[Genetic testing and reproductive intervention for 210 Chinese pedigrees affected with Hemophilia]

To explore the genetic etiology of 210 Chinese pedigrees affected with Hemophilia and provide prenatal diagnosis and preimplantation genetic testing (PGT) for them.

A total of 210 unrelated pedigrees diagnosed with Hemophilia (176 with Hemophilia A and 34 with Hemophilia B) at the Reproductive and Genetic Hospital of CITIC-Xiangya between 2011 and 2024 were selected as study subjects. Genetic testing was carried out on the probands, including whole-exome sequencing, PCR-Sanger sequencing, and detection of intron 22 and intron 1 inversions of the F8 gene. Pathogenicity of candidate variants was classified based on the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). After the determination of genetic causes, reproductive intervention was implemented through prenatal diagnosis or preimplantation genetic testing (PGT). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010).

In total 137 pathogenic or likely pathogenic variants of the F8 and F9 genes were identified among 207 pedigrees (detection rate = 98.5%), among which 16 were were unreported previously. Respectively, 105 pathogenic or likely pathogenic variants (including 13 novel ones) of the F8 gene were detected among 174 pedigrees with Hemophilia A, while 32 pathogenic or likely pathogenic variants (including 3 novel ones) of the F9 gene were identified among 33 pedigrees with Hemophilia B. Among the 207 pedigrees, 65 had opted for prenatal diagnosis, and 9 fetuses were diagnosed with Hemophilia, and the pregnancies were terminated. On the other hand, 71 pedigrees had opted PGT, with 454 embryos from 90 cycles completed testing, which yielded a diagnostic rate of 99.8% (453/454). As a result, 100 healthy infants were born through reproductive intervention.

This study has clarified the genetic basis of 207 pedigrees affected with Hemophilia. The results had expanded the mutational spectrum, and reduced the birth rate of Hemophilia by prenatal diagnosis and PGT.