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Genetic screening of children with suspected inherited bleeding disorders

Andersson, Nadine LU ; Rossing, Maria ; Fager Ferrari, Marcus LU orcid ; Gabrielaite, Migle ; Leinøe, Eva ; Ljung, Rolf LU orcid ; Mårtensson, Annika LU ; Norström, Eva LU and Zetterberg, Eva LU (2020) In Haemophilia 26(2). p.314-324
Abstract

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... (More)

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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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Haemophilia
volume
26
issue
2
pages
11 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:32100410
  • scopus:85082093740
ISSN
1351-8216
DOI
10.1111/hae.13948
language
English
LU publication?
yes
additional info
© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.
id
1b237416-cebd-41d5-a036-b95bdeb6267f
date added to LUP
2020-03-02 19:39:23
date last changed
2024-05-29 09:52:00
@article{1b237416-cebd-41d5-a036-b95bdeb6267f,
  abstract     = {{<p>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.</p><p>AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.</p><p>METHODS: After informed consent, children (&lt;18 years) with suspected IBD underwent genetic screening with 94 selected genes.</p><p>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).</p><p>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.</p>}},
  author       = {{Andersson, Nadine and Rossing, Maria and Fager Ferrari, Marcus and Gabrielaite, Migle and Leinøe, Eva and Ljung, Rolf and Mårtensson, Annika and Norström, Eva and Zetterberg, Eva}},
  issn         = {{1351-8216}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  pages        = {{314--324}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Haemophilia}},
  title        = {{Genetic screening of children with suspected inherited bleeding disorders}},
  url          = {{http://dx.doi.org/10.1111/hae.13948}},
  doi          = {{10.1111/hae.13948}},
  volume       = {{26}},
  year         = {{2020}},
}