Molecular spectrum of inherited FVII deficiency in North India revealed a recurrent variant with a founder effect

Autor: Ritika Sharma, Manu Jamwal, Hari Kishan Senee, Namrata Singh, Narender Kumar, Chander Hans, Anita Kler, Deepak Bansal, Amita Trehan, Pankaj Malhotra, Jasmina Ahluwalia, Reena Das
Rok vydání: 2022
Předmět:
Zdroj: Haemophilia. 29:591-599
ISSN: 1365-2516
1351-8216
DOI: 10.1111/hae.14730
Popis: Inherited Factor VII (FVII) deficiency is commonest among the rare bleeding disorders. A small number of patients present in infancy with severe bleeding, and many may remain asymptomatic but detected before surgery/invasive procedures. Genetic testing may be helpful in predictive testing/prenatal diagnosis in severe cases.Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency.Retro-prospectively, 35 cases with prolonged prothrombin time and FVII activity (FVII:C)50 IU/dl were subjected to targeted resequencing. After in-silico analysis, variant/s were validated by Sanger sequencing in index cases and family members. Haplotype analysis was done for F7 polymorphisms.Severe FVII deficiency was found in 50% of patients (FVII:C ≤1 IU/dl), and 42.9% were asymptomatic. Clinical severity assessment revealed 17% severe, 17% moderate and 22.9% patients with mild bleeds. FVII levels ranged from .3 to 38 IU/dl. Molecular analysis revealed variants in 30/35 cases, of which 17 were homozygous, 10 were compound heterozygous and 3 were heterozygous. Twelve genetic variants were identified, one promoter variant c.-30AC; seven missense (c.215CG, c.244TC, c.253GC, c.904GA, c.961CT, c.1109GT, c.1211GA), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634CT and splice-site variant c.316+1GA. Recurrent variants c.1109GT and c.215CG were found in 17 and 8 cases, 12 of the former cases were homozygous. They had the same haplotype, indicating the founder effect in North Indians.This is the largest cohort of FVII genotyping from India, confirming heterogeneity in terms of clinical manifestations, FVII activity and zygosity of the variants with a limited genotypic phenotypic correlation.
Databáze: OpenAIRE
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