Our 25 years of experience in carrier diagnosis of hemophilia A (HA) and B (HB) in Mexican population comprises linkage analysis of intragenic F8/F9 neutral variants along with, in severe HA (SHA), detection of F8 int22h and int1h inversions. In symptomatic carriers (SCs) we explored Lyonization to explain their symtomatology. From a DNA‐Bank of 3,000 samples, intragenic restriction fragment length (RFLPs) and short tandem repeats (STRs) of F8/F9 genes were assessed by PCR‐PAGE and GeneScan. In SHA patients, F8 inversions were detected by inverse shifting‐PCR/diagnostic and complementary tests. In SCs, we evaluated hemorrhagic symptoms, clotting FVIII/FIX and X‐chromosome inactivation (XCI) patterns were assessed by HUMARA assay and the search of XIST promoter pathogenic variants. Informativeness of linkage analysis for HA carrier diagnosis with RFLP's/STR's increased to 74% and reached 80% with five RFLPs for HB. Combined Inv22/Inv1 diagnosed 113 possible carriers, three de novo Inv22‐1, and confirmed 45 mothers as obligate or sporadic carriers. Among 21 SCs, four showed extreme skewed XCI pattern (~80:20) but had normal karyotype and no C43G pathogenic variant in XIST promoter. Clotting FVIII/FIX correlated with the active X in leukocytes. Our data integrate the largest comprehensive research worldwide on the molecular diagnosis of HA and HB carriers in terms of the number of studied and diagnosed cases, in addition to the genetic analysis in SCs. Intragenic RFLPs and STRs of F8/F9 genes along with F8 int22h/int1h inversions in SHA emerge as optimal variants for molecular diagnosis in Mexican population. In counseling SCs, inheritance of skewed X‐inactivation should be considered.

中文翻译：

---

墨西哥人群血友病 A 和 B 携带者诊断的遗传分析：25 年的经验

我们在墨西哥人群中血友病 A (HA) 和 B (HB) 携带者诊断方面的 25 年经验包括基因内F8 / F9中性变异的连锁分析，以及在严重 HA (SHA) 中检测F8 int22h和int1h倒位。在有症状的携带者 (SC) 中，我们探索了 Lyonization 来解释他们的症状。从 3,000 个样本的 DNA 库中，通过 PCR-PAGE 和 GeneScan 评估F8/F9基因的基因内限制性片段长度 (RFLP) 和短串联重复序列 (STR) 。在 SHA 患者中，F8通过反向移位 PCR/诊断和互补测试检测到倒位。在 SCs 中，我们评估了出血症状、凝血 FVIII/FIX 和 X 染色体失活 (XCI) 模式，通过HUMARA测定和XIST启动子致病变异的搜索进行评估。使用 RFLP's/STR's 诊断 HA 携带者的连锁分析的信息量增加到 74%，并在 HB 的五个 RFLPs 中达到 80%。联合INV22 /器Inv1确诊113个可能运营商，三从头Inv22-1，并确认45个母亲作为专或零星的载体。间21组的SC，四个表明极端倾斜XCI图案（〜80：20），但正常核型并且没有C43G致病变种中XIST发起人。凝血 FVIII/FIX 与白细胞中的活性 X 相关。我们的数据整合了全球最大的关于 HA 和 HB 携带者分子诊断的综合研究，除了 SCs 的遗传分析外，还包括研究和诊断病例的数量。F8/F9基因的基因内RFLP 和 STR以及SHA 中的F8 int22h/int1h倒置成为墨西哥人群分子诊断的最佳变体。在咨询 SCs 时，应考虑偏斜 X 失活的遗传。