<i>TCIRG1</i>-Associated Congenital Neutropenia

Makaryan, Vahagn; Rosenthal, Elisabeth; Bolyard, Audrey Anna; Kelley, Merideth L.; Below, Jennifer E.; Bamshad, Michael J.; Bofferding, Kathryn M.; Smith, Joshua D.; Buckingham, Kati J.; Boxer, Laurence A.; Skokowa, Julia; Welte, Karl; Nickerson, Deborah A.; Jarvik, Gail P.; Dale, David C.

doi:10.1002/humu.22563

Cited by 42 publications

(21 citation statements)

References 30 publications

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“…The results of this study provide supportive evidence for a role of TCIRG1 variation in determining ANC. Having previously shown that a single TCIRG1 variant co‐segregated and was associated with ANC [Makaryan et al., ], we now additionally demonstrate an association between rare, coding variants at conserved sites in TCIRG1 and ANC. Notably the more rare of these variants were associated with lower ANC than the ones seen in more than one individual, suggesting a spectrum of effect sizes may be associated with different variants.…”

Section: Discussionsupporting

confidence: 74%

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project

Rosenthal

Makaryan

Burt

et al. 2016

Genetic Epidemiology

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Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family. Here, we report on nine rare missense variants at evolutionarily conserved sites in TCIRG1 that are associated with lower absolute neutrophil count (ANC)(p=0.005) in 1058 participants from three cohorts: the Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA) and Jackson Heart (JHS) studies of the NHLBI Grand Opportunity Exome Sequencing Project (GO ESP). These results validate the effects of TCIRG1 coding variation on ANC and suggest that this gene may be associated with a spectrum of mild to severe effects on ANC.

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Section: Discussionsupporting

confidence: 74%

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project

Rosenthal

Makaryan

Burt

et al. 2016

Genetic Epidemiology

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“…Recombinant human granulocyte-colony stimulating factor (G-CSF) (for example filgrastim and lenograstim became available for clinical research in 1987 10 and was approved by the FDA for the treatment of congenital neutropenia in 1993 (Ref 14 ). First description of the: GFI1 gene mutation 150 the CXCR4 151 TCIRG1 152 . First description of the acquired CSF3R mutations in severe congenital neutropenia patients 153 …”

Section: Figurementioning

confidence: 99%

Severe congenital neutropenias

Skokowa

Dale

Touw

et al. 2017

Nat Rev Dis Primers

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Severe congenital neutropenias are a heterogeneous group of rare haematological diseases that are characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenetic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte-colony stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination, and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophils count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (e.g. trisomy 21, monosomy 7) as well as somatic pre-leukaemic mutations are recommended.

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“…3 In many instances, knowing the pedigree that is consistent with the generated genetic data is crucial to solving the disease. [4][5][6][7] Additionally, the collection of samples from a limited geographical region for a genetic analysis might introduce biases toward unintentionally obtaining samples of unknown relatedness for which a previously unknown pedigree could be reconstructed and used. As a result, large case-control consortia can harbor cryptic relatedness, 8 which can bias the analysis unless the cryptic relatedness is removed or investigators use a method that models a kinship matrix.…”

Section: Introductionmentioning

confidence: 99%

PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

Staples

Qiao

Cho

et al. 2014

The American Journal of Human Genetics

151

162

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Understanding and correctly utilizing relatedness among samples is essential for genetic analysis; however, managing sample records and pedigrees can often be error prone and incomplete. Data sets ascertained by random sampling often harbor cryptic relatedness that can be leveraged in genetic analyses for maximizing power. We have developed a method that uses genome-wide estimates of pairwise identity by descent to identify families and quickly reconstruct and score all possible pedigrees that fit the genetic data by using up to third-degree relatives, and we have included it in the software package PRIMUS (Pedigree Reconstruction and Identification of the Maximally Unrelated Set). Here, we validate its performance on simulated, clinical, and HapMap pedigrees. Among these samples, we demonstrate that PRIMUS can verify reported pedigree structures and identify cryptic relationships. Finally, we show that PRIMUS reconstructed pedigrees, all of which were previously unknown, for 203 families from a cohort collected in Starr County, TX (1,890 samples).

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TCIRG1-Associated Congenital Neutropenia

Cited by 42 publications

References 30 publications

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project

Severe congenital neutropenias

PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

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