Shipping requirements Gresele P. 2014. Diagnosis of inherited function disorders: guidance for the SSC of the ISTH. J Thromb and Haemost. 13:314-322. Ship on an ice pack or at room Hinckley J, Di Paola J. 2014. Genetic basis of congenital platelet disorders. temperature. Protect from freezing. Am Soc Hematol Educ Program. Dec5;(1): 3337-42. Place the specimen and the requisition Platelet Function Israels SJ, El-Ekiaby M, Quiroga T, Mezzano D. 2010. Inherited disorders of platelet into plastic bags and seal. Insert into function and challenges to diagnosis of mucocutaneous . . a Styrofoam container, seal and place 16 (Suppl 5):152-9. into a sturdy cardboard box, and Johnson B, Lowe GC et al. 2016. Whole exome sequencing identifies genetic tape securely. Ship the package in variants in inherited with secondary qualitative function Disorder Panel defects. Haematologica. 101(10):1170-1179. ORDER SHIP compliance with your overnight carrier guidelines. Label with the following Kunicki TJ, Williams SA, Nugent DJ. 2012. Genetic variants that affect platelet address: function. Current Opin Hematol.19:371-9. Client Services/Diagnostic Laboratory Lentaigne C, Freson K et al. 2016. Inherited platelet disorders: toward DNA-based BloodCenter of Wisconsin diagnosis. Blood. 127(23):2814-2823. 638 N. 18th St. Maclachlan A, Watson SP, Morgan NV. 2017. Inherited platelet disorders: Insight Milwaukee, WI 53233 from platelet genomics using next-generation sequencing. . Jan ;28(1);14- 19. Mumford AD, Nisar S et al. 2013. Platelet dysfunction associated with the novel platelet syndrome, FLI1-Paris Trousseau thrombocytopenia, and Trp29Cys thromboxane A₂ receptor variant. J Thromb Haemost. Mar;11(3):547-54. BloodCenter of Wisconsin offers a specifically Required forms a number of platelet-type bleeding disorders. Additional genes Nurden AT, Nurden P. 2011. Advances in our understanding of the molecular basis designed Platelet Function Disorder Panel Please complete all pages of the of disorders of platelet function. J Thromb Haemost. 9 Suppl 1:76-91. in this panel are associated with syndromes that have defective (test code 4835) optimized for detection of platelet function as a common finding among other non- requisition form. Clinical history Nurden AT, Nurden P. 2015. Inherited disorders of platelet function: selected (including patient’s ethnicity, clinical updates. J Thromb Haemost. Volume 13(Suppl1): S2- S9. germline variants in 31 genes known to cause hematologic features. diagnosis, family history and relevant Paterson AD, Rommens JM, et al. 2010. Persons with Quebec platelet disorder inherited platelet function disorders. This panel evaluates for single nucleotide variants and small laboratory findings) is necessary for have a tandem duplication of PLAU, the urokinase plasminogen activator gene. deletions and duplications, which are most commonly optimal interpretation of genetic test Blood.115:1264-6. responsible for genetic disease. However, large deletions and ORDER results and recommendations. ClinicalSHIP Rao AK. 2013. Inherited platelet function disorders: overview and disorders of Inherited platelet function disorders are a heterogeneous group duplications, also referred to as copy number variants (CNV), are and laboratory history can either be granules, secretion, and signal transduction. Hematol Oncol Clin North Am. Jun; of bleeding disorders of variable severity caused by defects in also known cause of genetic disorders, but can escape detection 27(3):585-611. recorded on the requisition form or platelet adhesion, glycoprotein expression, receptor function, by next-generation sequence analysis. Further testing with clinical and laboratory reports can be Rehm HL, Bale SJ et al. 2013. Working Group of the American College of Medical signaling pathways, aggregation, cytoskeleton proteins, secretion, the BloodCenter of Wisconsin custom designed, high-density Genetics and Genomics Laboratory Quality Assurance Committee. ACMG clinical granular contents and abnormalities in procoagulant activity. submitted with the sample. laboratory standards for next-generation sequencing. Genet Med.15:733-747. gene-focused array, aCGH Deletion/Duplication Analysis, allows These disorders are typically associated with normal platelet for the possible detection of large deletions and duplications Richards S, Aziz N A et al.2015. Standards and guidelines for the interpretation of counts and characterized by bleeding symptoms which may sequence variants: a joint consensus recommendation of the American College within a single exon of a given gene, encompassing one or CPT Codes/Billing/Turnaround time of Medical Genetics and Genomics and the Association for Molecular Pathology. include epistaxis, extensive bruising, menorrhagia in women, more exons, or affecting an entire gene. This testing may be and the possibility of life-threatening excessive bleeding when Test Code: 4835 Genet Med.17:405-424. warranted when results of sequence analysis do not fully explain Saultier P,Vidal, L.et al. 2017. Macrothrombocytopenia and dense granule challenged by surgery, injury, or childbirth. a clinical phenotype, or when a suspected disorder is known to CPT codes: 81404, 81479 deficiency associated with FLI1 variants: ultrastructural and pathogenic features. The diagnosis of a specific platelet function disorder may be be caused by deletions or duplications. Specifically, the Quebec Haematologica.102:1006-1016. Turnaround time: 21 days difficult to establish based solely on functional studies, especially Platelet Disorder is associated with a heterozygous 78-kb tandem Stevenson WS, Rabbolini DJ et al. 2015. Paris-Trousseau thrombocytopenia is The CPT codes provided are subject to change as more in patients with milder disorders, as these assays are often duplication of the PLAU gene, which will be detected by aCGH phenocopied by the autosomal recessive inheritance of a DNA-binding domain and not by the Platelet Function Disorder Panel. Please refer to information becomes available. CPT codes are provided only as mutation in FLI1. Blood. Oct 22;126(17); 2027-30. technically challenging, difficult to interpret, and typically require guidance to assist clients with billing. immediate testing on fresh patient platelets due to limited sample the aCGH Deletion/Duplication Analysis test description for more Songdej N, Rao AK. 2017. Inherited platelet dysfunction and hematopoietic information about specific genes included in this array. transcription factor mutations. Platelets Jan; 28(1):20-26. stability. Advances in genetic testing through next-generation For additional information related to shipping, billing or pricing, sequencing allow for identification of underlying genetic please contact, BloodCenter Client Services: (414) 937-6396 or Watson SP, Lowe M et al. 2013. Genotyping and phenotyping of platelet function For broader evaluation of unspecified platelet problems, disorders. J Thromb Haemost. 11(suppl.1):351-363. defects for platelet function disorders that have overlapping both the Platelet Function Disorder Panel and the Inherited 800-245-3117, Option 1, or [email protected]. clinical and laboratory findings. Accurate diagnosis provides Westbury SK, Mumford AD. 2016. Genomics of platelet disorders. Hemophilia. Thrombocytopenia Panel can be ordered together as the 22(Suppl.5): 20-24. information about the phenotype and prognosis, guides medical Comprehensive Platelet Disorder Panel. For broader evaluation management decisions, assists with the identification of affected References Zhou Y, Zhang J. 2014. Arthrogryposis–renal dysfunction–cholestasis (ARC) of unspecified bleeding disorders, the Platelet Function Disorder syndrome: from molecular genetics to clinical features. Italian J Pediatrics. 40:77. family members, and allows for accurate genetic recurrence risk Panel and Disorder Panel can be ordered together as Cox K, Price V, Kahr WHA. 2011. Inherited platelet disorders: a clinical approach to assessment. the Comprehensive Bleeding Disorder Panel. diagnosis and management. Expert Rev Hematol. Aug;4(4):455-72. Variants in several different genes known to cause syndromic or Faioni EM, Razzari C et al. 2014. and gastro-duodenal ulcers Refer to the table inside for further information about each in inherited cytosolic phospholipase-A2 alpha deficiency. Thromb Haemost. non-syndromic platelet function disorders may be inherited in gene in the Platelet Function Disorder Panel, including the Dec;112(6):1182-9. an autosomal recessive or autosomal dominant manner. More clinical phenotype, OMIM numbers and inheritance pattern. Freson K, Wijgaerts A, Van Geet C. 2014. Update on the causes of platelet disorders common and many rare types of inherited platelet function and functional consequences. John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 36, disorders will be identified with this panel, including Glanzmann 313–325. thrombasthenia, Bernard-Soulier syndrome, familial platelet disorder with associated myeloid malignancy (FPDMM), Scott syndrome, leukocyte integrity adhesion deficiency type III, gray

© Copyright 2017 r0818 BloodCenter of Wisconsin, Inc. , Part of Versiti. All rights reserved. Platelet Function Disorder Panel: gene, clinical phenotype, OMIM number and inheritance pattern. Platelet Function Disorder 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 ANO6 Scott syndrome: moderate bleeding disorder due to abnormality of platelet 262890/608663 Autosomal Recessive HPS1 Hermansky-Pudlak syndrome (HPS): multisystem disorder characterized by 203300/604982 Autosomal Recessive procoagulation activity with normal platelet count. Impaired exposure of HPS3 oculocutaneous albinism and platelet defects with reduced or absent delta granules on 614072/606118 Autosomal Recessive phosphatidylserine on the outer leaflet of platelet membrane. electron microscopy of platelets. Subtypes are caused by recessive pathogenic variants HPS4 614073/606682 Autosomal Recessive AP3B1 (HPS2) Hermansky-Pudlak syndrome (HPS): multisystem disorder characterized by 608233/603401 Autosomal Recessive in nine different genes and variable additional features including neutropenia and/or oculocutaneous albinism and platelet defects with reduced or absent delta granules on HPS5 immune defects (HPS2), pulmonary fibrosis HPS1( , HPS2 and HPS4), or granulomatous 614074/607521 Autosomal Recessive BLOC1S3 614077/609762 Autosomal Recessive colitis (HPS1 and HPS4). HPS3 is associated with milder bleeding symptoms and minimal (HPS8) electron microscopy of platelets. Subtypes are caused by recessive pathogenic variants HPS6 614075/607522 Autosomal Recessive in nine different genes and variable additional features including neutropenia and/or hypopigmentation. BLOC1S6 immune defects (HPS2), pulmonary fibrosis (HPS1, HPS2 and HPS4), or granulomatous 614171/604310 Autosomal Recessive ITGA2B Glanzmann thrombasthenia: mild to severe bleeding disorder with platelet aggregation 273800/607759 Autosomal Recessive (HPS9) colitis (HPS1 and HPS4). HPS3 is associated with milder bleeding symptoms and minimal abnormalities due to quantitative or qualitative defects of platelet glycoproteins IIb DTNBP1 hypopigmentation. 614076/607145 Autosomal Recessive and /or IIIa. caused by homozygous or compound heterozygous recessive pathogenic (HPS7) variants in ITGA2B or ITGB3. FERMT3 Leukocyte integrity adhesion deficiency type III: increased bleeding symptoms, poor 612840/607901 Autosomal Recessive Bleeding disorder, platelet-type 16 (BDPLT16): congenital macrothrombocytopenia 187800/607759 Autosomal Dominant wound healing, normal/ reduced platelets, bacterial infections and neutrophilia. 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. FLI1 Paris-Trousseau thrombocytopenia (TCPT): mild bleeding tendency with variable 188025/193067 Deletion syndrome 187800/173470 Autosomal Dominant thrombocytopenia, dysmorphic facies, abnormal giant alpha-granules in platelets and LYST Chediak-Higashi syndrome: multisystem disorder characterized by partial 214500/ 606897 Autosomal Recessive dysmegakaryopoiesis as part of contiguous gene deletion syndrome of 11q (Jacobsen oculocutaneous albinism, immunodeficiency with neutropenia and giant neutrophil syndrome). granules, bleeding tendency due to absent, reduced or abnormal platelet-dense bodies, Paris-Trousseau thrombocytopenia: moderate thrombocytopenia, absent collagen- 617443/ 193067 Autosomal Recessive/ malignant lymphoma and varying neurologic problems. Autosomal Dominant induced platelet aggregation and large, fused alpha granules in circulating platelets. NBEAL2 Gray platelet syndrome (GPS): large platelets that lack α-granules leading to mild 139090/614169 Autosomal Recessive Phenotype caused by FLI1 homozygous pathogenic variant or heterozygous variant in to moderate bleeding tendency and moderate thrombocytopenia with increased case reports (Stevenson WS, Rabbolini DJ et al. 2015. Blood. Oct 22;126(17); 2027-30. development of myelofibrosis and splenomegaly. GATA1 GATA1-related cytopenia: thrombocytopenia and/or anemia ranging from mild P2RY12 Bleeding disorder, platelet-type 8 (BDPLT8): mild to moderate mucocutaneous bleeding 609821/600515 Autosomal Recessive to severe; may be associated with platelet dysfunction, mild β-thalassemia, and excessive bleeding after surgery or trauma due to ADP receptor defect. neutropenia, and congenital erythropoietic porphyria (CEP). Thrombocytopenia present in infancy and anemia may range from mild to severe hydrops fetalis. Carrier PLA2G4A Recurrent episodes of multiple complicated ulcers of the small intestine, platelet See reference/ Autosomal Recessive females may have mild to moderate symptoms. dysfunction and globally decreased eicosanoid synthesis due to phospholipase A2 600522 deficiency (Faioni EM et al. 2014). 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 with 616176/176893 Autosomal Recessive moderate-severe bleeding tendency due to defects in proplatelet Thrombocytopenia with beta-thalassemia, X-linked (XLTT): variable thrombocytopenia, 314050/305371 splenomegaly, and unbalanced hemoglobin chain synthesis resembling that of beta- formation, platelet activation and cytoskeleton reorganization. thalassemia minor. RASGRP2 Bleeding disorder, platelet-type 18 (BDPLT18): mild bleeding wtih increased bleeding 615888/605577 Autosomal Recessive GFI1B Bleeding disorder, platelet-type 17 (Gray Platelet-like syndrome): variable 187900/604383 Autosomal Dominant times and platelets showed reduced aggregation in response to ADP or epineprhine bleeding symptoms due to disorder of platelet alpha granules with moderate RUNX1 Familial platelet disorder with associated myeloid malignancy (FPDMM): mild to 601399/151385 Autosomal Dominant macrothrombocytopenia and red cell anisopoikilocytosis. moderate thrombocytopenia, qualitative platelet defects and a predisposition to GP1BA Bernard-Soulier syndrome (BSS): mild to severe bleeding disorder due to absence 231200/606672 Autosomal Recessive development of myeloid malignancies. or dysfunction of the platelet glycoprotein receptor Ib/V/IX complex with mild to STIM1 Stormorken syndrome: multisystem disorder characterized by mild bleeding tendency 185070/ 605921 Autosomal Dominant moderate thrombocytopenia, unusually large platelets and abnormal platelet function due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate with absent or markedly reduced aggregation response to ristocetin. caused by myopathy, congenital miosis, and ichthyosis, with variable headache or recurrent stroke- homozygous or compound heterozygous pathogenic variants in GP1BA (606672), GP1BB like episodes. (138720), or GP9 (173515). TBXA2R Susceptibility to bleeding disorder platelet-type 13 (BDPLT13): susceptibility to mild 614009/188070 Autosomal Dominant Bernard-Soulier syndrome (BSSA2): autosomal dominant (mono-allelic) form of BSS with 153670/606672 Autosomal Dominant mucocutaneous bleeding due to defective platelet thromboxane A2 receptor, with mild thrombocytopenia, variable large platelets, and mild or no bleeding tendency, due bleeding phenotype occurring only in the presence of a second variant in this gene or to specific heterozygous variants in GP1BA gene or rarely in GP1BB or GP9. another gene affecting platelet function. Platelet-type (also known as pseudo-von Willebrand disease): 177820/606672 Autosomal Dominant VIPAS39 Arthrogryposis, renal dysfunction and cholestasis syndrome (ARCS1 and 2): multisystem 613404/613401 Autosomal Recessive thrombocytopenia and mucosal bleeding due to dominant pathogenic variants in (VIPAR) disorder characterized by early onset and limited survival with arthrogryposis, renal GP1BA that cause excessive binding of the GPIb-IX-V complex to von Willebrand factor. VPS33B dysfunction and cholestasis with additional symptoms of ichthyosis, abnormal platelet 208085/608552 Autosomal Recessive GP1BB 231200/138720 Autosomal Recessive count and function, secondary infection, and cardiovascular anomalies. 153670/138720 Autosomal Dominant GP9 231200/173515 Autosomal Recessive 153670/173515 Autosomal Dominant The PLAU gene is not included in this panel. For analysis of the Quebec Platelet Disorder associated with a heterozygous 78-kb tandem duplication of the PLAU gene, please order aCGH. GP6 Bleeding disorder, platelet-type 11 (BDPLT11): mild to moderate bleeding disorder 614201/605546 Autosomal Recessive due to glycoprotein VI deficiency with defective platelet activation and aggregation in response to collagen. Platelet Function Disorder Panel: gene, clinical phenotype, OMIM number and inheritance pattern. Platelet Function Disorder 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 ANO6 Scott syndrome: moderate bleeding disorder due to abnormality of platelet 262890/608663 Autosomal Recessive HPS1 Hermansky-Pudlak syndrome (HPS): multisystem disorder characterized by 203300/604982 Autosomal Recessive procoagulation activity with normal platelet count. Impaired exposure of HPS3 oculocutaneous albinism and platelet defects with reduced or absent delta granules on 614072/606118 Autosomal Recessive phosphatidylserine on the outer leaflet of platelet membrane. electron microscopy of platelets. Subtypes are caused by recessive pathogenic variants HPS4 614073/606682 Autosomal Recessive AP3B1 (HPS2) Hermansky-Pudlak syndrome (HPS): multisystem disorder characterized by 608233/603401 Autosomal Recessive in nine different genes and variable additional features including neutropenia and/or oculocutaneous albinism and platelet defects with reduced or absent delta granules on HPS5 immune defects (HPS2), pulmonary fibrosis HPS1( , HPS2 and HPS4), or granulomatous 614074/607521 Autosomal Recessive BLOC1S3 614077/609762 Autosomal Recessive colitis (HPS1 and HPS4). HPS3 is associated with milder bleeding symptoms and minimal (HPS8) electron microscopy of platelets. Subtypes are caused by recessive pathogenic variants HPS6 614075/607522 Autosomal Recessive in nine different genes and variable additional features including neutropenia and/or hypopigmentation. BLOC1S6 immune defects (HPS2), pulmonary fibrosis (HPS1, HPS2 and HPS4), or granulomatous 614171/604310 Autosomal Recessive ITGA2B Glanzmann thrombasthenia: mild to severe bleeding disorder with platelet aggregation 273800/607759 Autosomal Recessive (HPS9) colitis (HPS1 and HPS4). HPS3 is associated with milder bleeding symptoms and minimal abnormalities due to quantitative or qualitative defects of platelet glycoproteins IIb DTNBP1 hypopigmentation. 614076/607145 Autosomal Recessive and /or IIIa. caused by homozygous or compound heterozygous recessive pathogenic (HPS7) variants in ITGA2B or ITGB3. FERMT3 Leukocyte integrity adhesion deficiency type III: increased bleeding symptoms, poor 612840/607901 Autosomal Recessive Bleeding disorder, platelet-type 16 (BDPLT16): congenital macrothrombocytopenia 187800/607759 Autosomal Dominant wound healing, normal/ reduced platelets, bacterial infections and neutrophilia. 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. FLI1 Paris-Trousseau thrombocytopenia (TCPT): mild bleeding tendency with variable 188025/193067 Deletion syndrome 187800/173470 Autosomal Dominant thrombocytopenia, dysmorphic facies, abnormal giant alpha-granules in platelets and LYST Chediak-Higashi syndrome: multisystem disorder characterized by partial 214500/ 606897 Autosomal Recessive dysmegakaryopoiesis as part of contiguous gene deletion syndrome of 11q (Jacobsen oculocutaneous albinism, immunodeficiency with neutropenia and giant neutrophil syndrome). granules, bleeding tendency due to absent, reduced or abnormal platelet-dense bodies, Paris-Trousseau thrombocytopenia: moderate thrombocytopenia, absent collagen- 617443/ 193067 Autosomal Recessive/ malignant lymphoma and varying neurologic problems. Autosomal Dominant induced platelet aggregation and large, fused alpha granules in circulating platelets. NBEAL2 Gray platelet syndrome (GPS): large platelets that lack α-granules leading to mild 139090/614169 Autosomal Recessive Phenotype caused by FLI1 homozygous pathogenic variant or heterozygous variant in to moderate bleeding tendency and moderate thrombocytopenia with increased case reports (Stevenson WS, Rabbolini DJ et al. 2015. Blood. Oct 22;126(17); 2027-30. development of myelofibrosis and splenomegaly. GATA1 GATA1-related cytopenia: thrombocytopenia and/or anemia ranging from mild P2RY12 Bleeding disorder, platelet-type 8 (BDPLT8): mild to moderate mucocutaneous bleeding 609821/600515 Autosomal Recessive to severe; may be associated with platelet dysfunction, mild β-thalassemia, and excessive bleeding after surgery or trauma due to ADP receptor defect. neutropenia, and congenital erythropoietic porphyria (CEP). Thrombocytopenia present in infancy and anemia may range from mild to severe hydrops fetalis. Carrier PLA2G4A Recurrent episodes of multiple complicated ulcers of the small intestine, platelet See reference/ Autosomal Recessive females may have mild to moderate symptoms. dysfunction and globally decreased eicosanoid synthesis due to phospholipase A2 600522 deficiency (Faioni EM et al. 2014). 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 with 616176/176893 Autosomal Recessive moderate-severe bleeding tendency due to defects in megakaryocyte proplatelet Thrombocytopenia with beta-thalassemia, X-linked (XLTT): variable thrombocytopenia, 314050/305371 splenomegaly, and unbalanced hemoglobin chain synthesis resembling that of beta- formation, platelet activation and cytoskeleton reorganization. thalassemia minor. RASGRP2 Bleeding disorder, platelet-type 18 (BDPLT18): mild bleeding wtih increased bleeding 615888/605577 Autosomal Recessive GFI1B Bleeding disorder, platelet-type 17 (Gray Platelet-like syndrome): variable 187900/604383 Autosomal Dominant times and platelets showed reduced aggregation in response to ADP or epineprhine bleeding symptoms due to disorder of platelet alpha granules with moderate RUNX1 Familial platelet disorder with associated myeloid malignancy (FPDMM): mild to 601399/151385 Autosomal Dominant macrothrombocytopenia and red cell anisopoikilocytosis. moderate thrombocytopenia, qualitative platelet defects and a predisposition to GP1BA Bernard-Soulier syndrome (BSS): mild to severe bleeding disorder due to absence 231200/606672 Autosomal Recessive development of myeloid malignancies. or dysfunction of the platelet glycoprotein receptor Ib/V/IX complex with mild to STIM1 Stormorken syndrome: multisystem disorder characterized by mild bleeding tendency 185070/ 605921 Autosomal Dominant moderate thrombocytopenia, unusually large platelets and abnormal platelet function due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate with absent or markedly reduced aggregation response to ristocetin. caused by myopathy, congenital miosis, and ichthyosis, with variable headache or recurrent stroke- homozygous or compound heterozygous pathogenic variants in GP1BA (606672), GP1BB like episodes. (138720), or GP9 (173515). TBXA2R Susceptibility to bleeding disorder platelet-type 13 (BDPLT13): susceptibility to mild 614009/188070 Autosomal Dominant Bernard-Soulier syndrome (BSSA2): autosomal dominant (mono-allelic) form of BSS with 153670/606672 Autosomal Dominant mucocutaneous bleeding due to defective platelet thromboxane A2 receptor, with mild thrombocytopenia, variable large platelets, and mild or no bleeding tendency, due bleeding phenotype occurring only in the presence of a second variant in this gene or to specific heterozygous variants in GP1BA gene or rarely in GP1BB or GP9. another gene affecting platelet function. Platelet-type von Willebrand disease (also known as pseudo-von Willebrand disease): 177820/606672 Autosomal Dominant VIPAS39 Arthrogryposis, renal dysfunction and cholestasis syndrome (ARCS1 and 2): multisystem 613404/613401 Autosomal Recessive thrombocytopenia and mucosal bleeding due to dominant pathogenic variants in (VIPAR) disorder characterized by early onset and limited survival with arthrogryposis, renal GP1BA that cause excessive binding of the GPIb-IX-V complex to von Willebrand factor. VPS33B dysfunction and cholestasis with additional symptoms of ichthyosis, abnormal platelet 208085/608552 Autosomal Recessive GP1BB 231200/138720 Autosomal Recessive count and function, secondary infection, and cardiovascular anomalies. 153670/138720 Autosomal Dominant GP9 231200/173515 Autosomal Recessive 153670/173515 Autosomal Dominant The PLAU gene is not included in this panel. For analysis of the Quebec Platelet Disorder associated with a heterozygous 78-kb tandem duplication of the PLAU gene, please order aCGH. GP6 Bleeding disorder, platelet-type 11 (BDPLT11): mild to moderate bleeding disorder 614201/605546 Autosomal Recessive due to glycoprotein VI deficiency with defective platelet activation and aggregation in response to collagen. Indications for testing Assay sensitivity and limitations Platelet Function Disorder 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. This clinical findings of a platelet function disorder or an associated assay does not detect large deletions or duplications (>20 bp) genetic syndrome when patient’s history suggests multiple or deletions, duplications or variants that are outside the regions possible platelet function disorders sequenced. To order analysis of copy number variants 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 platelet function disorder to provide accurate reproductive risk your order. assessment and genetic counseling Single gene sequencing or custom gene panel: Reporting of results • Analysis of genes included in the Platelet Function Disorder Panel may also be ordered as a stand-alone single gene While this assay is designed to detect germline genetic sequencing test or custom panel (2-10 genes) as dictated by variants associated with platelet function disorders, variants the patient’s clinical and laboratory phenotype unrelated to the indication for testing, but with other clinical and/or reproductive implications, may also be detected. A Targeted familial variant analysis: comprehensive database of gene-phenotype relationships listed • Targeted variant analysis for clinical diagnosis, carrier by gene name can be found 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 31 genes, Parental/Patient/Pediatric: 3-5 mL Whole Blood (EDTA tube, spanning the full coding regions plus a minimum 30bp of non- lavender top), 2-5 mL Bone Marrow (EDTA tube, lavender top), 3-4 coding DNA including intron-exon junctions. These targeted Buccal Swabs, or ≥1ug of DNA at ≥50ng/uL of High Quality DNA. regions are captured by hybridization, amplified and sequenced by massively parallel sequencing. Regions will have a minimum Fetal: 7-15 mL Amniotic fluid, 5-10 mg Chorionic villi; back up coverage of 50x and those regions with less than 50 sequencing culture of amniocytes or chorionic villi is highly recommended. reads or low quality coverage are supplemented with Sanger Cultured: Two T25 flasks cultured amniocytes or chorionic villi sequencing. All regions are covered by bi-directional analysis. (2x106 minimum). Maternal Blood sample of 3-5 mL Whole Blood Variants are identified by a customized bioinformatics pipeline, (EDTA tube, lavender top) is requested for all prenatal samples for analyzed and comprehensively interpreted by our team of maternal cell contamination studies. directors, scientists, and genetic counselors. All reported variants, If questions please contact the laboratory to discuss sample including pathogenic, likely pathogenic, and variants of uncertain requirements. 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.

Platelet Function Disorder Panel, Page 3 Insert Shipping requirements Gresele P. 2014. Diagnosis of inherited platelet function disorders: guidance for the SSC of the ISTH. J Thromb and Haemost. 13:314-322. Ship on an ice pack or at room Hinckley J, Di Paola J. 2014. Genetic basis of congenital platelet disorders. temperature. Protect from freezing. Hematology Am Soc Hematol Educ Program. Dec5;(1): 3337-42. Place the specimen and the requisition Platelet Function Israels SJ, El-Ekiaby M, Quiroga T, Mezzano D. 2010. Inherited disorders of platelet into plastic bags and seal. Insert into function and challenges to diagnosis of mucocutaneous bleeding. Haemophilia. a Styrofoam container, seal and place 16 (Suppl 5):152-9. into a sturdy cardboard box, and Johnson B, Lowe GC et al. 2016. Whole exome sequencing identifies genetic tape securely. Ship the package in variants in inherited thrombocytopenia with secondary qualitative function Disorder Panel defects. Haematologica. 101(10):1170-1179. ORDER SHIP compliance with your overnight carrier guidelines. Label with the following Kunicki TJ, Williams SA, Nugent DJ. 2012. Genetic variants that affect platelet address: function. Current Opin Hematol.19:371-9. Client Services/Diagnostic Laboratory Lentaigne C, Freson K et al. 2016. Inherited platelet disorders: toward DNA-based BloodCenter of Wisconsin diagnosis. Blood. 127(23):2814-2823. 638 N. 18th St. Maclachlan A, Watson SP, Morgan NV. 2017. Inherited platelet disorders: Insight Milwaukee, WI 53233 from platelet genomics using next-generation sequencing. Platelets. Jan ;28(1);14- 19. Mumford AD, Nisar S et al. 2013. Platelet dysfunction associated with the novel platelet syndrome, FLI1-Paris Trousseau thrombocytopenia, and Trp29Cys thromboxane A₂ receptor variant. J Thromb Haemost. Mar;11(3):547-54. BloodCenter of Wisconsin offers a specifically Required forms a number of platelet-type bleeding disorders. Additional genes Nurden AT, Nurden P. 2011. Advances in our understanding of the molecular basis designed Platelet Function Disorder Panel Please complete all pages of the of disorders of platelet function. J Thromb Haemost. 9 Suppl 1:76-91. in this panel are associated with syndromes that have defective (test code 4835) optimized for detection of platelet function as a common finding among other non- requisition form. Clinical history Nurden AT, Nurden P. 2015. Inherited disorders of platelet function: selected (including patient’s ethnicity, clinical updates. J Thromb Haemost. Volume 13(Suppl1): S2- S9. germline variants in 31 genes known to cause hematologic features. diagnosis, family history and relevant Paterson AD, Rommens JM, et al. 2010. Persons with Quebec platelet disorder inherited platelet function disorders. This panel evaluates for single nucleotide variants and small laboratory findings) is necessary for have a tandem duplication of PLAU, the urokinase plasminogen activator gene. deletions and duplications, which are most commonly optimal interpretation of genetic test Blood.115:1264-6. responsible for genetic disease. However, large deletions and ORDER results and recommendations. ClinicalSHIP Rao AK. 2013. Inherited platelet function disorders: overview and disorders of Inherited platelet function disorders are a heterogeneous group duplications, also referred to as copy number variants (CNV), are and laboratory history can either be granules, secretion, and signal transduction. Hematol Oncol Clin North Am. Jun; of bleeding disorders of variable severity caused by defects in also known cause of genetic disorders, but can escape detection 27(3):585-611. recorded on the requisition form or platelet adhesion, glycoprotein expression, receptor function, by next-generation sequence analysis. Further testing with clinical and laboratory reports can be Rehm HL, Bale SJ et al. 2013. Working Group of the American College of Medical signaling pathways, aggregation, cytoskeleton proteins, secretion, the BloodCenter of Wisconsin custom designed, high-density Genetics and Genomics Laboratory Quality Assurance Committee. ACMG clinical granular contents and abnormalities in procoagulant activity. submitted with the sample. laboratory standards for next-generation sequencing. Genet Med.15:733-747. gene-focused array, aCGH Deletion/Duplication Analysis, allows These disorders are typically associated with normal platelet for the possible detection of large deletions and duplications Richards S, Aziz N A et al.2015. Standards and guidelines for the interpretation of counts and characterized by bleeding symptoms which may sequence variants: a joint consensus recommendation of the American College within a single exon of a given gene, encompassing one or CPT Codes/Billing/Turnaround time of Medical Genetics and Genomics and the Association for Molecular Pathology. include epistaxis, extensive bruising, menorrhagia in women, more exons, or affecting an entire gene. This testing may be and the possibility of life-threatening excessive bleeding when Test Code: 4835 Genet Med.17:405-424. warranted when results of sequence analysis do not fully explain Saultier P,Vidal, L.et al. 2017. Macrothrombocytopenia and dense granule challenged by surgery, injury, or childbirth. a clinical phenotype, or when a suspected disorder is known to CPT codes: 81404, 81479 deficiency associated with FLI1 variants: ultrastructural and pathogenic features. The diagnosis of a specific platelet function disorder may be be caused by deletions or duplications. Specifically, the Quebec Haematologica.102:1006-1016. Turnaround time: 21 days difficult to establish based solely on functional studies, especially Platelet Disorder is associated with a heterozygous 78-kb tandem Stevenson WS, Rabbolini DJ et al. 2015. Paris-Trousseau thrombocytopenia is The CPT codes provided are subject to change as more in patients with milder disorders, as these assays are often duplication of the PLAU gene, which will be detected by aCGH phenocopied by the autosomal recessive inheritance of a DNA-binding domain and not by the Platelet Function Disorder Panel. Please refer to information becomes available. CPT codes are provided only as mutation in FLI1. Blood. Oct 22;126(17); 2027-30. technically challenging, difficult to interpret, and typically require guidance to assist clients with billing. immediate testing on fresh patient platelets due to limited sample the aCGH Deletion/Duplication Analysis test description for more Songdej N, Rao AK. 2017. Inherited platelet dysfunction and hematopoietic information about specific genes included in this array. transcription factor mutations. Platelets Jan; 28(1):20-26. stability. Advances in genetic testing through next-generation For additional information related to shipping, billing or pricing, sequencing allow for identification of underlying genetic please contact, BloodCenter Client Services: (414) 937-6396 or Watson SP, Lowe M et al. 2013. Genotyping and phenotyping of platelet function For broader evaluation of unspecified platelet problems, disorders. J Thromb Haemost. 11(suppl.1):351-363. defects for platelet function disorders that have overlapping both the Platelet Function Disorder Panel and the Inherited 800-245-3117, Option 1, or [email protected]. clinical and laboratory findings. Accurate diagnosis provides Westbury SK, Mumford AD. 2016. Genomics of platelet disorders. Hemophilia. Thrombocytopenia Panel can be ordered together as the 22(Suppl.5): 20-24. information about the phenotype and prognosis, guides medical Comprehensive Platelet Disorder Panel. For broader evaluation management decisions, assists with the identification of affected References Zhou Y, Zhang J. 2014. Arthrogryposis–renal dysfunction–cholestasis (ARC) of unspecified bleeding disorders, the Platelet Function Disorder syndrome: from molecular genetics to clinical features. Italian J Pediatrics. 40:77. family members, and allows for accurate genetic recurrence risk Panel and Coagulation Disorder Panel can be ordered together as Cox K, Price V, Kahr WHA. 2011. Inherited platelet disorders: a clinical approach to assessment. the Comprehensive Bleeding Disorder Panel. diagnosis and management. Expert Rev Hematol. Aug;4(4):455-72. Variants in several different genes known to cause syndromic or Faioni EM, Razzari C et al. 2014. Bleeding diathesis and gastro-duodenal ulcers Refer to the table inside for further information about each in inherited cytosolic phospholipase-A2 alpha deficiency. Thromb Haemost. non-syndromic platelet function disorders may be inherited in gene in the Platelet Function Disorder Panel, including the Dec;112(6):1182-9. an autosomal recessive or autosomal dominant manner. More clinical phenotype, OMIM numbers and inheritance pattern. Freson K, Wijgaerts A, Van Geet C. 2014. Update on the causes of platelet disorders common and many rare types of inherited platelet function and functional consequences. John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 36, disorders will be identified with this panel, including Glanzmann 313–325. thrombasthenia, Bernard-Soulier syndrome, familial platelet disorder with associated myeloid malignancy (FPDMM), Scott syndrome, leukocyte integrity adhesion deficiency type III, gray

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