Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

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Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia. / Leinøe, Eva; Zetterberg, Eva; Kinalis, Savvas; Østrup, Olga; Kampmann, Peter; Norström, Eva; Gretenkort Andersson, Nadine; Klintman, Jenny; Qvortrup, Klaus; Nielsen, Finn Cilius; Rossing, Maria.

I: British Journal of Haematology, Vol. 179, Nr. 2, 2017, s. 308-322.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Leinøe, Eva ; Zetterberg, Eva ; Kinalis, Savvas ; Østrup, Olga ; Kampmann, Peter ; Norström, Eva ; Gretenkort Andersson, Nadine ; Klintman, Jenny ; Qvortrup, Klaus ; Nielsen, Finn Cilius ; Rossing, Maria. / Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia. I: British Journal of Haematology. 2017 ; Vol. 179, Nr. 2. s. 308-322.

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TY - JOUR

T1 - Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

AU - Leinøe, Eva

AU - Zetterberg, Eva

AU - Kinalis, Savvas

AU - Østrup, Olga

AU - Kampmann, Peter

AU - Norström, Eva

AU - Gretenkort Andersson, Nadine

AU - Klintman, Jenny

AU - Qvortrup, Klaus

AU - Nielsen, Finn Cilius

AU - Rossing, Maria

PY - 2017

Y1 - 2017

N2 - Rare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty-seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five-tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work-up of IBD is of great benefit.

AB - Rare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty-seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five-tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work-up of IBD is of great benefit.

KW - Bleeding disorders

KW - Genetic analysis

KW - Platelet disorders

UR - http://www.scopus.com/inward/record.url?scp=85026326289&partnerID=8YFLogxK

U2 - 10.1111/bjh.14863

DO - 10.1111/bjh.14863

M3 - Article

VL - 179

SP - 308

EP - 322

JO - British Journal of Haematology

T2 - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 2

ER -