Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report

BMC Medical Genetics

Stylianos E Antonarakis⁴  Abdulrahman A Muhsin³  Nasir Al-Allawi²  Periklis Makrythanasis¹  Hanan Hamamy¹ 

[1] Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland;Department of Pathology, College of Medicine, University of Dohuk, Dohuk, Iraq;Hematology/Oncology unit, JIN Center, Dohuk, Iraq;Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland

关键词: Iraq;    FYB gene;    Recessive;    Familial;    Thrombocytopenia;    Platelets;   

Others  :  1090057
DOI  :  10.1186/s12881-014-0135-0

 received in 2014-09-05, accepted in 2014-12-08,  发布年份 2014

【 摘 要 】

Background

Inherited thrombocytopenias (IT) are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. The frequency of IT is probably underestimated because of diagnostic difficulties and because not all the existing forms have as yet been identified, with some patients remaining without a definitive diagnosis. Exome Sequencing has made possible the identification of almost all variants in the coding regions of protein-coding genes, thereby providing the opportunity to identify the disease causing gene in a number of patients with indefinite diagnoses, specifically in consanguineous families.

Case presentation

Familial thrombocytopenia with small size platelets was present in several members of a highly consanguineous family from Northern Iraq. Genotyping of all affected, their unaffected siblings and parents, followed by exome sequencing revealed a strong candidate loss of function variant in a homozygous state: a frameshift mutation in the FYB gene. The protein encoded by this gene is known to be a cytosolic adaptor molecule expressed by T, natural killer (NK), myeloid cells and platelets, and is involved in platelet activation and controls the expression of interleukin-2. Knock-out mice were reported to show isolated thrombocytopenia.

Conclusion

Inherited thrombocytopenias differ in their presentation, associated features, and molecular etiologies. An accurate diagnosis is needed to provide appropriate management as well as counseling for the individuals and their family members. Exome sequencing may become a first diagnostic tool to identify the molecular basis of undiagnosed familial IT. In this report, the clinical evaluation combined with the power and efficiency of genomic analysis defined the FYB gene as the possible underlying cause of autosomal recessive thrombocytopenia with small platelet size. This is the first report linking pathogenic variants in FYB and thrombocytopenia in humans.

【 授权许可】

   
2014 Hamamy et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Balduini CL, Savoia A: Genetics of familial forms of thrombocytopenia. Hum Genet 2012, 131:1821-1832.
• [2]Cattaneo M: Inherited platelet-based bleeding disorders. J Thromb Haemost 2003, 1:1628-1636.
• [3]Pecci A: Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists. Int J Hematol 2013, 98:34-47.
• [4]Makrythanasis P, Nelis M, Santoni FA, Guipponi M, Vannier A, Bena F, Gimelli S, Stathaki E, Temtamy S, Mégarbané A, Masri A, Aglan MS, Zaki MS, Bottani A, Fokstuen S, Gwanmesia L, Aliferis K, Bustamante Eduardo M, Stamoulis G, Psoni S, Kitsiou-Tzeli S, Fryssira H, Kanavakis E, Al-Allawi N, Sefiani A, Al Hait S, Elalaoui SC, Jalkh N, Al-Gazali L, Al-Jasmi F, et al.: Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families. Hum Mutat 2014, 10:1203-1210.
• [5]Nurden AT, Freson K, Seligsohn U: Inherited platelet disorders. Haemophilia 2012, 18(Suppl 4):154-160.
• [6]Lambert MP, Poncz M: They’re not your daddy’s inherited platelet disorders anymore. J Thromb Haemost 2013, 11:2037-2038.
• [7]Togni M, Engelmann S, Reinhold D, Schraven B, Reinhold A: The adapter protein ADAP is required for selected dendritic cell functions. Cell Commun Signal 2012, 10:14. BioMed Central Full Text
• [8]Peterson EJ, Woods ML, Dmowski SA, Derimanov G, Jordan MS, Wu JN, Myung PS, Liu QH, Pribila JT, Freedman BD, Shimizu Y, Koretzky GA: Coupling of the TCR to integrin activation by Slap-130/Fyb. Science 2001, 293:2263-2265.
• [9]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81:559-575.
• [10]Balduini CL, Iolascon A, Savoia A: Inherited thrombocytopenias: from genes to therapy. Haematologica 2002, 87:860-880.
• [11]Drachman JG: Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood 2004, 103:390-398.
• [12]Jarvis GE, Bihan D, Hamaia S, Pugh N, Ghevaert CJ, Pearce AC, Hughes CE, Watson SP, Ware J, Rudd CE, Farndale RW: A role for adhesion and degranulation-promoting adapter protein in collagen-induced platelet activation mediated via integrin alpha(2) beta(1). J Thromb Haemost 2012, 10:268-277.
• [13]Kasirer-Friede A, Moran B, Nagrampa-Orje J, Swanson K, Ruggeri ZM, Schraven B, Neel BG, Koretzky G, Shattil SJ: ADAP is required for normal alphaIIbbeta3 activation by VWF/GP Ib-IX-V and other agonists. Blood 2007, 109:1018-1025.
• [14]Kasirer-Friede A, Ruggeri ZM, Shattil SJ: Role for ADAP in shear flow-induced platelet mechanotransduction. Blood 2010, 115:2274-2282.