Strengths and limitations of high‐throughput sequencing for the diagnosis of inherited bleeding and platelet disorders

Abstract

Inherited bleeding and platelet disorders (BPD) are highly heterogeneous and their diagnosis involves a combination of clinical investigations, laboratory tests and genetic screening. This review will outline some of the challenges that geneticists and experts in clinical hemostasis face when implementing high-throughput sequencing (HTS) for patient care. We will provide an overview of the strengths and limitations of the different HTS techniques that can be used to diagnose BPD. A HTS test is cost efficient and expected to increase the diagnostic rate with a possibility to detect unexpected diagnoses and decrease the turnaround time to diagnose patients. On the other hand, technical shortcomings, variant interpretation difficulties and ethical issues related to HTS for BPD will also be documented. Delivering a genetic diagnosis to patients is highly desirable to improve clinical management and allow family counseling, but making incorrect assumptions about variants and providing insufficient information to patients before initiating the test could be harmful. Data-sharing and improved HTS guidelines are essential to limit these major drawbacks of HTS.

Circular RNA circCUL3 Accelerates the Warburg Effect Progression of Gastric Cancer through Regulating the STAT3/HK2 Axis

“…With the tremendous advancement of high-throughput sequencing technology, great numbers of noncoding RNAs have been identified in human cancer. 20 , 21 , 22 In addition, bioinformatics tools bring greater analytical capability to process the microarray data and unlock a potential regulator for cancers. For GC tumorigenesis, numerous circRNAs have been identified to participate in the pathophysiological process and regulate different tumorigenic phenotypes.…”

Clinical management, ethics and informed consent related to multi‐gene panel‐based high throughput sequencing testing for platelet disorders: Communication from the SSC of the ISTH

“…Clinical testing of candidate genes by Sanger sequencing and linkage analysis have now largely been replaced by sequencing techniques, mostly using targeted gene panel tests or whole exome sequencing, to survey multiple genes simultaneously. These tests are routinely used in many countries 6 . To improve HTS testing in a clinical setting, the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee for Genetics in Thrombosis and Hemostasis has recently curated the “diagnostic‐grade genes” (Table S1) associated with bleeding, thrombotic, and platelet disorders, which is updated annually 1 .…”

Advances in Platelet Function Testing—Light Transmission Aggregometry and Beyond

“…Genetic screening has also become an integral part of evaluating a patient presenting with inherited bleeding and platelet disorders [ 41 , 42 ], and has identified a number of important transcription factors involved in granule biogenesis and maturation that lead to bleeding disorders. Although informative, genetic screening cannot be taken in isolation, as the phenotype or functional readout of genetic findings is hard to predict.…”

“…However, inherited platelet disorders are very heterogeneous, with more than 50 currently known genes [ 88 ], and in most cases, a single candidate gene cannot be found despite sometimes extensive family histories. In recent decades, next generation sequencing (NGS) has revolutionized the landscape of molecular diagnostics by increasing throughput, providing an unbiased genetic screen, and identifying rare variants not always accessible with other technologies [ 41 ]. Allowing much faster identification of known genetic defects, but also discovery of new defects, NGS is promising for overcoming diagnostic wandering [ 88 ].…”

“…Allowing much faster identification of known genetic defects, but also discovery of new defects, NGS is promising for overcoming diagnostic wandering [ 88 ]. However, it still suffers from limitations, such as lack of accessibility, high cost, and sometimes difficulties in assigning pathogenicity to novel identified variants, in addition to ethical debates around its use [ 41 , 89 ]. Notwithstanding, future laboratory assessment of individuals with inherited platelet function disorders will certainly rely on a mix of clinical, genetic, morphological, and functional investigations, altogether harnessing a more exhaustive platelet characterization.…”