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Cornelis A Albers - One of the best experts on this subject based on the ideXlab platform.
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new insights into the genetic basis of TAR thrombocytopenia absent radii Syndrome
Current Opinion in Genetics & Development, 2013Co-Authors: Cornelis A Albers, Ruth Newburyecob, Willem H Ouwehand, Cedric GhevaertAbstract:Thrombocytopenia with absent radii (TAR) Syndrome is a rare disorder combining specific skeletal abnormalities with a reduced platelet count. Rare proximal microdeletions of 1q21.1 are found in the majority of patients but are also found in unaffected parents. Recently it was shown that TAR Syndrome is caused by the compound inheritance of a low-frequency noncoding SNP and a rare null allele in RBM8A, a gene encoding the exon-junction complex subunit member Y14 located in the deleted region. This finding provides new insight into the complex inheritance pattern and new clues to the molecular mechanisms underlying TAR Syndrome. We discuss TAR Syndrome in the context of abnormal phenotypes associated with proximal and distal 1q21.1 microdeletion and microduplications with incomplete penetrance and variable expressivity.
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effect of single nucleotide polymorphism in the gene rbm8a together with the microdeletion 1q21 in thrombocytopenia absent radii Syndrome
Blood, 2012Co-Authors: Harald Schulze, Cornelis A Albers, Kathleen Freson, Ruth Newburyecob, Gabriele Strauss, Janine Fiedler, Markus Schmugge, Willem H Ouwehand, Cedric GhaevertAbstract:Abstract 2372 Thrombocytopenia-absent radii Syndrome (TAR) is a rare congenital disorder characterized by bilateral radius aplasia and thrombocytopenia due to virtual absence of bone marrow megakaryocytes (MKs). As other blood lineages are not affected, TAR is considered to be a bone marrow failure Syndrome. At birth, platelet counts are often below 50/nL, but ameliorate in many patients during the first two years of life, however, without reaching the lower norm. Platelet reactivity in reponse to thrombopoietin is abrogated, mostly when patients are young while it is restored to normal in older patients. Interestingly, this patterning is not correlated with platelet counts. In 2007 we described a microdeletion on chromosome 1q21 in all patients analyzed as necessary, but not sufficient to cause TAR, as it was also present in unaffected family members. Using next generation sequencing, we recently identified the presence of one of two single nucleotide polymorphisms (SNPs) in non-coding, regulatory regions of the gene RBM8A whose compound inheritance together with the microdeletion causes TAR Syndrome (Nature Genetics, 44, 435). All patients inherited one of the two SNPs from one of one parents and the microdeletion from the other. In 25% of cases the microdeletion was acquired de novo. This gene, which is located within the microdeleted region, encodes for Y14, a major subunit of the exon junction complex. In the German/Swiss/Polish cohort of 28 patients, 20 patients had the more frequent SNP in the 5'UTR, whereas 8 patients had a previously undescribed SNP in intron 1. The 5'UTR G->A introduces a novel binding site for transcriptional repressor Evi1. This factor is expressed in megakaryocytes and still present in platelets. Using electrophoretic mobility shift assays (EMSA) with lysates from platelets we found a complex exclusively present when a labeled oligonucleotide with the 5'UTR-SNP G->C was used and not with the wildtype sequence. This complex could be partially supershifted with an anti-Evi1 antibody, suggesting that an additional factor might bind to this complex. In contrast, the intronic SNP is predicted to abrogate a binding site for Mzf1. We used EMSA with oligonucleotides of both intronic SNP and wildtype sequence and indeed found a complex binding to the wildtype sequence as well as to a consensus sequence for Mzf1, but no or reduced binding to the intronic SNP. This complex could not be supershifted by adding an anti-Mzf1 antibody. However, when nuclear extracts from Meg01 cells were used, we found that one of three subcomplexes showed reduced binding in the presence of the antibody, even when the intronic SNP was used. As both SNPs showed different binding properties we carefully evaluated clinical data and found that platelet counts were more severely reduced in patients with the 5'UTR compared to patients harboring the intronic SNP. Although case numbers for the intronic SNP are low, in a direct comparison of age-matched patients, platelet counts were always higher in TAR patients with the intronic SNP. However, we did not find any obvious differences in skeletal features between the two groups. Further work is ongoing to better understand the causative role of either SNP for impaired megakaryopoiesis and thrombocytopenia in TAR Syndrome. Disclosures: No relevant conflicts of interest to declare.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:Cornelis Albers, Cedric Ghevaert and colleagues report that a majority of thrombocytopenia with absent radii (TAR) Syndrome cases are caused by compound heterzygosity of a null allele and a low-frequency SNP in the regulatory regions of the RBM8A gene, which encodes the Y14 subunit of the exon-junction complex (EJC). TAR Syndrome is the first reported human disorder caused by a defect in an EJC component.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation Syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR Syndrome.
Peter A Smethurst - One of the best experts on this subject based on the ideXlab platform.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:Cornelis Albers, Cedric Ghevaert and colleagues report that a majority of thrombocytopenia with absent radii (TAR) Syndrome cases are caused by compound heterzygosity of a null allele and a low-frequency SNP in the regulatory regions of the RBM8A gene, which encodes the Y14 subunit of the exon-junction complex (EJC). TAR Syndrome is the first reported human disorder caused by a defect in an EJC component.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation Syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR Syndrome.
Harald Schulze - One of the best experts on this subject based on the ideXlab platform.
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impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii TAR Syndrome
British Journal of Haematology, 2017Co-Authors: Georgi Manukjan, Markus Schmugge, Gabriele Straus, Hendrik Bosing, Harald SchulzeAbstract:Thrombocytopenia absent radii (TAR) Syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR Syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5' untranslated region (5'UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR Syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5'UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5'UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR Syndrome.
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effect of single nucleotide polymorphism in the gene rbm8a together with the microdeletion 1q21 in thrombocytopenia absent radii Syndrome
Blood, 2012Co-Authors: Harald Schulze, Cornelis A Albers, Kathleen Freson, Ruth Newburyecob, Gabriele Strauss, Janine Fiedler, Markus Schmugge, Willem H Ouwehand, Cedric GhaevertAbstract:Abstract 2372 Thrombocytopenia-absent radii Syndrome (TAR) is a rare congenital disorder characterized by bilateral radius aplasia and thrombocytopenia due to virtual absence of bone marrow megakaryocytes (MKs). As other blood lineages are not affected, TAR is considered to be a bone marrow failure Syndrome. At birth, platelet counts are often below 50/nL, but ameliorate in many patients during the first two years of life, however, without reaching the lower norm. Platelet reactivity in reponse to thrombopoietin is abrogated, mostly when patients are young while it is restored to normal in older patients. Interestingly, this patterning is not correlated with platelet counts. In 2007 we described a microdeletion on chromosome 1q21 in all patients analyzed as necessary, but not sufficient to cause TAR, as it was also present in unaffected family members. Using next generation sequencing, we recently identified the presence of one of two single nucleotide polymorphisms (SNPs) in non-coding, regulatory regions of the gene RBM8A whose compound inheritance together with the microdeletion causes TAR Syndrome (Nature Genetics, 44, 435). All patients inherited one of the two SNPs from one of one parents and the microdeletion from the other. In 25% of cases the microdeletion was acquired de novo. This gene, which is located within the microdeleted region, encodes for Y14, a major subunit of the exon junction complex. In the German/Swiss/Polish cohort of 28 patients, 20 patients had the more frequent SNP in the 5'UTR, whereas 8 patients had a previously undescribed SNP in intron 1. The 5'UTR G->A introduces a novel binding site for transcriptional repressor Evi1. This factor is expressed in megakaryocytes and still present in platelets. Using electrophoretic mobility shift assays (EMSA) with lysates from platelets we found a complex exclusively present when a labeled oligonucleotide with the 5'UTR-SNP G->C was used and not with the wildtype sequence. This complex could be partially supershifted with an anti-Evi1 antibody, suggesting that an additional factor might bind to this complex. In contrast, the intronic SNP is predicted to abrogate a binding site for Mzf1. We used EMSA with oligonucleotides of both intronic SNP and wildtype sequence and indeed found a complex binding to the wildtype sequence as well as to a consensus sequence for Mzf1, but no or reduced binding to the intronic SNP. This complex could not be supershifted by adding an anti-Mzf1 antibody. However, when nuclear extracts from Meg01 cells were used, we found that one of three subcomplexes showed reduced binding in the presence of the antibody, even when the intronic SNP was used. As both SNPs showed different binding properties we carefully evaluated clinical data and found that platelet counts were more severely reduced in patients with the 5'UTR compared to patients harboring the intronic SNP. Although case numbers for the intronic SNP are low, in a direct comparison of age-matched patients, platelet counts were always higher in TAR patients with the intronic SNP. However, we did not find any obvious differences in skeletal features between the two groups. Further work is ongoing to better understand the causative role of either SNP for impaired megakaryopoiesis and thrombocytopenia in TAR Syndrome. Disclosures: No relevant conflicts of interest to declare.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:Cornelis Albers, Cedric Ghevaert and colleagues report that a majority of thrombocytopenia with absent radii (TAR) Syndrome cases are caused by compound heterzygosity of a null allele and a low-frequency SNP in the regulatory regions of the RBM8A gene, which encodes the Y14 subunit of the exon-junction complex (EJC). TAR Syndrome is the first reported human disorder caused by a defect in an EJC component.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation Syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR Syndrome.
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complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia absent radius Syndrome
American Journal of Human Genetics, 2007Co-Authors: Eva Klopocki, Harald Schulze, Judith G. Hall, Gabriele Straus, Clauseric Ott, Fabienne Trotier, Silke Fleischhauer, Lynn Greenhalgh, Ruth Newburyecob, Luitgard M NeumannAbstract:Thrombocytopenia-absent radius (TAR) Syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR Syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR Syndrome. We hypothesize that TAR Syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).
Jonathan Stephens - One of the best experts on this subject based on the ideXlab platform.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:Cornelis Albers, Cedric Ghevaert and colleagues report that a majority of thrombocytopenia with absent radii (TAR) Syndrome cases are caused by compound heterzygosity of a null allele and a low-frequency SNP in the regulatory regions of the RBM8A gene, which encodes the Y14 subunit of the exon-junction complex (EJC). TAR Syndrome is the first reported human disorder caused by a defect in an EJC component.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation Syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR Syndrome.
Kathleen Freson - One of the best experts on this subject based on the ideXlab platform.
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effect of single nucleotide polymorphism in the gene rbm8a together with the microdeletion 1q21 in thrombocytopenia absent radii Syndrome
Blood, 2012Co-Authors: Harald Schulze, Cornelis A Albers, Kathleen Freson, Ruth Newburyecob, Gabriele Strauss, Janine Fiedler, Markus Schmugge, Willem H Ouwehand, Cedric GhaevertAbstract:Abstract 2372 Thrombocytopenia-absent radii Syndrome (TAR) is a rare congenital disorder characterized by bilateral radius aplasia and thrombocytopenia due to virtual absence of bone marrow megakaryocytes (MKs). As other blood lineages are not affected, TAR is considered to be a bone marrow failure Syndrome. At birth, platelet counts are often below 50/nL, but ameliorate in many patients during the first two years of life, however, without reaching the lower norm. Platelet reactivity in reponse to thrombopoietin is abrogated, mostly when patients are young while it is restored to normal in older patients. Interestingly, this patterning is not correlated with platelet counts. In 2007 we described a microdeletion on chromosome 1q21 in all patients analyzed as necessary, but not sufficient to cause TAR, as it was also present in unaffected family members. Using next generation sequencing, we recently identified the presence of one of two single nucleotide polymorphisms (SNPs) in non-coding, regulatory regions of the gene RBM8A whose compound inheritance together with the microdeletion causes TAR Syndrome (Nature Genetics, 44, 435). All patients inherited one of the two SNPs from one of one parents and the microdeletion from the other. In 25% of cases the microdeletion was acquired de novo. This gene, which is located within the microdeleted region, encodes for Y14, a major subunit of the exon junction complex. In the German/Swiss/Polish cohort of 28 patients, 20 patients had the more frequent SNP in the 5'UTR, whereas 8 patients had a previously undescribed SNP in intron 1. The 5'UTR G->A introduces a novel binding site for transcriptional repressor Evi1. This factor is expressed in megakaryocytes and still present in platelets. Using electrophoretic mobility shift assays (EMSA) with lysates from platelets we found a complex exclusively present when a labeled oligonucleotide with the 5'UTR-SNP G->C was used and not with the wildtype sequence. This complex could be partially supershifted with an anti-Evi1 antibody, suggesting that an additional factor might bind to this complex. In contrast, the intronic SNP is predicted to abrogate a binding site for Mzf1. We used EMSA with oligonucleotides of both intronic SNP and wildtype sequence and indeed found a complex binding to the wildtype sequence as well as to a consensus sequence for Mzf1, but no or reduced binding to the intronic SNP. This complex could not be supershifted by adding an anti-Mzf1 antibody. However, when nuclear extracts from Meg01 cells were used, we found that one of three subcomplexes showed reduced binding in the presence of the antibody, even when the intronic SNP was used. As both SNPs showed different binding properties we carefully evaluated clinical data and found that platelet counts were more severely reduced in patients with the 5'UTR compared to patients harboring the intronic SNP. Although case numbers for the intronic SNP are low, in a direct comparison of age-matched patients, platelet counts were always higher in TAR patients with the intronic SNP. However, we did not find any obvious differences in skeletal features between the two groups. Further work is ongoing to better understand the causative role of either SNP for impaired megakaryopoiesis and thrombocytopenia in TAR Syndrome. Disclosures: No relevant conflicts of interest to declare.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:Cornelis Albers, Cedric Ghevaert and colleagues report that a majority of thrombocytopenia with absent radii (TAR) Syndrome cases are caused by compound heterzygosity of a null allele and a low-frequency SNP in the regulatory regions of the RBM8A gene, which encodes the Y14 subunit of the exon-junction complex (EJC). TAR Syndrome is the first reported human disorder caused by a defect in an EJC component.
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compound inheritance of a low frequency regulatory snp and a rare null mutation in exon junction complex subunit rbm8a causes TAR Syndrome
Nature Genetics, 2012Co-Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan Stephens, Peter A SmethurstAbstract:The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation Syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR Syndrome.
