Molecular genetic diagnosis of Glanzmann syndrome in Iranian population; reporting novel and recurrent mutations

F. Zafarghandi Motlagh,
M. S. Fallah,
H. Bagherian,
T. Shirzadeh,
S. Ghasri,
S. Dabbagh,
M. Jamali,
Z. Salehi,
M. AbiriEmail author and
S. ZeinaliEmail author

Orphanet Journal of Rare Diseases201914:87

https://doi.org/10.1186/s13023-019-1042-4

Received: 4 January 2018
Accepted: 5 March 2019
Published: 27 April 2019

Abstract

Background

Glanzmann thrombasthenia (GT) is a rare autosomal recessive abnormality of platelet aggregation with quantitative and/or qualitative abnormality of αIIbβ3 integrin. The αIIbβ3 is a platelet fibrinogen receptor, which is required for platelet aggregation, firm adhesion, and also spreading.

The disease is more prevalent in the populations with a higher rate of consanguineous marriages as in some Middle Eastern populations including Iraq, Jordan, and Iran. Different types of mutations in ITGA2B and ITGB3 genes have been previously reported to cause the disease.

Result

In this study, 16 patients with the clinical diagnosis of GT were studied. Direct sequencing of the exons and exon-intron boundaries of the above genes revealed mutations in 14 patients (detection rate: 87.5%). Briefly, out of fifteen types of identified mutations, 14 were novel. Seven mutations in the ITGB3 gene included 4 missense [c.2T > C, c.155 G > T, c. 538 G > A, c.1990 G > T], one nonsense mutation [c.1303 G > T], a small deletion [c.1656_1658delCTC] and a deletion of one nucleotide [c.401delA]. Mutations in the ITGA2B were 8 different mutations consisting 2 missense [c.286 T > A, c.842 C > T], 2 deletions [c.1899 del T, c.189-319_236del], an insertion [c.1071_1072insG] and one splice site mutations [c.409–3 C > G], one synonymous mutation that might alter the normal splicing process [c.1392 A > G] and a nonsense mutation [c.1555 C > T].

The causative mutation in 2 patients remained unknown. Using long-range PCR and sequencing, we found a rather large deletion. The break point of this deletion covers 319 nt from the last part of the first intron and 48 nt from the beginning of the second exon of ITGA2B gene. The deletion was also detected in two unrelated patients with the same ethnicity. In addition, in silico analyses of novel mutations were performed.

Conclusion

There was no recurrent mutation in the studied population. This may be due to either small sample size or the heterogeneity of the studied population.