Outcome of an enhanced diagnostic pipeline for patients suspected of inherited thrombocytopenia

Leinøe, Eva; Gabrielaitė, Miglė; Funding, Eva; Greinacher, Andreas; Ostrowski, Sisse Rye; Zetterberg, Eva; Rossing, Maria

doi:10.1111/bjh.15886

Cited by 13 publications

(28 citation statements)

References 10 publications

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“…The results of the present study are comparable with results previously published like the recently published large cohort from Downes et al (n = 2396, including bleeding and thrombosis patients) and our own previously published adult cohort (n = 156), where eight patients (6%) were diagnosed as a direct consequence of WES, and 20 previously unreported class 4‐5 mutations were identified in 12% (18/156 patients) . As in the adult cohorts, children with thrombocytopenia were diagnosed more frequently than those with normal platelet count and benefit the most from genetic screening …”

Section: Discussionsupporting

confidence: 91%

Genetic screening of children with suspected inherited bleeding disorders

et al. 2020

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Introduction Genetic screening using high‐throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear. Aim To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing. Methods After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes. Results A total of 68 heterozygous class 3‐5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009). Conclusion We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work‐up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.

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Section: Discussionsupporting

confidence: 91%

Genetic screening of children with suspected inherited bleeding disorders

et al. 2020

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“…125,126 The use of NGS and high-throughput procedures for diagnosing platelet disorders including thrombocytopenias has quickly expanded worldwide as is illustrated by reports from Italy, Japan, Spain, France, Holland and Scandinavia as well as North America. 46,60,77,78,80,87,108,113,128,129 The question now is not whether to apply NGS procedures in the mainstream of diagnosis but when and how. 128 Certainly, a strong argument can now be made to use them upfront: early identification of a causal mutation in a known gene will avoid much unnecessary biological characterization, as we have stated recently in this journal.…”

Section: Diagnosismentioning

confidence: 99%

Section: Diagnosismentioning

confidence: 99%

Inherited thrombocytopenias: history, advances and perspectives

Nurden

2020

Haematologica

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In the late 19 th century improvements to the light microscope led to anucleate platelets being visualized in great numbers in human blood. Early pioneers in the field of platelet research included the Canadian William Osler, a Paris hematologist, George Hayem, who performed the first accurate platelet count, and the Italian Giulio Bizzozero. 1 In 1906, James Homer Wright confirmed that platelets were produced by bone marrow megakaryocytes. 2 When, in 1951, Harrington et al. 3 observed purpura in a child of a mother with immune thrombocytopenic purpura, a maternal factor was said to be destroying the platelets. Anti-platelet antibodies were identified as the cause and platelet transfusions, immunosuppressive therapy and splenectomy became standard treatments. Acquired thrombocytopenia, often with defective platelet function, has many causes. For example, it may be an immune response linked to blood transfusions and drugs, a direct consequence of viral or bacterial infections, be the result of other hematologic disorders or be secondary to many major illnesses. However, some thrombocytopenias are inherited and Professors Jean Bernard and Jean-Pierre Soulier in Paris were pioneers in this domain, describing in 1948 what they called in French "dystrophie thrombocytaire hémorragipare congénitale", later renamed the Bernard-Soulier syndrome (BSS). 4 Strikingly, many platelets were enlarged and some were giant. A key to the molecular defect was the platelet deficit of sialic acid, a negatively charged monosaccharide terminating many of the oligosaccharides of platelet glycoproteins (GP) and

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“…The patients were screened using an in silico 94‐gene panel including 63 platelet‐related and 31 non‐platelet‐related genes (Table ). DNA sequencing and germline variant calling was performed as previously described 6,7 . Allele frequencies were derived from gnomAD v2.1.1 (https://gnomad.broadinstitute.org).…”

Section: Methodsmentioning

confidence: 99%

Collagen remodelling and plasma ascorbic acid levels in patients suspected of inherited bleeding disorders harbouring germline variants in collagen‐related genes

et al. 2020

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Introduction Variants in collagen‐related genes COL1A1, COL3A1, COL5A1 and COL5A2 are associated with Ehlers‐Danlos syndrome (EDS), a heterogeneous group of connective tissue disorders strongly associated with increased bleeding. Of patients with incompletely explained bleeding diathesis, a relatively high proportion were shown to harbour at least one heterozygous variant of unknown significance (VUS) in one of these genes, the vast majority without meeting the clinical criteria for EDS. Aim To investigate the functional consequences of the identified variants by assessing the formation and degradation of types I, III and V collagen, in addition to plasma levels of ascorbic acid (AA). Methods A total of 31 patients harbouring at least one heterozygous VUS in COL1A1, COL3A1, COL5A1 or COL5A2 and 20 healthy controls were assessed using monoclonal antibodies targeting neo‐epitopes specific for collagen formation and degradation. Plasma AA levels were measured in patients using high‐performance liquid chromatography. Results Serum levels of C5 M (degradation of type V collagen) were decreased in patients compared with healthy controls (p = .033). No significant differences were found in biomarkers for remodelling of types I and III collagen. A significant negative correlation between bleeding (ISTH‐BAT score) and plasma AA levels was shown (r = −.42; r2 = .17; p = .020). Suboptimal or marginally deficient AA status was found in 8/31 patients (26%). Conclusion Functional investigations of collagen remodelling were not able to identify any clear associations between the identified variants and increased bleeding. The negative correlation between plasma AA levels and ISTH‐BAT score motivates further investigations.

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Outcome of an enhanced diagnostic pipeline for patients suspected of inherited thrombocytopenia

Cited by 13 publications

References 10 publications

Genetic screening of children with suspected inherited bleeding disorders

Genetic screening of children with suspected inherited bleeding disorders

Inherited thrombocytopenias: history, advances and perspectives

Collagen remodelling and plasma ascorbic acid levels in patients suspected of inherited bleeding disorders harbouring germline variants in collagen‐related genes

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