Hypofibrinogenemia caused by a heterozygous variant in the FGA gene: a case report

Abstract

Background

Hereditary Fibrinogen Disorders (HFDs) are conventionally classified as quantitative (type I) or qualitative (type II) deficiencies based on the plasma concentration. Quantitative deficiencies include afibrinogenemia/severe hypofibrinogenemia and hypofibrinogenemia, while qualitative deficiencies comprise dysfibrinogenemia and hypodysfibrinogenemia.

Objective

To identify the molecular pathogenesis of hypofibrinogenemia in a pregnant patient and her family, and explore the clinical characteristics and peripartum management strategy of this disease.

Methods

We described the clinical data and genetic findings of a 28-year-old pregnant woman and her mother with hypofibrinogenemia. Sanger sequencing was used to verify the heterozygous variant c.1517del (exon 5) of the FGA gene (NM_021871.4). Relevant published literatures were analyzed to summarize the research progress and clinical implications of this variant.

Results

We identified a novel pathogenic FGA c.1517del variant in a Chinese family with hereditary hypofibrinogenemia. The proband presented with decreased fibrinogen activity (1.6 g/L) and antigen level (1.7 g/L), with an activity/antigen ratio of 0.94; her mother showed similar laboratory abnormalities. The patient received 1.5 g intravenous fibrinogen before neuraxial anesthesia-assisted lower-segment cesarean section. A 3.53 kg female neonate was delivered smoothly without obvious intraoperative hemorrhage.

Conclusion

The diagnosis of HFDs relies on combined detection of fibrinogen function, antigen level and genetic analysis. Genetic screening facilitates clinical diagnosis and genetic counseling. For pregnant patients with hypofibrinogenemia in late gestation, preoperative fibrinogen supplementation can effectively correct coagulation defects and ensure safe delivery.

Introduction

Hereditary Fibrinogen Disorders (HFDs) are a genetic disorder characterized by abnormal fibrinogen levels or/and function, and which including two types. Type I is quantitative deficiency (afibrinogenemia, hypofibrinogenemia); Type II is qualitative deficiency (dysfibrinogenemia, hypodysfibrinogenemia) [1]. The first patient was reported by Imperato in 1958 [2]. Hypofibrinogenemia, is clinically heterogeneous and may present with a range of manifestations, from asymptomatic laboratory abnormalities to life-threatening hemorrhages [3]. Clinical management must account for the dual risks of bleeding and thrombosis. Fibrinogen replacement alone may not adequately address the underlying thrombotic risk. HFDs with an estimated prevalence of one to two cases per million individuals worldwide [4].

Here, we report a novel heterozygous variant (c.1517del, exon 5) in the FGA gene (NM_021871.4) identified in a pregnant woman with hypofibrinogenemia.

Case presentation

A 28-year-old primigravida woman presented with decreased plasma fibrinogen level during routine prenatal examination at 33 weeks of gestation. She had no personal history of bleeding or thrombotic events and had not received any medication related to coagulation function before. The routine coagulation test of the proband showed a normal prothrombin time (PT) of 12.2 s, a normal activated partial thromboplastin time (APTT) of 26.7 s, but a longer thrombin time (TT) of 29.0 s and a lower fibrinogen (Fib) activity of 1.6 g/L (tested by the Clauss method). Given the clinical suspicion of dysfibrinogenemia, immunological quantification showed the Fib antigen level was 1.7 g/L. Peripheral blood was collected from the patient’s mother for coagulation function testing, with results showing a normal PT of 11.1 s, a normal APTT of 24.1 s, but a longer TT of 22.5 s and a lower fibrinogen of 1.04 g/L (Table 1). Immunological quantification showed the Fib antigen level was 1.1 g/L. The Clauss fibrinogen activity/antigen ratios in the proband and her mother were nearly 1. The patient’s mother exhibited significantly reduced Fib levels and prolonged TT, suggesting coexisting coagulation dysfunction with possible familial inheritance.

Table 1.

Routine coagulation and fibrinogen activity/antigen levels in the proband and her mother

	Normal Reference Range	Proband	Mother
PT (s)	9.4–12.5	12.2	11.1
APTT (s)	25.4–38.4	26.7	24.1
TT (s)	10.3–16.6	29.0	22.5
Fibrinogen activity(g/L, Clauss method)	2.38–4.98	1.6	1.04
Fibrinogen antigen	(g/L) 2.0–4.0	1.7	1.1
Clauss activity/antigen ratio		0.94	0.95

No bleeding or thrombotic history was present in her mother.

Genetic analysis was performed on peripheral blood DNA from the proband via next‑generation sequencing (NGS) and validated by Sanger sequencing in the mother. Reads were aligned to the GRCh37/hg19 reference genome, targeting exons and 20 bp flanking introns of hemostasis‑ and thrombosis‑related genes to detect single‑nucleotide variants and small indels (≤ 20 bp). The mean sequencing depth was 281.49×, with 99.20% of targets covered at ≥ 10× and 98.69% at ≥ 20×. Variants were interpreted per ACMG guidelines, retaining only pathogenic, likely pathogenic, or uncertain significance variants. Common polymorphisms were excluded using population databases (1000 Genomes, ESP6500, EXAC, EXAC‑EAS). Functional effects were assessed via REVEL and spliceAI, prioritizing deleterious, splicing‑disruptive, and loss‑of‑function variants with prior clinical reports. Sequencing results revealed a heterozygous deletion variant (c.1517del) in exon 5 of the FGA gene (NM_021871.4) in both the patient and her mother (Fig. 1). This single-nucleotide deletion causes a frameshift mutation (p.Leu506ArgfsTer32), altering the translational reading frame starting at codon 506. Consequently, the amino acid sequence from position 506 onward is completely aberrant, and a premature termination codon is introduced 32 codons downstream at position 537, resulting in truncated, nonfunctional fibrinogen alpha-chain protein. According to the American College of Medical Genetics and Genomics (ACMG) variant classification guidelines, this variant was classified as Pathogenic, supported by the following evidence. (1) PVS1: The variant causes a loss-of-function effect via frameshift and premature termination codon, which is expected to trigger nonsense-mediated mRNA decay and abrogate protein production. Haploinsufficiency of FGA is a well-established mechanism underlying congenital fibrinogen disorders. (2) PM2: The variant is absent from population databases including gnomAD, consistent with an extremely low allele frequency in the general population. (3) PP4: This evidence is interpreted with caution, as segregation analysis is limited to only two affected family members (the proband and her mother). The variant was found to co-segregate with the clinical phenotype in these two individuals. However, since genetic testing was not performed on the proband’s father, complete familial segregation verification could not be achieved. Family verification results confirmed the proband’s mother carried the FGA c.1517del heterozygous variant, while the paternal genotype remains unknown (Fig. 2).

Fig. 1.

Confirmation of the FGA c.1517del variant by Sanger sequencing. (a) Chromatogram of the proband, showing the heterozygous single-nucleotide deletion at position chr4:155507064 (indicated by the red arrow). (b) Chromatogram of the proband’s mother, demonstrating the identical heterozygous variant, confirming maternal inheritance

Fig. 2.

Pedigree of the family with FGA c.1517del variant. The proband (II-1, arrow) and her mother (I-2) are heterozygous carriers of the pathogenic FGA c.1517del (p.Leu506ArgfsTer32) variant. The father (I-1) was not tested (NT), and his genotype remains unknown. Squares represent males; circles represent females. Filled symbols indicate variant carriers

On March 6, 2026, the patient was admitted at 38 + 4 weeks of gestation. Her plasma Fib level was 1.90 g/L (tested by the Clauss method). The patient received 1.5 g of fibrinogen intravenously prior to undergoing a lower-segment cesarean section under neuraxial anesthesia. A female infant weighing 3.53 kg was delivered uneventfully. The estimated intraoperative blood loss was approximately 200 mL, and no severe hemorrhage occurred.

Routine blood tests of the newborn showed WBC was 19.84 × 10⁹/L, red blood cell (RBC) count was 5.28 × 10¹²/L, hemoglobin (HB) was 193.00 g/L, platelet (PLT) count was 379 × 10⁹/L. Cranial magnetic resonance imaging revealed dilatation of the bilateral lateral ventricles, third and fourth ventricles as well as cisterna magna. The infant had stable vital signs, regular breathing and normal body temperature, with no clinical neurological abnormalities. Coagulation and fibrinogen tests were not performed for the newborn. The baby was discharged 5 days after birth.

Postoperatively, the mother received prophylactic antibiotics with cefuroxime sodium 0.75 g intravenously every 8 h, and oxytocin 10 U twice daily by intramuscular injection to promote uterine contraction. On postoperative day 5, the patient remained afebrile, with good wound healing and adequate uterine involution. Her plasma fibrinogen level was 1.9 g/L at this time. She was subsequently discharged.

Discussion

Fibrinogen is a liver-synthesized glycoprotein composed of Aα, Bβ and γ chains encoded by FGA, FGB and FGG respectively [5]. Pathogenic variants in these genes lead to hereditary fibrinogen disorders, among which FGA variants are the most common causes of quantitative fibrinogen deficiency [6]. The frameshift variant FGA c.1517del identified in this study generates a truncated non-functional α-chain via premature termination, resulting in reduced synthesis of structurally normal fibrinogen, which is consistent with the pathogenesis of hypofibrinogenemia, a type I quantitative fibrinogen disorder.

As a newly identified variant, FGA c.1517del expands the mutational spectrum of FGA among the Chinese population. Distinct from common missense variants in exon 2 and other frameshift variants in exon 5, this single-base deletion in the 3’ region of exon 5 triggers premature termination earlier and yields a shorter abnormal peptide. As a loss-of-function variant, it results in FGA haploinsufficiency and decreased circulating fibrinogen levels. Both the proband and her mother carrying this variant showed a mild quantitative fibrinogen deficiency, with no spontaneous bleeding or thrombotic events under non-pregnant conditions. This finding supplements the genotype–phenotype correlation data for hereditary hypofibrinogenemia and provides a new reference for clinical genetic diagnosis and variant classification.

Pregnancy represents a high-risk state for patients with hereditary hypofibrinogenemia. Gestational physiological changes disrupt the coagulation equilibrium and further elevate bleeding risks. Carriers of FGA c.1517del have intrinsically low fibrinogen levels, which increases the likelihood of adverse obstetric outcomes such as spontaneous abortion, placental abruption, intrapartum and postpartum hemorrhage. Since both carriers in this family are asymptomatic in the non-pregnant state, this variant is considered to confer a mild phenotype. Nevertheless, physiological gestational hypercoagulability cannot completely compensate for the underlying coagulation defect, so standardized intervention is required during pregnancy and delivery. The newborn in this case showed dilatation of the cerebral ventricles and cisterna magna on cranial MRI, but remained free of neurological signs. To date, we cannot establish a direct link between the maternal variant and fetal imaging abnormalities, and long-term follow-up of the infant is recommended.

Standardized peripartum management is essential for pregnant women with hereditary hypofibrinogenemia to ensure maternal and fetal safety. According to current clinical consensus, the target plasma fibrinogen level is set above 1.0 g/L for minor surgeries and above 1.5 g/L for major obstetric procedures including cesarean section. In this case, the patient’s baseline fibrinogen level was 1.90 g/L before treatment. We administered 1.5 g fibrinogen intravenously preoperatively to meet the safety threshold for cesarean delivery, and the estimated intraoperative blood loss was within the normal range, confirming the efficacy of preoperative fibrinogen replacement. For ostpartum care, coagulation function and fibrinogen levels should be monitored regularly within the first week after delivery. The patient’s fibrinogen level was 1.9 g/L on postoperative day 5, with stable vital signs, satisfactory wound healing and no bleeding complications. We recommend dynamic detection of fibrinogen every 2 to 3 days in the early postpartum period. Short-term fibrinogen supplementation is advised for patients with persistently low levels. For female carriers of childbearing age, long-term follow-up is necessary. Preconception genetic counseling, regular coagulation monitoring across all trimesters, and individualized delivery plans are key to reducing adverse pregnancy events.

We searched relevant literature, the Human Gene Mutation Database (HGMD), ClinVar, and the dedicated fibrinogen variant database (https://site.geht.org/base-de-donnees-fibrinogene/) to characterize FGA c.1517del (p.Leu506ArgfsTer32) [7]. A unified search of ClinVar, HGMD, LOVD and gnomAD was performed on May 20, 2026. This single-nucleotide deletion induces a frameshift mutation and a premature stop codon, resulting in a truncated non-functional Aα-chain. The variant was classified as pathogenic according to ACMG guidelines, supported by PVS1, PM2 and PP4 evidence. No records of this variant were identified in public databases, confirming it as a novel variant and highlighting the novelty of our findings.

Several limitations of this study should be acknowledged. The pathogenicity of FGA c.1517del was determined based on bioinformatic prediction, ACMG classification and familial phenotype co-segregation. Direct in vitro or in vivo functional experiments to verify its impact on fibrinogen function are lacking. Further cellular and molecular studies are needed to clarify its exact molecular mechanism. In addition, the small size of the enrolled family limits a comprehensive analysis of its inheritance pattern.

Hereditary hypofibrinogenemia is generally consistent with autosomal dominant inheritance, and heterozygous variants in fibrinogen-related genes commonly lead to reduced levels of normal circulating fibrinogen [8]. Unlike dysfibrinogenemia, no dysfunctional protein exists in the circulation of hypofibrinogenemia patients. In our study, both the proband and her mother carried the heterozygous null variant FGA c.1517del, which impairs α-chain synthesis and secretion and ultimately reduces fibrinogen production.

Since genetic testing for the proband’s father was not performed, we can only tentatively infer an autosomal dominant inheritance pattern based on limited familial data, and definitive confirmation requires additional family genetic analysis. We cannot rule out the possibility that the proband carries compound heterozygous variants, which would alter the disease mechanism and clinical severity. The absence of paternal genetic data also affects the accuracy of genetic counseling for this family, including recurrence risk assessment for the patient’s future offspring and other family members. Complete family genetic data is therefore required to provide precise prenatal and reproductive guidance.

Hypofibrinogenemia is a rare bleeding disorder accompanied by a paradoxical risk of thromboembolism, which occurs in approximately 20% of patients [9, 10]. Fibrinogen levels are closely correlated with clinical severity, and levels below 0.5 g/L usually lead to obvious bleeding symptoms [11]. Thrombin time (TT) is a sensitive indicator for hypofibrinogenemia; reduced fibrinogen prolongs TT, and fibrinogen supplementation can effectively reverse this abnormality [12]. Consistent with previous reports, prolonged TT was observed in both carriers in this family.

Hereditary fibrinogen disorders present diverse clinical phenotypes ranging from asymptomatic status to severe bleeding or thrombosis [4]. The diagnosis relies on combined detection of fibrinogen activity, antigen levels and genetic testing. During early pregnancy, fibrinogen participates in the formation of fetal–maternal vasculature and normal placental development [13]. Pregnant women with hypofibrinogenemia are at increased risk of miscarriage, fetal growth restriction, preeclampsia, placental abruption and postpartum hemorrhage. Current clinical management for this population mainly depends on monitoring and correcting fibrinogen levels [14].

This case describes familial hypofibrinogenemia associated with a heterozygous pathogenic FGA variant. Given the lack of paternal genetic data, an autosomal dominant inheritance pattern is only tentatively proposed. The proband and her mother shared consistent coagulation abnormalities. This novel variant enriches the genetic spectrum of hereditary fibrinogen disorders and provides practical experience for the management of gestational coagulopathy, and the patient achieved a favorable pregnancy outcome.

Considering the hereditary nature of this disease, professional genetic counseling is strongly recommended. Carriers have an approximately 50% risk of passing the variant to their offspring. We suggest genetic screening for all immediate family members to identify asymptomatic carriers for early intervention. For future pregnancies, preconception counseling, regular gestational coagulation monitoring, and joint care by hematologists and obstetricians are essential. Prenatal diagnosis is also recommended to minimize adverse pregnancy risks.

Author contributions

Xinhong Yang and Haoyu Wei: conceptualization. Xinhong Yang: writing, reviewing and editing.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Affiliated Hospital of Chengde Medical College. All participants provided written informed consent prior to genetic testing and data collection. All procedures were carried out in accordance with the Declaration of Helsinki. Consent for publication Written informed consent for the publication of clinical data, laboratory findings and genetic information was obtained from the proband and her mother. All personal identifiable details have been removed to protect patient confidentiality.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.