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Silent variant in F8:c.222G>T (p.Thr74Thr) causes a partial exon skipping in a patient with mild hemophilia A

Letelier, Anna LU ; Ljung, Rolf LU orcid ; Olsson, Anna and Andersson, Nadine G LU (2022) In Molecular Genetics & Genomic Medicine 10(1).
Abstract

One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47-year-old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G>T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be "likely benign" in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing... (More)

One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47-year-old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G>T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be "likely benign" in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1-4 and a defect transcript lacking exon 2. These findings explain the patient's low FVIII:C level and led to the diagnosis of mild hemophilia A instead of VWD type 1. This case illustrates that mRNA work-up may be needed to clarify a patient's phenotype-genotype.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Genetics & Genomic Medicine
volume
10
issue
1
article number
e1856
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85122065711
  • pmid:34962362
ISSN
2324-9269
DOI
10.1002/mgg3.1856
language
English
LU publication?
yes
additional info
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
id
d3f02a34-7052-4176-ac63-e763fb045381
date added to LUP
2022-01-02 23:16:05
date last changed
2024-06-19 23:56:47
@article{d3f02a34-7052-4176-ac63-e763fb045381,
  abstract     = {{<p>One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47-year-old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G&gt;T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be "likely benign" in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1-4 and a defect transcript lacking exon 2. These findings explain the patient's low FVIII:C level and led to the diagnosis of mild hemophilia A instead of VWD type 1. This case illustrates that mRNA work-up may be needed to clarify a patient's phenotype-genotype.</p>}},
  author       = {{Letelier, Anna and Ljung, Rolf and Olsson, Anna and Andersson, Nadine G}},
  issn         = {{2324-9269}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Molecular Genetics & Genomic Medicine}},
  title        = {{Silent variant in F8:c.222G>T (p.Thr74Thr) causes a partial exon skipping in a patient with mild hemophilia A}},
  url          = {{http://dx.doi.org/10.1002/mgg3.1856}},
  doi          = {{10.1002/mgg3.1856}},
  volume       = {{10}},
  year         = {{2022}},
}