the corresponding segment of the mouse alpha globin cluster demonstrated conserved non-coding sequences correspondin...

Research paper thumbnail of Hemophagocytic lymphohistiocytosis following dengue hemorrhagic fever in Hb H/Hb Constant Spring patient

Pediatrics International, 2015

Infection-associated hemophagocytic syndrome (IAHS), a secondary form of hemophagocytic lymphohis... more Infection-associated hemophagocytic syndrome (IAHS), a secondary form of hemophagocytic lymphohistiocytosis (HLH), has been found following several types of infections and can be fatal. We report herein a case of IAHS following dengue infection in a 14-year-old patient with underlying α-thalassemia syndrome (non-deletional Hb H/Hb Constant Spring disease). He developed prolonged fever, thrombocytopenia, and progressive splenomegaly. Further investigations indicated hyperferritinemia, and increased reactive histiocytes with hemophagocytic activity in the bone marrow. He responded promptly to dexamethasone and i.v. immune globulin. Physicians should be aware of this condition, especially in countries where both dengue hemorrhagic fever and thalassemia are prevalent. The fatal outcome of IAHS can be prevented with prompt appropriate treatment.

Research paper thumbnail of Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

Research paper thumbnail of A normal reference of bone mineral density (BMD) measured by dual energy X-ray absorptiometry in healthy thai children and adolescents aged 5-18 years: a new reference for Southeast Asian Populations

PloS one, 2014

Ethnic-specific normative data of bone mineral density (BMD) is essential for the accurate interp... more Ethnic-specific normative data of bone mineral density (BMD) is essential for the accurate interpretation of BMD measurement. There have been previous reports of normative BMD data for Caucasian and Asian children including Japanese, Chinese, Korean and Indian. However, the normative BMD data for Southeast Asian including Thai children and adolescents are not currently available. The goals of our study were 1) to establish normative data of BMD, bone mineral content (BMC), bone area (BA) and lean body mass (LBM) for healthy Thai children and adolescents; aged 5-18 years measured by dual energy X-ray absorptiometry (DXA, Lunar Prodigy) and 2) to evaluate the relationships between BMD vs. age, sex, puberty, weight, height, calcium intake and the age of menarche in our population. Gender and age-specific BMD (L2-4; LS and total body; TB), BMADLS (apparent BMD of the lumbar spine), BMC (L2-4 and total body), BA (L2-4 and total body) and LBM were evaluated in 367 children (174 boys and 1...

Research paper thumbnail of Prevalence of HFE mutations among the Thai population and correlation with iron loading in haemoglobin E disorder

Co-inheritance of HFE mutations has a substantial role in iron overload in beta-thalassaemia carr... more Co-inheritance of HFE mutations has a substantial role in iron overload in beta-thalassaemia carriers in north European populations where two HFE mutations, C282Y and H63D, are prevalent. In Thailand, there was little information about the allele frequency of HFE mutations. It is of interest to determine whether such determinants represent a potential risk in developing iron overload as nearly 40% of the Thai population carry either one of thalassaemia or haemoglobinpathy alleles. A total of 380 normal controls from five different regions including Bangkok were screened for the HFE C282Y, H63D and IVS5+1 G-->A alleles. In addition, 70 individuals with homozygous haemoglobin E (Hb EE) were also tested and their genotypes were correlated with levels of serum ferritin. H63D is the major HFE mutation found in the Thai population with an average allele frequency of 3% (range 1-5%). One individual was heterozygous for the splice site mutation IVS5 + 1 G --> A, and the C282Y allele was not detected. In the Hb EE group, five individuals had iron deficiency (ferritin <12 microg/L) and the remaining 65 individuals had a wide range of serum ferritin levels of 16-700 microg/L. Four individuals with Hb EE were heterozygous for the H63D allele. No significant difference in serum ferritin level was detected in this group with or without the HFE mutation (137.2 +/- 78 vs. 116.3 +/- 128 microg/L). HFE mutations are relatively uncommon among the Thai population, and the average allele frequency of the ancient H63D mutation is similar to that of other countries in this region. Because of their paucity, it appears that these alleles are less likely to be responsible for high ferritin levels and iron loading in individuals with Hb E related disorders.

Research paper thumbnail of Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

Blood, Jan 6, 2014

In this study, we report on 8 compound heterozygotes for mutations in the key erythroid transcrip... more In this study, we report on 8 compound heterozygotes for mutations in the key erythroid transcription factor Krüppel-like factor 1 in patients who presented with severe, transfusion-dependent hemolytic anemia. In most cases, the red cells were hypochromic and microcytic, consistent with abnormalities in hemoglobin synthesis. In addition, in many cases, the red cells resembled those seen in patients with membrane defects or enzymopathies, known as chronic nonspherocytic hemolytic anemia (CNSHA). Analysis of RNA and protein in primary erythroid cells from these individuals provided evidence of abnormal globin synthesis, with persistent expression of fetal hemoglobin and, most remarkably, expression of large quantities of embryonic globins in postnatal life. The red cell membranes were abnormal, most notably expressing reduced amounts of CD44 and, consequently, manifesting the rare In(Lu) blood group. Finally, all tested patients showed abnormally low levels of the red cell enzyme pyru...

Research paper thumbnail of Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment

European journal of haematology, Jan 18, 2015

Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overlo... more Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade(®) ) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), pre-dose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n=1114), myelodysplastic syndromes (MDS, n=336) and sickle cell disease (SCD, n=80). Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in SCD patients, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised ...

Research paper thumbnail of Iron chelation therapy for non-transfusion-dependent thalassemia (NTDT): a status quo

Blood cells, molecules & diseases

Research paper thumbnail of A Regulatory SNP Causes a Human Genetic Disease by Creating a New Transcriptional Promoter

Research paper thumbnail of Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition

Proceedings of the National Academy of Sciences, 2009

Research paper thumbnail of IRON CHELATION THERAPY WITH DEFERASIROX (EXJADE®) IN REDUCING CARDIAC SIDEROSIS IN β-THALASSEMIA PATIENTS: 2-YEAR RESULTS FROM THE EPIC CARDIAC SUBSTUDY

Journal of the American College of Cardiology, 2010

Research paper thumbnail of Iron chelation therapy in the management of thalassemia: the Asian perspectives

International Journal of Hematology, 2009

Research paper thumbnail of Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox

International Journal of Hematology, 2011

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy a... more Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

Research paper thumbnail of Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis

Human Molecular Genetics, 2003

Research paper thumbnail of Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias

Research paper thumbnail of What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1?

Epidemiology and Infection, 2010

Research paper thumbnail of Molecular analysis of unknown β-globin gene mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique and its application in Thai families with β-thalassemias and β-globin variants

Clinical Biochemistry, 2005

Research paper thumbnail of ATR-X Syndrome Protein Targets Tandem Repeats and Influences Allele-Specific Expression in a Size-Dependent Manner

Cell, 2010

ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retarda... more ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRX mutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated.