Congenital factor V deficiency in Taiwan: identification of a novel variant p.Tyr1813 ∗ and two variants specific to East Asians.

Congenital coagulation factor V deficiency (FVD) is a rare, autosomal recessive bleeding disorder. We characterized the clinical presentations, laboratory features, and genetic alterations of Taiwanese patients with FVD. From 1983 to 2010, five women, one man, and one boy diagnosed with FVD were enrolled in this study. The factor V coagulant activity was determined using a one-stage prothrombin time-based test. The factor V antigen level was measured in an ELISA. Sanger sequencing was performed for genetic analyses of F5 , the gene responsible for the disease. One novel and de novo F5 genetic variant, p.Tyr1813 ∗ , was identified. Based on the presence of a premature termination codon with a resultant truncated factor V-protein lacking an intact light chain fragment, the variant is pathogenic. In addition, we identified seven variants previously found to cause FVD. Among them, p.Gly420Cys and p.Asp96His were repeatedly detected in five and four patients, respectively. Both variants are found to be specific to the East Asian populations. Various FVD-associated bleeding manifestations were observed, predominantly mucocutaneous bleeding and hypermenorrhea. All patients exhibited very low factor V coagulant activity (<1-2.5 IU/dl, reference range: 60-133 IU/dl). The factor V antigen level was less than 2% in six patients (reference range: 75-157%). The novel F5 genetic variant p.Tyr1813 ∗ and two distinct, East Asians-specific, recurrent variants p.Gly420Cys and p.Asp96His were identified among seven index patients with FVD in Taiwan. Our clinical and laboratory findings support the reported features of FVD.

Characterization of congenital factor XII deficiency in Taiwanese patients: identification of one novel and one common mutation.

BACKGROUND: Factor XII (FXII) deficiency is an interesting condition that causes prolonged activated partial thromboplastin time without bleeding diathesis. FXII may be not important in hemostasis, but still plays roles in thrombosis and inflammation. In order to raise clinical awareness about this condition, we studied patients with severe FXII deficiency and their relatives. METHODS: Consecutive severely FXII deficient patients presenting from 1995 to 2020 were recruited from two medical centers in Taiwan. Index patients and their families were tested for FXII function, antigen and F12 gene. F12 variants were constructed into the pIRES-hrGFP vector and expressed on human embryonic kidney cells (HEK293T). FXII antigen and activity were analyzed. RESULTS: We found five severely FXII deficient patients, three women and two men, aged 44-71 years. FXII antigen results ranged from undetectable to 43.7%. Three different mutations were identified: c.1681C>A (p.Gly542Ser), c.1561G>A (p.Glu502Lys), and a novel mutation c.1556T>A (p.Leu500Gln). HEK293T cells expressed consistently low FXII activity with all mutations. FXII antigen expression was similar to the wild type in c.1681C>A (p.Gly542Ser), but reduced in c.1556T>A (p.Leu500Gln) and c.1561G>A (p.Glu502Lys). CONCLUSIONS: We report five unrelated patients with severe FXII deficiency, one of whom carried a novel, cross-reacting material negative mutation c.1556T>A (p.Leu500Gln).

Clinical features and genetic defect in six index patients with congenital fibrinogen disorders: Three novel mutations with one common mutation in Taiwan's population.

INTRODUCTION: Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities of fibrinogen. Although the diagnosis of CFDs is based on antigenic and functional level of fibrinogen, few genotypes are clearly correlated with phenotype. METHODS: In this study, we investigated all of the referred patients diagnosed as CFDs in Taiwan's population between 1995 and 2020. Clinical features, laboratory data and genetic defects were analysed. Functional fibrinogen level was determined by the Clauss method. Antigenic fibrinogen was measured by an enzyme-linked immunosorbent assay. Fibrinogen genes were assessed for mutations by polymerase chain reaction and sequencing. RESULTS: A total of 18 patients from six unrelated families with CFDs were identified. One patient from a consanguineous family was diagnosed as afibrinogenemia type 1A with a novel homozygous frameshift mutation in FGB exon 4. The other five (83.3 %) index patients were all diagnosed as dysfibrinogenemia type 3A caused by two novel and one known mutation. Six (33.3 %) patients from three families had a novel mutation in FGB exon 8. The clinical features and laboratory data were highly variable among these patients with the same mutation. CONCLUSIONS: Three novel mutations of CFDs causing afibrinogenemia and dysfibrinogenemia were identified. The point mutation in FGB exon 8 is also a common mutation in Taiwan's population. Considerable phenotypic variability among the patients with an identical mutation was observed.

Relationships between depression and anxiety symptoms and adipocyte-derived proteins in postmenopausal women.

INTRODUCTION: Studies on the association between adiponectin and leptin and anxiety and depression among postmenopausal women are limited. Therefore, the present study specifically evaluates the mutual relationships between adiponectin and leptin and anxiety and depression in postmenopausal women. PARTICIPANTS AND DESIGN: In this cross-sectional study, a total of 190 women aged 40-65 years were enrolled. Depression symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D), and anxiety symptoms were evaluated using the Hamilton Anxiety Rating Scale (HAM-A). Fasting specimens were collected to measure sex hormone, glucose, insulin, and adipokine levels. Multiple linear regression analysis was performed to evaluate the associations between depression and anxiety and adipocyte-derived hormones. SETTINGS: The study was performed in a hospital medical center. RESULTS: Among 190 enrolled postmenopausal women, Spearman's rank correlation analysis revealed significant correlations between CES-D and HAM-A (r = 0.715, P < 0.0001), between CES-D and adiponectin (p = 0.009) and leptin (p = 0.015), and between HAM-A and adiponectin (p = 0.01) and leptin (p = 0.001). The subjects with CES-D ≥ 16 and with HAM-A ≥ 18 had higher adiponectin levels than those with CES-D < 16 and HAM-A < 18, respectively. After adjusting for age, body mass index, exercise, alanine amino transferase and parameters of lipid profiles, Log adiponectin levels were found to be significantly associated with both CES-D and HAM-A, and Log leptin levels were only significantly associated with HAM-A. CONCLUSIONS: The data show that adiponectin and leptin levels are significantly associated with depression and anxiety symptoms. These results suggest that higher adiponectin and lower leptin levels may serve as potential markers related to anxiety and mood in postmenopausal women. More future research that is designed to deal with the important confounders (e.g., population heterogeneity) is needed to investigate comprehensively on these associations.

Relationships between Follicle-Stimulating Hormone and Adiponectin in Postmenopausal Women.

Beyond fertility, follicle-stimulating hormone (FSH) may exert action on adipocytes, which are the major source of adiponectin and leptin, linking to insulin resistance. Therefore, we evaluated the relationships between FSH and adipocyte-derived hormones. This cross-sectional study enrolled postmenopausal women aged 40-65 years. The variables measured in this study included clinical parameters, fasting levels of sex hormones, glucose, insulin, and adipokines. A total of 261 women without breast cancer, 88 women with breast cancer receiving tamoxifen, and 59 women with breast cancer receiving additional gonadotropin-releasing hormone analogs were enrolled in this study. Significant differences in the levels of adiponectin, leptin, and FSH were observed between the non-breast cancer group and the breast cancer groups. Spearman's rank test revealed significant associations of FSH with either body mass index (BMI) or homeostatic model assessment of insulin resistance (HOMA-IR) values in the non-breast cancer group. After adjusting for BMI, age, and menopause duration, FSH levels were significantly associated with adiponectin (p < 0.001) and the leptin-to-adiponectin ratio (p = 0.008) in the non-breast cancer group, but they were only significantly associated with adiponectin (p = 0.001) in the breast cancer group receiving tamoxifen. Our data show that FSH levels are independently associated with adiponectin levels in postmenopausal women, suggesting that adiponectin may link FSH to metabolic relationships in postmenopausal female.

Segmental uniparental disomy as a rare cause of congenital severe factor XIII deficiency in a girl with only one heterozygous carrier parent.

Uniparental disomy (UPD) refers to a situation when a person inherits both homologs of a region or complete part of a chromosome from only one parent. Here, we present an unusual case of UPD in congenital severe factor (F) XIII deficiency. A 6-year-old girl experienced cephalhematoma and umbilical bleeding after birth and easy bruising, and postextraction bleeding since early infancy. FXIII activity was 0% [mother 53.7% and father 132.5% (normal 70-140%)] and the FXIII antigen level was 2.5% [mother 38.9% and father 151% (normal 75-155%)]. The washed platelet FXIII activity was 0.1% in the patient (normal 64-144%), suggesting a deficiency of FXIII-A subunit. The FXIII-A subunit genetic analysis detected a homozygous p.Arg382Ser mutation. A similar heterozygous mutation was detected in the mother but surprisingly, not in the father. Kinship was confirmed by a paternity test. To confirm the possibility of UPD, a test using four markers in the vicinity of the F13A1 gene revealed that she inherited duplicate mutations from a heterozygous mutation in her mother, presenting a unique case of unusual maternal segmental UPD in otherwise unexplained congenital (homozygous) severe FXIII deficiency. UPD as a rare cause of autosomal recessive bleeding disorder when only one parent is affected is critical for genetic counseling.