Using Whole Exome Sequencing to Identify the Pathogenic Variant of F7 C.681+1 G>t As a Potential Cause of Severe Bleeding Clinic Presentation in a Newborn Baby

Ching-Tien Peng^{1, 2, 3} Chien-Yu Lin⁴ Yin-Ting Chen¹

1.Division of Pediatric Hematology & Oncology, China Medical University Children's Hospital, Taichung, 40447, Taiwan

2.Department of Biotechnology, Asia University, Taichung, 40447, Taiwan

3.Divisions of Pediatrics, China Medical University Hsinchu Hospital, Zhubei City, Hsinchu County, 30272, Taiwan.

4.Divisions of Laboratory Medicine, China Medical University Hsinchu Hospital, Zhubei City, Hsinchu County, 30272, Taiwan.

Objective: The clinical manifestations of Factor VII deficiency vary, most cases remain asymptomatic or mild, and cases with severe clinical presentation are rarely reported. It is a rare hereditary hemorrhagic disorder passed on through autosomal recessive inheritance. We present a 2-day-old male infant with large cephalohematoma and intracranial hemorrhage, who was diagnosed using whole exome sequencing with Factor VII deficiency.

Materials and Methods: Whole exome sequencing and Sanger sequencing were used to verify related variants. Other routine blood coagulation and factor activity tests were conducted by Divisions of Laboratory Medicine, China Medical University Hospital, Taiwan. Results: A 2-day-old male newborn was identified to develop left intracranial hemorrhage with unknown causes. The laboratory coagulation factor test results indicated a prolonged prothrombin time and normal activated partial thromboplastin time. The test results for Fibrinogen (279.9 mg/dL) and Factor activity analysis, included Factor VIII (85.6%), Factor V (49.3%), Factor VII (<1.0%), Factor IX (81.3%), and Factor X (42.7%). The results for VWF activity and antigen are normal. Subsequently, whole exome sequencing was used to conduct genetic tests, which revealed the homozygote mutation at F7 c.681+1 G>T (NM_000131). Further variant tests on the family members suggested that the father, mother, and older sister had heterozygote mutation at the same site.

Conclusions: We used next-generation sequencing, which uses array-based sequencing to process reactions in parallel and enables the simultaneous investigation of multiple genes at a manageable cost, to identify the variants. While there is still little research on whether there is a relationship between different gene mutations and clinical presentations. The sequencing results revealed homozygote mutation at F7 c.681+1 G>T (NM_000131). The pathogenicity level was indicated to be "Highly pathogenic" in the ClinVar archive. Studies have reported the association of such mutation with severe hemorrhage disorders. Therefore, the present study offers critical empirical insights in that it applies to clinical practice in a clinical setting and identifies a pathogenic variant. We will present the hypothesis mechanism at the ASH meetings.

No relevant conflicts of interest to declare.