Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia

Dasouki, Majed; Rafi, Syed K.; Olm-Shipman, Adam J.; Wilson, Nathan R.; Abhyankar, Sunil; Ganter, Brigitte; Furness, L. Mike; Fang, Jianwen; Calado, Rodrigo T.; Saadi, Irfan

doi:10.1182/blood-2012-12-473538

Cited by 58 publications

(66 citation statements)

References 52 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In humans, loss of function mutations in c-MPL result in congenital amegakaryocytic thrombocytopenia, with affected children presenting initially with isolated thrombocytopenia and progressive pancytopenia due to a reduction in bone marrow HSCs 23 . Recently, a mutation in the gene encoding TPO ( THPO ) was demonstrated in a family with autosomal recessive aplastic anemia 24 .…”

Section: Thrombopoietin and Hematopoiesismentioning

confidence: 99%

Eltrombopag in Aplastic Anemia

Desmond

Townsley

Dunbar

et al. 2015

Seminars in Hematology

View full text Add to dashboard Cite

The treatment of aplastic anemia is currently with immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. Modifications to this standard approach using alternative immunosuppressive agents or adding hematopoietic cytokines such as G-CSF and erythropoietin have not improved outcome. A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST refractory SAA and in moderate disease.

show abstract

Section: Thrombopoietin and Hematopoiesismentioning

confidence: 99%

Eltrombopag in Aplastic Anemia

Desmond

Townsley

Dunbar

et al. 2015

Seminars in Hematology

View full text Add to dashboard Cite

show abstract

“…The ability to comprehensively survey genetic variations and their associations with diseases is currently central to personalized medicine and can potentially transform clinical diagnosis and disease management. Indeed, whole-genome sequencing and whole-exome sequencing (WES) have been used successfully to investigate both common and rare diseases (1)(2)(3)(4)(5)(6)(7), as well as to provide guidance for drug treatment (8). Despite these successes, significant limitations remain on applying NGS in clinical settings for patient care (9)(10)(11).…”

Section: Liningmentioning

confidence: 99%

Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

Guo

Milburn

Ryals

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

144

View full text Add to dashboard Cite

Precision medicine, taking account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy, has shown great promise to transform medical care. Nontargeted metabolomics, with the ability to detect broad classes of biochemicals, can provide a comprehensive functional phenotype integrating clinical phenotypes with genetic and nongenetic factors. To test the application of metabolomics in individual diagnosis, we conducted a metabolomics analysis on plasma samples collected from 80 volunteers of normal health with complete medical records and three-generation pedigrees. Using a broadspectrum metabolomics platform consisting of liquid chromatography and GC coupled with MS, we profiled nearly 600 metabolites covering 72 biochemical pathways in all major branches of biosynthesis, catabolism, gut microbiome activities, and xenobiotics. Statistical analysis revealed a considerable range of variation and potential metabolic abnormalities across the individuals in this cohort. Examination of the convergence of metabolomics profiles with whole-exon sequences (WESs) provided an effective approach to assess and interpret clinical significance of genetic mutations, as shown in a number of cases, including fructose intolerance, xanthinuria, and carnitine deficiency. Metabolic abnormalities consistent with early indications of diabetes, liver dysfunction, and disruption of gut microbiome homeostasis were identified in several volunteers. Additionally, diverse metabolic responses to medications among the volunteers may assist to identify therapeutic effects and sensitivity to toxicity. The results of this study demonstrate that metabolomics could be an effective approach to complement next generation sequencing (NGS) for disease risk analysis, disease monitoring, and drug management in our goal toward precision care.metabolomics | whole-exome sequencing | functional phenotyping | gene penetrance | disease assessment T he rapid progression of next generation sequencing (NGS) technology in recent years has significantly reduced the cost and time required to query a patient's genome accurately. The ability to comprehensively survey genetic variations and their associations with diseases is currently central to personalized medicine and can potentially transform clinical diagnosis and disease management. Indeed, whole-genome sequencing and whole-exome sequencing (WES) have been used successfully to investigate both common and rare diseases (1-7), as well as to provide guidance for drug treatment (8). Despite these successes, significant limitations remain on applying NGS in clinical settings for patient care (9-11). One of the key challenges is the proper interpretation of NGS data. It is known that human exome sequencing identifies ∼10,000 nonsynonymous single-nucleotide variants (12). The computational algorithms and databases for predicting and prioritizing functional pathogenic variants are not yet fully effective. More importantly, the impact of nongenetic factors, such ...

show abstract

“…Rare variants in THPO and MPL, the genes encoding thrombopoietin 3,4 and its receptor Mpl, 5,6 cause congenital thrombocytopenia, and 7 IPD genes encode transcription factors (GATA1, 7,8 RUNX1, 9 FLI1, 10 ETV6,…”

Section: Megakaryopoiesis and Platelet Formationmentioning

confidence: 99%

Inherited platelet disorders: toward DNA-based diagnosis

Lentaigne

Freson

Laffan

et al. 2016

Blood

118

101

View full text Add to dashboard Cite

Variations in platelet number, volume, and function are largely genetically controlled, and many loci associated with platelet traits have been identified by genome-wide association studies (GWASs).1 The genome also contains a large number of rare variants, of which a tiny fraction underlies the inherited diseases of humans. Research over the last 3 decades has led to the discovery of 51 genes harboring variants responsible for inherited platelet disorders (IPDs). However, the majority of patients with an IPD still do not receive a molecular diagnosis. Alongside the scientific interest, molecular or genetic diagnosis is important for patients. There is increasing recognition that a number of IPDs are associated with severe pathologies, including an increased risk of malignancy, and a definitive diagnosis can inform prognosis and care. In this review, we give an overview of these disorders grouped according to their effect on platelet biology and their clinical characteristics. We also discuss the challenge of identifying candidate genes and causal variants therein, how IPDs have been historically diagnosed, and how this is changing with the introduction of high-throughput sequencing. Finally, we describe how integration of large genomic, epigenomic, and phenotypic datasets, including whole genome sequencing data, GWASs, epigenomic profiling, protein–protein interaction networks, and standardized clinical phenotype coding, will drive the discovery of novel mechanisms of disease in the near future to improve patient diagnosis and management.

show abstract

Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia

Cited by 58 publications

References 52 publications

Eltrombopag in Aplastic Anemia

Eltrombopag in Aplastic Anemia

Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

Inherited platelet disorders: toward DNA-based diagnosis

Contact Info

Product

Resources

About