Bilal Jradeh, Lead Clinical Scientist for Haemophilia and Thrombosis Molecular Diagnostics, outlines the investigation into a stillbirth with evidence of fetal coagulopathy in a family with no bleeding history.
Usually when we receive samples from individuals with an unknown bleeding disorder, we do not find a genetic basis for the clinical phenotype. This is generally because in these cases there may not be strong family history, and there are many causes that are not heritable.
Recently, we investigated a family that had suffered the loss of a pregnancy at 28 weeks after the fetus suffered a massive intracranial haemorrhage. We analysed a post-mortem sample from the fetus and blood from both parents. In our panel of 126 genes involved in haemostasis we found 99 sequence variants that required classification.
Of those, 91 were benign, likely benign or excluded, seven were of uncertain significance, and incredibly, one was pathogenic. The fetus was homozygous and both parents were heterozygous.
This pathogenic variant caused severe Factor X (F10) deficiency, an extremely rare (1:1,000,000) autosomal recessive condition, in the fetus, and is known to cause intracranial haemorrhage. This is the first time we have ever been able to diagnose such a case as there was no family history of a genetic condition to guide us, only an abnormal phenotype in the stillborn baby.
The parents, whose relationship was not consanguineous and had no family history of bleeding, were both asymptomatic carriers for the same variant.
This case was unusual as we did not have a laboratory phenotype to guide our investigation, and has shown how genetic analysis can directly guide clinical management in patients with bleeding disorders. The parents will now be able to receive pre-natal diagnosis in future pregnancies following genetic counselling.