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. 2023 Mar;29(2):591-599.
doi: 10.1111/hae.14730. Epub 2022 Dec 26.

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

Ritika Sharma  1 , Manu Jamwal  1 , Hari Kishan Senee  1 , Namrata Singh  1 , Narender Kumar  1 , Chander Hans  1 , Anita Kler  1 , Deepak Bansal  2 , Amita Trehan  2 , Pankaj Malhotra  3 , Jasmina Ahluwalia  1 , Reena Das  1
Affiliations

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

Ritika Sharma et al. Haemophilia. 2023 Mar.

Abstract

Introduction: 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.

Aim: Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency.

Methods: 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.

Results: 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.-30A>C; seven missense (c.215C>G, c.244T>C, c.253G>C, c.904G>A, c.961C>T, c.1109G>T, c.1211G>A), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634C>T and splice-site variant c.316+1G>A. Recurrent variants c.1109G>T and c.215C>G 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.

Conclusion: 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.

Keywords: FVII deficiency; coagulation disorders; founder effect; haplotype; molecular diagnosis.

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References

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