title: Whole exome sequencing identifies a mutation in thrombomodulin as the genetic cause of a suspected platelet disorder in a family with normal platelet function.
abstract: Here, we describe a mother and son with a lifelong bleeding tendency and posttraumatic bleeding who were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study with a suspected platelet function disorder. However, despite a clinically significant bleeding score, both had normal platelet counts and normal platelet function. The patients' blood was analyzed by light transmission aggregometry and genotyping by whole exome sequencing, as outlined by the GAPP study. Approximately 25 000 genetic variants were found for each patient as a result of sequencing and were filtered using a specialized bioinformatics pipeline. A heterozygous variant displaying autosomal dominant inheritance (c.1611 C>A) was found in the gene THBD which encodes the glycoprotein thrombomodulin. This sequence change results in a stop codon (p.Cys537Stop) and truncation of the protein and has been previously described in two other families with bleeding events which suggests it may be a recurrent mutation. In summary, this study shows that patients with a suspected platelet disorder but who present with a normal pattern of platelet aggregation should be investigated for defects in nonplatelet genes.
authors.affiliation: a Institute of Cardiovascular Sciences, College of Medical and Dental Sciences , University of Birmingham , Birmingham , UK.
authors.forename: Annabel
authors.initials: A
authors.lastname: Maclachlan
authors.affiliation: b Nottingham Haemophilia Centre , Nottingham University Hospital , Nottingham , UK.
authors.forename: Gerry
authors.initials: G
authors.lastname: Dolan
authors.affiliation: b Nottingham Haemophilia Centre , Nottingham University Hospital , Nottingham , UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Grimley
authors.affiliation: a Institute of Cardiovascular Sciences, College of Medical and Dental Sciences , University of Birmingham , Birmingham , UK.
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.affiliation: a Institute of Cardiovascular Sciences, College of Medical and Dental Sciences , University of Birmingham , Birmingham , UK.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.lastname: On Behalf Of The Uk Gapp Study Group
mesh_terms: D001791:Blood Platelet Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D018388:Codon, Terminator; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010974:Platelet Aggregation; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism
chemical_list: D018388:Codon, Terminator; C546931:THBD protein, human; D018180:Thrombomodulin
keywords: Genetics; inherited bleeding; next-generation sequencing; platelets; thrombomodulin