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A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.

Abstract：

:Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD.

journal_name

Blood

journal_title

Blood

authors

Simeoni I,Stephens JC,Hu F,Deevi SV,Megy K,Bariana TK,Lentaigne C,Schulman S,Sivapalaratnam S,Vries MJ,Westbury SK,Greene D,Papadia S,Alessi MC,Attwood AP,Ballmaier M,Baynam G,Bermejo E,Bertoli M,Bray PF,Bury L,

doi

10.1182/blood-2015-12-688267

subject

Has Abstract

pub_date

2016-06-09 00:00:00

pages

2791-803

issue

eissn

0006-4971

issn

1528-0020

pii

blood-2015-12-688267

journal_volume

127

pub_type

杂志文章

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A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.