Identification of novel pathogenic F13A1 mutation and novel NBEAL2 gene missense mutation in a pedigree with hereditary congenital factor XIII deficiency

Jia, Siyuan; Lu, Miao; Liao, Ning; Yonghong, Lei; Nikuze, Lauriane; Liang, Kairong; Wei, Hongying

doi:10.1016/j.gene.2019.03.067

Cited by 4 publications

(5 citation statements)

References 16 publications

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“…As previously reported [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , most CML-BC patients in our cohort acquired additional mutations, which not only included mutations previously reported in haematological malignancies and CML-BC, but also included previously unreported recurrent mutations, such as NBEAL2, PHIP, and KLC2 mutations. NBEAL2 encodes a protein with a role in megakaryocyte alphagranule biogenesis and has been reported to be mutated in patients with Grey platelet syndrome [38][39][40] and factor XIII deficiency 41 . In contrast, to the best of our knowledge, mutations in PHIP and KLC2 have not been reported in the context of haematological disorders.…”

Section: Resultsmentioning

confidence: 99%

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

et al. 2021

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Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

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Section: Resultsmentioning

confidence: 99%

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

et al. 2021

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“…28 A proband with a deletion, c.1652delC in F13A gene and a missense variant (c.1367C > T, Ala456Val) in the NBEAL2 gene, has severe FXIII deficiency (FXIII:Ag < 1% and positive clot solubility test), but heterozygous individuals had no bleeding despite heterozygous variants in both genes. 26 The Arg382Ser variant was detected in homozygous form in a proband with severe FXIII deficiency, but the proband's mother and father were heterozygous and normal, respectively. Further studies revealed the first case with segmental maternal uniparental disomy in FXIII deficiency.…”

Section: Molecular Basis Of Heterozygous Fxiii Deficiencymentioning

confidence: 99%

“…A variety of gene variants have been observed in heterozygous FXIII deficiency, including missense, nonsense, splice site, and small and large deletions throughout F13A gene. 6,11,[25][26][27][28][29][30][31][32][33][34][35][36][37] A total of 49 gene defects were observed throughout F13A gene in heterozygous FXIII deficiency, and most of them (n: 30, 61.2%) were missense, while large deletions were the rarest (n: 3, 6.1%). Although early studies showed that most variants in heterozygous FXIII deficiency are in domains other than the catalytic core, the current pattern of gene variants in heterozygous FXIII deficiency is comparable to the spectrum of F13A gene variants in homozygous (severe) FXIII deficiency, in which 48.8% of variants are missense and 10.5% are nonsense.…”

Section: Molecular Basis Of Heterozygous Fxiii Deficiencymentioning

confidence: 99%

“…On the other hand, 17 family members with the same gene variant have the same clinical presentation. [26][27][28][31][32][33][35][36][37]84 Interestingly, all three variants in exon 13 and two variants of exon 7, which account for 50% of all variants with bleeding tendency, are associated with bleeding tendency.…”

Section: Molecular Basis Of Heterozygous Fxiii Deficiencymentioning

confidence: 99%

“…Molecular features of heterozygous factor XIII deficiency and its comparison with severe factor XIII deficiency6,11,[26][27][28][29][30][31][32][33][34][35][36][37][38]85 …”

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confidence: 99%

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Novel Insights into Heterozygous Factor XIII Deficiency

Dorgalaleh¹

2023

Semin Thromb Hemost

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The prevalence and clinical significance of heterozygous factor XIII (FXIII) deficiency has long been debated, with controversial reports emerging since 1988. In the absence of large epidemiologic studies, but based on a few studies, a prevalence of 1 per 1,000 to 5,000 is estimated. In southeastern Iran, a hotspot area for the disorder, a study of more than 3,500 individuals found an incidence of 3.5%. Between 1988 and 2023, a total of 308 individuals were found with heterozygous FXIII deficiency, of which molecular, laboratory, and clinical presentations were available for 207 individuals. A total of 49 variants were found in the F13A gene, most of which were missense (61.2%), followed by nonsense (12.2%) and small deletions (12.2%), most occurring in the catalytic domain (52.1%) of the FXIII-A protein and most frequently in exon 4 (17%) of the F13A gene. This pattern is relatively similar to homozygous (severe) FXIII deficiency. In general, heterozygous FXIII deficiency is an asymptomatic condition without spontaneous bleeding tendency, but it can lead to hemorrhagic complications in hemostatic challenges such as trauma, surgery, childbirth, and pregnancy. Postoperative bleeding, postpartum hemorrhage, and miscarriage are the most common clinical manifestations, while impaired wound healing has been rarely reported. Although some of these clinical manifestations can also be observed in the general population, they are more common in heterozygous FXIII deficiency. While studies of heterozygous FXIII deficiency conducted over the past 35 years have shed light on some of the ambiguities of this condition, further studies on a large number of heterozygotes are needed to answer the major questions related to heterozygous FXIII deficiency.

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Congenital Factor XIII Deficiency, Diagnosis, and Management

Dorgalaleh

2023

Congenital Bleeding Disorders

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Identification of novel pathogenic F13A1 mutation and novel NBEAL2 gene missense mutation in a pedigree with hereditary congenital factor XIII deficiency

Cited by 4 publications

References 16 publications

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

Novel Insights into Heterozygous Factor XIII Deficiency

Congenital Factor XIII Deficiency, Diagnosis, and Management

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