Genetic Spectrum in F13A1 Detected by Next-Generation Sequencing Among North Indian Patients with FXIII Deficiency

• Published in: Indian journal of hematology & blood transfusion 2023-04, Vol.39 (2), p.276-283
• Main Authors: Sharma, Ritika, Jamwal, Manu, Singh, Namrata, Sharma, Prashant, Bansal, Deepak, Trehan, Amita, Malhotra, Pankaj, Jain, Arihant, Ahluwalia, Jasmina, Das, Reena, Kumar, Narender
• Format: Article
• Language: English
• Subjects: Blood diseases; Blood Transfusion Medicine; Diagnostic tests; Genetic disorders; Hematology; Hemorrhage; Human Genetics; Medicine; Medicine & Public Health; Mutation; Oncology; Original; Original Article
• ISSN: 0971-4502; 0974-0449; 0974-0449; 0971-4502
• DOI: 10.1007/s12288-022-01579-1

Purpose The study aimed to explore the molecular defects underlying FXIII deficiency. Materials and Methods Sixteen unrelated cases were enrolled based on the indication of the urea clot solubility test and Factor XIII-A antigen levels. Cases were further subjected to targeted next-generation sequencing (custom gene panel: F7 , F8 , VWF , F9 , F13A1, F13B). The pathogenic/likely pathogenic variants were validated by Sanger sequencing in the patients and family members. Results Mean age of referral to our center was 27.2 years (8 week-67 years). Consanguinity was found in only one of the 16 cases and 9 cases presented in infancy. The most common symptoms were skin bleeds (69%) and umbilical cord bleed (50%). The clot solubility test was positive in 12, inconclusive in 1, and normal in 3. Mean FXIII-A levels were 15.7 IU/dL (range 0.6 to 49.5 IU/dL). Pathogenic/likely pathogenic variants in F13A1 were found in 11 (69%). Nine cases (82%) were homozygous, and two were compound heterozygous. Total eleven variants were found of which four were missense (c.1226G>A; c.998C>T; c.631G>C; c.2134A>C); three deletion (c.521delG; c.742delA; c.1405_1408delCAAA); two nonsense (c.1112G>A; c.1127G>A) and two splice site (c.1909-1G>C; c.2045G>A). No probably pathogenic variant was found in the F13B . Conclusion Inherited FXIII deficiency with bleeding is associated with genetic defects in predominantly the F13A1 gene. A variety of variants were seen in this cohort. A nonsense variant c.1127G>A found in three of our cases seems to be recurrent. This data will contribute to designing functional studies and antenatal testing in affected families.