Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

Abstract

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.

Skewed X-inactivation is associated with retinal dystrophy in female carriers ofRPGRmutations

“…There is an ongoing debate about whether skewed XCI should be defined as a ratio of ≥80:20 or ≥90:10 ( Fahim et al, 2020 ; González-Ramos et al, 2020 ). In our analysis, we applied the ≥80:20 ratio to define skewed XCI.…”

The Spectrum of Pathogenic Variants in Iranian Families with Hemophilia A

“…Nearly all other pathogenic variants are rare and usually confined to a single-family. [4][5][6][7] Despite the advances in treating HA and increasing life expectancy, there are still challenges in management, most notably the development of inhibitors in a significant proportion of patients. Previous studies have shown that inhibitor development depends on multiple variables including genetic factors.…”

“…These issues show the importance of the genetic study on HA patients. [4][5][6][7][8] Iran is a country in the Middle East with a population of more than 80 million; where the prevalence of hemophilia is approximately 14 per 100 000. Although several studies have already been done on the molecular defects causing HA, there is still no comprehensive information about the molecular genetics of HA in Iran.…”

Introduction to the special issue on Clinical Genetics in Latin America

“…This study presents valuable phenotypic and genotype information to help develop public health measurements to identify at‐risk individuals and population screening based on risk stratification and appropriate genetic counseling. A comprehensive analysis of genetic studies to detect carriers of hemophilia A and B was performed in the Mexican population (González‐Ramos et al, 2020). This study presents data from 558 independent families with hemophilia A ( n = 1,389) and 74 families with hemophilia B ( n = 320).…”