Inherited Thrombocytopenia Panel Thrombocytopenia Will Be Identified with This Panel, Including Aug; 43(8): 732–734

Shipping requirements References Ship on an ice pack or at room Albers CA, Paul DS et al. 2012. Compound inheritance of a low-frequency temperature. Protect from freezing. regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012 Feb 26; 44(4):435-9. Place the specimen and the requisition Inherited into plastic bags and seal. Insert into Ali S, Ghosh K et al. 2016. Congenital macrothrombocytopenia is a heterogeneous disorder in India. Haemophilia. Jul; 22(4):570-82. a Styrofoam container, seal and place Balduini CL, Pecci A, Savoia A. 2011. Recent advances in the understanding and into a sturdy cardboard box, and management of MYH9-related inherited thrombocytopenias. Br J Haematol. tape securely. Ship the package in Jul;154(2):161-174. Thrombocytopenia compliance with your overnight carrier IP Balduini CL, Melazzini F, Pecci A. 2017. Inherited thrombocytopenias-recent guidelines. Label with the following advances in clinical and molecular aspects. Platelets. Jan;28(1):3-13. address: Bastida JM, Del Rey M et al. 2016. Wiskott-Aldrich syndrome in a child presenting Client Services/Diagnostic Laboratory with macrothrombocytopenia Platelets. Nov 25:1-4. Panel BloodCenter of Wisconsin Bottega R, Marconi C et al. 2015. ACTN1-related thrombocytopenia: identification 638 N. 18th St. of novel families for phenotypic characterization. Blood. Jan 29;125(5):748-50. Milwaukee, WI 53233 Favier R, Raslova H. 2015. Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias. Br J Haematol. Sep;170 (5):626-39. Gunay-Aygun M, Falik-Zaccai TC et al. 2011. NBEAL2 is mutated in Gray Platelet BloodCenter of Wisconsin offers a specifically recessive manner. More common and rare types of inherited Required forms Syndrome and is required for biogenesis of platelet alpha-granules. Nat Genet. designed Inherited Thrombocytopenia Panel thrombocytopenia will be identified with this panel, including Aug; 43(8): 732–734. MYH9-related disorders, Bernard-Soulier syndrome, congenital Please complete all pages of the (test code 4840) optimized for detection of requisition form. Clinical history Kumar R, Kahr WHA. 2013. Congenital Thrombocytopenia: Clinical Manifestations, amegakaryocytic thrombocytopenia, familial platelet disorder Laboratory Abnormalities, and Molecular Defects of a Heterogeneous Group of germline variants in 23 genes known to cause with predisposition to acute myelogenous leukemia, ANKRD26- (including patient’s ethnicity, clinical Conditions. Hematol Oncol Clin North Am. June; 27(3):465-94. diagnosis, family history and relevant inherited thrombocytopenia. related thrombocytopenia, WAS-related thrombocytopenia, gray Manchev VT, Hilpert M et al. 2014. A new form of macrothrombocytopenia platelet syndrome and others. Additional genes in this panel are laboratory findings) is necessary for induced by a germ-line mutation in the PRKACG gene. Blood.Oct 16;124(16):2554- optimal interpretation of genetic test 63. associated with syndromes that have thrombocytopenia as a Inherited thrombocytopenia is a heterogeneous group of common finding among other non-hematologic features. results and recommendations. Clinical Noris P, Biino G et al. 2014. Platelet diameters in inherited thrombocytopenias: disorders characterized by low platelet counts typically less than and laboratory history can eitherIP be analysis of 376 patients with all known disorders. Aug 7; 124(6):e4-e10. This panel evaluates for single nucleotide variants and small 150,000/uL, but often can vary with age, gender and ethnic recorded on the requisition form or Noris P, Favier R et al. 2013. ANKRD26-related thrombocytopenia and myeloid deletions and duplications, which are most commonly clinical and laboratory reports can be malignancies. Blood .122:1987-1989. background. Symptoms of thrombocytopenia may include responsible for genetic disease. However, large deletions and submitted with the sample. Ok Bozkaya I, Yarali N et al. Severe Clinical Course in a Patient with Congenital purpura, petechiae, prolonged bleeding from cuts, epistaxis, gum duplications, also referred to as copy number variants (CNV), are Amegakaryocytic Thrombocytopenia Due to a Missense Mutation of the c-MPL bleeding, excessive bleeding after surgery, hemoptysis, hematuria a known cause of genetic disorders, but can escape detection Gene. Turk J Haematol.Jun; 32(2): 172-4. and menorrhagia in women. Severe inherited thrombocytopenias by next-generation sequence analysis. Further testing with CPT Codes/Billing/Turnaround time Pagel J, Beutel K et al. 2012. Distinct mutations in STXBP2 are associated can present in the newborn period, while mild thrombocytopenia the BloodCenter of Wisconsin custom designed, high density with variable clinical presentations in patients with familial hemophagocytic may remain undiagnosed until incidental detection on gene-focused array, aCGH Deletion/Duplication Analysis, allows Test Code: 4840 lymphohistiocytosis type 5 (FHL5). Blood. 119:6016-6024. routine blood testing in adulthood. Some inherited types of for the possible detection of large deletions and duplications CPT codes: 81404, 81406, 81479 Saultier P,Vidal, L.et al. 2017. Macrothrombocytopenia and dense granule thrombocytopenia have only hematologic manifestations, within a single exon of a given gene, encompassing one or more deficiency associated with FLI1 variants: ultrastructural and pathogenic features. such as differences in platelet size or distinctive granulocyte Turnaround time: 21 days Haematologica.102:1006-1016. exons, or affecting an entire gene. This testing may be warranted inclusions, while other syndromic types present with additional when results of sequence analysis do not fully explain a clinical The CPT codes provided are subject to change as more Savoia A. 2016. Molecular basis of Inherited thrombocytopenias. Clin Genet non-hematologic manifestations. Certain types of inherited information becomes available. CPT codes are provided only as Feb;89(2):154-62. phenotype, or when a suspected disorder is known to be caused thrombocytopenia cause predisposition to acute myelogenous by deletions or duplications. Please refer to the aCGH Deletion/ guidance to assist clients with billing. Savoia A. 2016. Molecular basis of Inherited thrombocytopenias: an update. leukemia or myelodysplastic syndromes. Current Opinion in Hematology. Sep;23(5):486-492. Duplication Analysis test description for more information about For additional information related to shipping, billing or pricing, Misdiagnosis of inherited thrombocytopenia as autoimmune specific genes included in this array. please contact, BloodCenter Client Services: (414) 937-6396 or Kunishima Shinji S, Kobayashi R et al. 2009. Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule thrombocytopenia (ITP) can result in inappropriate therapies and 800-245-3117, Option 1, or [email protected]. Inherited platelet disorders associated with platelet dysfunction assembly. Blood. 113:458-461. inadequate surveillance for additional medical complications, are included in the Platelet Function Disorder Panel. For broader Stevenson WS, Rabbolini DJ et al. 2015. Paris-Trousseau thrombocytopenia is underscoring the importance of accurate diagnosis. Advances in evaluation of unspecified platelet problems, both the Inherited phenocopied by the autosomal recessive inheritance of a DNA-binding domain genetic testing through next-generation sequencing allow for Thrombocytopenia Panel and Platelet Function Disorder Panel mutation in FLI1. Blood. Oct 22;126(17); 2027-30. identification of underlying genetic defects and for distinguishing can be ordered together as part of the Comprehensive Platelet Zhang My, Churpek JE et al. 2015. Germline ETV6 mutations in familial inherited cases from immune thrombocytopenia. Accurate Disorder Panel. thrombocytopenia and hematologic malignancy. Nat Genet. Feb; 47(2):180-185. diagnosis provides information about the phenotype and prognosis, guides medical management decisions, assists with the Refer to the table inside for further information about each identification of affected family members, and allows for accurate gene in the Inherited Thrombocytopenia Panel, including the genetic recurrence risk assessment. clinical phenotype, OMIM numbers and inheritance pattern. Variants in several different genes known to cause syndromic or non-syndromic thrombocytopenia may be inherited in an autosomal recessive, autosomal dominant or X-linked

© Copyright 2017 r0818 BloodCenter of Wisconsin, Inc. , Part of Versiti. All rights reserved. Inherited Thrombocytopenia Panel: gene, clinical phenotype, OMIM number and inheritance pattern. Inherited Thrombocytopenia Panel: gene, clinical phenotype, OMIM number and inheritance pattern. Gene Clinical Phenotype Phenotype/Gene Inheritance Gene Clinical Phenotype Phenotype/Gene Inheritance OMIM number OMIM number ACTN1 Bleeding disorder, platelet-type 15 (BDPT15): macrothrombocytopenia with mild or 615193/102575 Autosomal Dominant MPL Congenital amegakaryocytic thrombocytopenia (CAMT): type 1-onset in infancy with 604498/159530 Autosomal Recessive absent bleeding tendency. severe thrombocytopenia and progressing to pancytopenia; type II with transient increases in platelet counts with onset of bone marrow failure at age 3 or later. ANKRD26 Thrombocytopenia-2 (THC2): mild bleeding tendency with normal platelet function and 188000/610855 Autosomal Dominant morphology with increased predisposition to hematologic myeloid malignancies. MYH9 MYH9-related disorders: large platelets and thrombocytopenia at birth with variable 160775 later onset of non-hematologic manifestations including progressive sensorineural CYCS Thrombocytopenia-4 (THC4): bleeding tendency may be mild or absent with normal 612004/123970 Autosomal Dominant hearing loss, glomerulonephritis, presenile cataracts and elevation of liver enzymes. platelet size and morphology. MYH9-related disorders includes previously characterized disorders: ETV6 Thrombocytopenia-5 (THC5): onset is typically in early childhood with an increased 616216/600618 Autosomal Dominant May-Hegglin anomaly: thrombocytopenia, giant platelets, and Dohle body-like 155100/160775 susceptibility to develop various hematologic and solid malignancies throughout life. inclusions. FLI1 Paris-Trousseau thrombocytopenia (TCPT): mild bleeding tendency with variable 188025/193067 Deletion syndrome Epstein syndrome: thrombocytopenia, giant platelets, nephritis, and deafness. 153650/160775 thrombocytopenia, dysmorphic facies, abnormal giant alpha-granules in platelets and Autosomal Dominant dysmegakaryopoiesis as part of contiguous gene deletion syndrome of 11q (Jacobsen Fechtner syndrome: thrombocytopenia, giant platelets, and Dohle body-like inclusions in 153640/160775 syndrome). peripheral blood leukocytes, with nephritis, hearing loss, and eye abnormalities, mostly cataracts. Bleeding disorder, platelet-type, 21 (BDPLT21): moderate macrothrombocytopenia, 617443/ 193067 Autosomal Recessive/ abnormal giant alpha-granules in platelets, functional platelet disorder. Phenotype Autosomal Dominant Sebastian syndrome: thrombocytopenia, giant platelets, and leukocyte inclusions 605249/160775 caused by heterozygous and homozygous pathogenic variants. composed of highly dispersed filaments and few ribosomes. GATA1 GATA1-related cytopenia: thrombocytopenia and/or anemia ranging from mild to DNFA17: nonsyndromic progressive hearing loss with onset in childhood or later; hearing 603622/160775 severe; may be associated with platelet dysfunction, mild β-thalassemia, neutropenia, loss progresses from high frequency to moderate-severe deafness over time. and congenital erythropoietic porphyria (CEP). Thrombocytopenia present in infancy and anemia may range from mild to severe hydrops fetalis. Carrier females may have NBEAL2 Gray platelet syndrome (GPS): large platelets that lack α-granules leading to mild 139090/614169 Autosomal Recessive mild to moderate symptoms. to moderate bleeding tendency and moderate thrombocytopenia with increased development of myelofibrosis and splenomegaly. X-linked dyserythropoietic anemia and thrombocytopenia (XLTDA): variable severity of 300367/305371 thrombocytopenia and dyserythropoietic anemia may be present. X-linked Recessive PRKACG Bleeding disorder, platelet-type 19 (BDPLT19): severe macrothrombocytopenia and 616176/176893 Autosomal Recessive bleeding symptoms. Thrombocytopenia with beta-thalassemia, X-linked (XLTT): variable thrombocytopenia, 314050/305371 splenomegaly, and unbalanced hemoglobin chain synthesis resembling that of beta- RBM8A Thrombocytopenia-Absent Radius syndrome (TAR): characterized by bilateral absence 274000/605313 Autosomal Recessive thalassemia minor. of the radius with presence of thumbs, thrombocytopenia which may be congenital or develop early in life and decreases with age. Other anomalies of the skeleton (upper and GFI1B Bleeding disorder, platelet-type 17 (Gray Platelet-like syndrome): variable 187900/604383 Autosomal Dominant lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and bleeding symptoms due to disorder of platelet alpha granules with moderate agenesis of uterus, cervix, and upper part of the vagina) can occur. macrothrombocytopenia and red cell anisopoikilocytosis. RUNX1 Familial platelet disorder with associated myeloid malignancy (FPDMM): characterized by 601399/151385 Autosomal Dominant GP1BA Bernard-Soulier syndrome (BSS): mild to severe bleeding disorder due to absence or 231200/606672 Autosomal Recessive mild to moderate thrombocytopenia, qualitative platelet defects and a predisposition to dysfunction of the platelet glycoprotein receptor Ib/V/IX complex with mild to moderate development of myeloid malignancies. thrombocytopenia, unusually large platelets and abnormal platelet function with absent or markedly reduced aggregation response to ristocetin. Caused by homozygous or STXBP2 Familial hemophagocytic lymphohistiocytosis (FHL5): immune dysregulation with 613101/601717 Autosomal Recessive compound heterozygous pathogenic variants in GP1BA (606672), GP1BB (138720), or GP9 hypercytokinemia, defective function of natural killer cells, and macrophages that (173515). infiltrate multiple organs; characterized by variable age of onset and severity with fever, chronic diarrhea, hepatosplenomegaly, pancytopenia, coagulation abnormalities and Bernard-Soulier syndrome (BSSA2): autosomal dominant (mono-allelic) form of BSS with 153670/606672 Autosomal Dominant CNS problems. mild thrombocytopenia, variable large platelets, and mild or no bleeding tendency, due to specific heterozygous variants in GP1BA or rarely in GP1BB or GP9. TUBB1 Congenital macrothrombocytopenia. 613112/612901 Autosomal Dominant Platelet-type von Willebrand disease (also known as pseudo-von Willebrand disease): 177820/606672 Autosomal Dominant WAS WAS-related disorders comprise a spectrum of disorders, not distinct entities, as thrombocytopenia and mucosal bleeding due to dominant pathogenic variants in GP1BA clinical manifestations can vary, even within the same family. that cause excessive binding of the GPIb-IX-V complex to von Willebrand factor. Wiskott-Aldrich syndrome (WAS): profound thrombocytopenia, small platelet size, 301000/ 300392 GP1BB 231200/138720 Autosomal Recessive eczema and recurrent infections; increased risk for autoimmune disorders and 153670/138720 Autosomal Dominant lymphoma; absent or decreased intracellular WAS protein (WASP) detection in hematopoietic cells by flow cytometry or western blotting. GP9 231200/173515 Autosomal Recessive X-linked Recessive 153670/173515 Autosomal Dominant X-linked neutropenia: congenital neutropenia; variable severity, infectious history, 300299/ 300392 myelodysplasia and increased risk for MDS and AML. Normal WAS protein (WASP) HOXA11 Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 (RUSAT1): possible 605432/142958 Autosomal Dominant expression by flow cytometry or western blotting. aplastic anemia and proximal fusion of the radius and ulna. Thrombocytopenia symptoms may be present at birth and require bone marrow or umbilical-cord stem-cell X-linked thrombocytopenia: thrombocytopenia, possibly intermittent, with small platelet 313900 / 300392 transplantation. volume; variable severity of bleeding, autoimmune disease and malignancies, variable WASP expression by flow cytometry or western blotting. ITGA2B Glanzmann thrombasthenia: mild to severe bleeding disorder with platelet aggregation 273800/607759 Autosomal Recessive abnormalities due to quantitative or qualitative defects of platelet glycoproteins IIb and/ WIPF1 Wiskott-Aldrich syndrome-2 (WAS2): thrombocytopenia, recurrent infections, eczema, 614493/602357 Autosomal Recessive or IIIa. caused by homozygous or compound heterozygous recessive pathogenic variants B-cell and T-cell deficiency, impaired NK cell function; normal WASP sequence and mRNA; in ITGA2B or ITGB3. defective WASP expression. Bleeding disorder, platelet-type 16 (BDPLT16): congenital macrothrombocytopenia 187800/607759 Autosomal Dominant ITGB3 associated with platelet anisocytosis with mild to or absent symptoms due to specific 273800/173470 Autosomal Recessive heterozygous dominant activating mutations in ITGA2B or ITGB3. 187800/173470 Autosomal Dominant Inherited Thrombocytopenia Panel: gene, clinical phenotype, OMIM number and inheritance pattern. Inherited Thrombocytopenia Panel: gene, clinical phenotype, OMIM number and inheritance pattern. Gene Clinical Phenotype Phenotype/Gene Inheritance Gene Clinical Phenotype Phenotype/Gene Inheritance OMIM number OMIM number ACTN1 Bleeding disorder, platelet-type 15 (BDPT15): macrothrombocytopenia with mild or 615193/102575 Autosomal Dominant MPL Congenital amegakaryocytic thrombocytopenia (CAMT): type 1-onset in infancy with 604498/159530 Autosomal Recessive absent bleeding tendency. severe thrombocytopenia and progressing to pancytopenia; type II with transient increases in platelet counts with onset of bone marrow failure at age 3 or later. ANKRD26 Thrombocytopenia-2 (THC2): mild bleeding tendency with normal platelet function and 188000/610855 Autosomal Dominant morphology with increased predisposition to hematologic myeloid malignancies. MYH9 MYH9-related disorders: large platelets and thrombocytopenia at birth with variable 160775 later onset of non-hematologic manifestations including progressive sensorineural CYCS Thrombocytopenia-4 (THC4): bleeding tendency may be mild or absent with normal 612004/123970 Autosomal Dominant hearing loss, glomerulonephritis, presenile cataracts and elevation of liver enzymes. platelet size and morphology. MYH9-related disorders includes previously characterized disorders: ETV6 Thrombocytopenia-5 (THC5): onset is typically in early childhood with an increased 616216/600618 Autosomal Dominant May-Hegglin anomaly: thrombocytopenia, giant platelets, and Dohle body-like 155100/160775 susceptibility to develop various hematologic and solid malignancies throughout life. inclusions. FLI1 Paris-Trousseau thrombocytopenia (TCPT): mild bleeding tendency with variable 188025/193067 Deletion syndrome Epstein syndrome: thrombocytopenia, giant platelets, nephritis, and deafness. 153650/160775 thrombocytopenia, dysmorphic facies, abnormal giant alpha-granules in platelets and Autosomal Dominant dysmegakaryopoiesis as part of contiguous gene deletion syndrome of 11q (Jacobsen Fechtner syndrome: thrombocytopenia, giant platelets, and Dohle body-like inclusions in 153640/160775 syndrome). peripheral blood leukocytes, with nephritis, hearing loss, and eye abnormalities, mostly cataracts. Bleeding disorder, platelet-type, 21 (BDPLT21): moderate macrothrombocytopenia, 617443/ 193067 Autosomal Recessive/ abnormal giant alpha-granules in platelets, functional platelet disorder. Phenotype Autosomal Dominant Sebastian syndrome: thrombocytopenia, giant platelets, and leukocyte inclusions 605249/160775 caused by heterozygous and homozygous pathogenic variants. composed of highly dispersed filaments and few ribosomes. GATA1 GATA1-related cytopenia: thrombocytopenia and/or anemia ranging from mild to DNFA17: nonsyndromic progressive hearing loss with onset in childhood or later; hearing 603622/160775 severe; may be associated with platelet dysfunction, mild β-thalassemia, neutropenia, loss progresses from high frequency to moderate-severe deafness over time. and congenital erythropoietic porphyria (CEP). Thrombocytopenia present in infancy and anemia may range from mild to severe hydrops fetalis. Carrier females may have NBEAL2 Gray platelet syndrome (GPS): large platelets that lack α-granules leading to mild 139090/614169 Autosomal Recessive mild to moderate symptoms. to moderate bleeding tendency and moderate thrombocytopenia with increased development of myelofibrosis and splenomegaly. X-linked dyserythropoietic anemia and thrombocytopenia (XLTDA): variable severity of 300367/305371 thrombocytopenia and dyserythropoietic anemia may be present. X-linked Recessive PRKACG Bleeding disorder, platelet-type 19 (BDPLT19): severe macrothrombocytopenia and 616176/176893 Autosomal Recessive bleeding symptoms. Thrombocytopenia with beta-thalassemia, X-linked (XLTT): variable thrombocytopenia, 314050/305371 splenomegaly, and unbalanced hemoglobin chain synthesis resembling that of beta- RBM8A Thrombocytopenia-Absent Radius syndrome (TAR): characterized by bilateral absence 274000/605313 Autosomal Recessive thalassemia minor. of the radius with presence of thumbs, thrombocytopenia which may be congenital or develop early in life and decreases with age. Other anomalies of the skeleton (upper and GFI1B Bleeding disorder, platelet-type 17 (Gray Platelet-like syndrome): variable 187900/604383 Autosomal Dominant lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and bleeding symptoms due to disorder of platelet alpha granules with moderate agenesis of uterus, cervix, and upper part of the vagina) can occur. macrothrombocytopenia and red cell anisopoikilocytosis. RUNX1 Familial platelet disorder with associated myeloid malignancy (FPDMM): characterized by 601399/151385 Autosomal Dominant GP1BA Bernard-Soulier syndrome (BSS): mild to severe bleeding disorder due to absence or 231200/606672 Autosomal Recessive mild to moderate thrombocytopenia, qualitative platelet defects and a predisposition to dysfunction of the platelet glycoprotein receptor Ib/V/IX complex with mild to moderate development of myeloid malignancies. thrombocytopenia, unusually large platelets and abnormal platelet function with absent or markedly reduced aggregation response to ristocetin. Caused by homozygous or STXBP2 Familial hemophagocytic lymphohistiocytosis (FHL5): immune dysregulation with 613101/601717 Autosomal Recessive compound heterozygous pathogenic variants in GP1BA (606672), GP1BB (138720), or GP9 hypercytokinemia, defective function of natural killer cells, and macrophages that (173515). infiltrate multiple organs; characterized by variable age of onset and severity with fever, chronic diarrhea, hepatosplenomegaly, pancytopenia, coagulation abnormalities and Bernard-Soulier syndrome (BSSA2): autosomal dominant (mono-allelic) form of BSS with 153670/606672 Autosomal Dominant CNS problems. mild thrombocytopenia, variable large platelets, and mild or no bleeding tendency, due to specific heterozygous variants in GP1BA or rarely in GP1BB or GP9. TUBB1 Congenital macrothrombocytopenia. 613112/612901 Autosomal Dominant Platelet-type von Willebrand disease (also known as pseudo-von Willebrand disease): 177820/606672 Autosomal Dominant WAS WAS-related disorders comprise a spectrum of disorders, not distinct entities, as thrombocytopenia and mucosal bleeding due to dominant pathogenic variants in GP1BA clinical manifestations can vary, even within the same family. that cause excessive binding of the GPIb-IX-V complex to von Willebrand factor. Wiskott-Aldrich syndrome (WAS): profound thrombocytopenia, small platelet size, 301000/ 300392 GP1BB 231200/138720 Autosomal Recessive eczema and recurrent infections; increased risk for autoimmune disorders and 153670/138720 Autosomal Dominant lymphoma; absent or decreased intracellular WAS protein (WASP) detection in hematopoietic cells by flow cytometry or western blotting. GP9 231200/173515 Autosomal Recessive X-linked Recessive 153670/173515 Autosomal Dominant X-linked neutropenia: congenital neutropenia; variable severity, infectious history, 300299/ 300392 myelodysplasia and increased risk for MDS and AML. Normal WAS protein (WASP) HOXA11 Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 (RUSAT1): possible 605432/142958 Autosomal Dominant expression by flow cytometry or western blotting. aplastic anemia and proximal fusion of the radius and ulna. Thrombocytopenia symptoms may be present at birth and require bone marrow or umbilical-cord stem-cell X-linked thrombocytopenia: thrombocytopenia, possibly intermittent, with small platelet 313900 / 300392 transplantation. volume; variable severity of bleeding, autoimmune disease and malignancies, variable WASP expression by flow cytometry or western blotting. ITGA2B Glanzmann thrombasthenia: mild to severe bleeding disorder with platelet aggregation 273800/607759 Autosomal Recessive abnormalities due to quantitative or qualitative defects of platelet glycoproteins IIb and/ WIPF1 Wiskott-Aldrich syndrome-2 (WAS2): thrombocytopenia, recurrent infections, eczema, 614493/602357 Autosomal Recessive or IIIa. caused by homozygous or compound heterozygous recessive pathogenic variants B-cell and T-cell deficiency, impaired NK cell function; normal WASP sequence and mRNA; in ITGA2B or ITGB3. defective WASP expression. Bleeding disorder, platelet-type 16 (BDPLT16): congenital macrothrombocytopenia 187800/607759 Autosomal Dominant ITGB3 associated with platelet anisocytosis with mild to or absent symptoms due to specific 273800/173470 Autosomal Recessive heterozygous dominant activating mutations in ITGA2B or ITGB3. 187800/173470 Autosomal Dominant Indications for testing Assay sensitivity and limitations Inherited Thrombocytopenia Panel: The analytical sensitivity of this test is >99% for single nucleotide • Clarification and/or confirmation of diagnosis in a patient with changes and insertions and deletions of less than 20 bp. Our clinical findings of thrombocytopenia or an associated genetic analysis does not detect large deletions or duplications (>20 bp) syndrome when patient’s history suggests the possibility of or deletions, duplications or variants that are outside the regions multiple inherited thrombocytopenia disorders sequenced. To order the Analysis of copy number variation at the exon or gene level, please refer to the aCGH Deletion/Duplication • Identification of carriers with family history of an unspecified Analysis test, if available, or contact Client Services before placing thrombocytopenia disorder to provide accurate reproductive your order. risk assessment and genetic counseling Single gene sequencing or custom gene panel: Reporting of results • Analysis of genes included in the Inherited Thrombocytopenia Panel may also be ordered as a stand-alone single gene While this assay is designed to detect germline genetic variants sequencing test or custom panel (2-10 genes) as dictated by associated with thrombocytopenia, variants unrelated to the the patient’s clinical and laboratory phenotype indication for testing, but with other clinical and/or reproductive implications, may also be detected. A comprehensive database of Targeted familial variant analysis: gene-phenotype relationships listed by gene name can be found • Targeted variant analysis for clinical diagnosis, carrier at http://www.omim.org. identification or prenatal diagnosis can also be performed on Results are classified and reported in accordance with ACMG any gene in the panel when the pathogenic variant(s) is known next-generation sequencing standards. Variants predicted to in the family (test code: 4970) be pathogenic, likely pathogenic, and of uncertain significance For clinical questions about laboratory tests and test utilization will be reported; variants classified as likely benign or benign are support, contact BloodCenter Client Services: (414) 937-6396 or typically not reported but such data are available upon request. 800-245-3117, Option 1, to be directed to our genetic counselors Sequence variants are described using standard Human Genome and clinical support team. Variation Society (HGVS) nomenclature (http://hgvs.org).

Test method Specimen requirements This next generation sequencing assay analyzes 23 genes, Parental/Patient/Pediatric: 3-5 mL Whole Blood (EDTA tube, spanning the full coding regions plus a minimum 30bp of lavender top), 2-5 mL Bone Marrow (EDTA tube, lavender top), 3-4 non-coding DNA including intron-exon junctions, and to Buccal Swabs, or ≥1ug of DNA at ≥50ng/uL of High Quality DNA. approximately 200bp upstream of ANKRD26 coding region (5’ UTR). These targeted regions are captured by hybridization, Fetal: 7-15 mL Amniotic Fluid, 5-10 mg Chorionic Villi; back up amplified and sequenced by massively parallel sequencing. culture of Amniocytes or Chorionic Villi is highly recommended. Regions will have a minimum coverage of 50x and those regions Cultured: Two T25 flasks cultured Amniocytes or Chorionic Villi with less than 50 sequencing reads or low quality coverage are (2x106 minimum). Maternal Blood sample of 3-5 mL Whole Blood supplemented with Sanger sequencing. All regions are covered (EDTA tube, lavender top) is requested for all prenatal samples for by bi-directional analysis. Variants are identified by a customized maternal cell contamination studies. bioinformatics pipeline, analyzed and comprehensively If questions please contact the laboratory to discuss sample interpreted by our team of directors, scientists, and genetic requirements. counselors. All reported variants, including pathogenic, likely pathogenic, and variants of uncertain significance, are confirmed by Sanger sequencing. For prenatal testing, analysis of variable number tandem repeats (VNTR) is used to confirm results are not affected by maternal cell contamination.

Inherited Thrombocytopenia Panel, Page 3 Insert Shipping requirements References Ship on an ice pack or at room Albers CA, Paul DS et al. 2012. Compound inheritance of a low-frequency temperature. Protect from freezing. regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012 Feb 26; 44(4):435-9. Place the specimen and the requisition Inherited into plastic bags and seal. Insert into Ali S, Ghosh K et al. 2016. Congenital macrothrombocytopenia is a heterogeneous disorder in India. Haemophilia. Jul; 22(4):570-82. a Styrofoam container, seal and place Balduini CL, Pecci A, Savoia A. 2011. Recent advances in the understanding and into a sturdy cardboard box, and management of MYH9-related inherited thrombocytopenias. Br J Haematol. tape securely. Ship the package in Jul;154(2):161-174. Thrombocytopenia compliance with your overnight carrier IP Balduini CL, Melazzini F, Pecci A. 2017. Inherited thrombocytopenias-recent guidelines. Label with the following advances in clinical and molecular aspects. Platelets. Jan;28(1):3-13. address: Bastida JM, Del Rey M et al. 2016. Wiskott-Aldrich syndrome in a child presenting Client Services/Diagnostic Laboratory with macrothrombocytopenia Platelets. Nov 25:1-4. Panel BloodCenter of Wisconsin Bottega R, Marconi C et al. 2015. ACTN1-related thrombocytopenia: identification 638 N. 18th St. of novel families for phenotypic characterization. Blood. Jan 29;125(5):748-50. Milwaukee, WI 53233 Favier R, Raslova H. 2015. Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias. Br J Haematol. Sep;170 (5):626-39. Gunay-Aygun M, Falik-Zaccai TC et al. 2011. NBEAL2 is mutated in Gray Platelet BloodCenter of Wisconsin offers a specifically recessive manner. More common and rare types of inherited Required forms Syndrome and is required for biogenesis of platelet alpha-granules. Nat Genet. designed Inherited Thrombocytopenia Panel thrombocytopenia will be identified with this panel, including Aug; 43(8): 732–734. MYH9-related disorders, Bernard-Soulier syndrome, congenital Please complete all pages of the (test code 4840) optimized for detection of requisition form. Clinical history Kumar R, Kahr WHA. 2013. Congenital Thrombocytopenia: Clinical Manifestations, amegakaryocytic thrombocytopenia, familial platelet disorder Laboratory Abnormalities, and Molecular Defects of a Heterogeneous Group of germline variants in 23 genes known to cause with predisposition to acute myelogenous leukemia, ANKRD26- (including patient’s ethnicity, clinical Conditions. Hematol Oncol Clin North Am. June; 27(3):465-94. diagnosis, family history and relevant inherited thrombocytopenia. related thrombocytopenia, WAS-related thrombocytopenia, gray Manchev VT, Hilpert M et al. 2014. A new form of macrothrombocytopenia platelet syndrome and others. Additional genes in this panel are laboratory findings) is necessary for induced by a germ-line mutation in the PRKACG gene. Blood.Oct 16;124(16):2554- optimal interpretation of genetic test 63. associated with syndromes that have thrombocytopenia as a Inherited thrombocytopenia is a heterogeneous group of common finding among other non-hematologic features. results and recommendations. Clinical Noris P, Biino G et al. 2014. Platelet diameters in inherited thrombocytopenias: disorders characterized by low platelet counts typically less than and laboratory history can eitherIP be analysis of 376 patients with all known disorders. Aug 7; 124(6):e4-e10. This panel evaluates for single nucleotide variants and small 150,000/uL, but often can vary with age, gender and ethnic recorded on the requisition form or Noris P, Favier R et al. 2013. ANKRD26-related thrombocytopenia and myeloid deletions and duplications, which are most commonly clinical and laboratory reports can be malignancies. Blood .122:1987-1989. background. Symptoms of thrombocytopenia may include responsible for genetic disease. However, large deletions and submitted with the sample. Ok Bozkaya I, Yarali N et al. Severe Clinical Course in a Patient with Congenital purpura, petechiae, prolonged bleeding from cuts, epistaxis, gum duplications, also referred to as copy number variants (CNV), are Amegakaryocytic Thrombocytopenia Due to a Missense Mutation of the c-MPL bleeding, excessive bleeding after surgery, hemoptysis, hematuria a known cause of genetic disorders, but can escape detection Gene. Turk J Haematol.Jun; 32(2): 172-4. and menorrhagia in women. Severe inherited thrombocytopenias by next-generation sequence analysis. Further testing with CPT Codes/Billing/Turnaround time Pagel J, Beutel K et al. 2012. Distinct mutations in STXBP2 are associated can present in the newborn period, while mild thrombocytopenia the BloodCenter of Wisconsin custom designed, high density with variable clinical presentations in patients with familial hemophagocytic may remain undiagnosed until incidental detection on gene-focused array, aCGH Deletion/Duplication Analysis, allows Test Code: 4840 lymphohistiocytosis type 5 (FHL5). Blood. 119:6016-6024. routine blood testing in adulthood. Some inherited types of for the possible detection of large deletions and duplications CPT codes: 81404, 81406, 81479 Saultier P,Vidal, L.et al. 2017. Macrothrombocytopenia and dense granule thrombocytopenia have only hematologic manifestations, within a single exon of a given gene, encompassing one or more deficiency associated with FLI1 variants: ultrastructural and pathogenic features. such as differences in platelet size or distinctive granulocyte Turnaround time: 21 days Haematologica.102:1006-1016. exons, or affecting an entire gene. This testing may be warranted inclusions, while other syndromic types present with additional when results of sequence analysis do not fully explain a clinical The CPT codes provided are subject to change as more Savoia A. 2016. Molecular basis of Inherited thrombocytopenias. Clin Genet non-hematologic manifestations. Certain types of inherited information becomes available. CPT codes are provided only as Feb;89(2):154-62. phenotype, or when a suspected disorder is known to be caused thrombocytopenia cause predisposition to acute myelogenous by deletions or duplications. Please refer to the aCGH Deletion/ guidance to assist clients with billing. Savoia A. 2016. Molecular basis of Inherited thrombocytopenias: an update. leukemia or myelodysplastic syndromes. Current Opinion in Hematology. Sep;23(5):486-492. Duplication Analysis test description for more information about For additional information related to shipping, billing or pricing, Misdiagnosis of inherited thrombocytopenia as autoimmune specific genes included in this array. please contact, BloodCenter Client Services: (414) 937-6396 or Kunishima Shinji S, Kobayashi R et al. 2009. Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule thrombocytopenia (ITP) can result in inappropriate therapies and 800-245-3117, Option 1, or [email protected]. Inherited platelet disorders associated with platelet dysfunction assembly. Blood. 113:458-461. inadequate surveillance for additional medical complications, are included in the Platelet Function Disorder Panel. For broader Stevenson WS, Rabbolini DJ et al. 2015. Paris-Trousseau thrombocytopenia is underscoring the importance of accurate diagnosis. Advances in evaluation of unspecified platelet problems, both the Inherited phenocopied by the autosomal recessive inheritance of a DNA-binding domain genetic testing through next-generation sequencing allow for Thrombocytopenia Panel and Platelet Function Disorder Panel mutation in FLI1. Blood. Oct 22;126(17); 2027-30. identification of underlying genetic defects and for distinguishing can be ordered together as part of the Comprehensive Platelet Zhang My, Churpek JE et al. 2015. Germline ETV6 mutations in familial inherited cases from immune thrombocytopenia. Accurate Disorder Panel. thrombocytopenia and hematologic malignancy. Nat Genet. Feb; 47(2):180-185. diagnosis provides information about the phenotype and prognosis, guides medical management decisions, assists with the Refer to the table inside for further information about each identification of affected family members, and allows for accurate gene in the Inherited Thrombocytopenia Panel, including the genetic recurrence risk assessment. clinical phenotype, OMIM numbers and inheritance pattern. Variants in several different genes known to cause syndromic or non-syndromic thrombocytopenia may be inherited in an autosomal recessive, autosomal dominant or X-linked

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