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The methylation-based PCR assay at the polymorphic (CAG)n repeat in exon 1 of the human androgen receptor _AR_ gene (HUMARA) is a standard method for determination of the methylation state of alleles in active X (Xa) and inactive X (Xi) chromosomes. HUMARA assay is endowed with heterozygosity rates ~85% worldwide. This means that in a proportion of females it is uninformative. The HUMARA genotype is not neutral, being linked to Kennedy&#xb4;s disease. Moreover, allele designation and quantification from trinucleotide repeats demand normalizing for minor (stutter) products differing from the original template by multiples of the repeat unit. Here, we report on the identification of a highly polymorphic tetranucleotide repeat (named DXpS) mapping to within a CpG island on Xp. This island is 191 bp downstream from the start of the repeat element, and contains sites for the HhaI, HpaII and BstUI methyl-sensitive restriction enzymes. We developed the DXpS and the HUMARA markers into a biplex methylation-based quantitative fluorescent PCR assay. For DXpS we observed twelve alleles with negligible stuttering. DXpS exhibited a heterozygosity rate of 87% (n = 60), matching that of HUMARA. The combined informativeness of the biplex assay was 98%. Random and nonrandom X-inactivation patterns inferred with DXpS in phenotypically normal females and haemophiliac females carrying a defective F8 gene were highly concordant (r^2^ = 0.96) with HUMARA patterns. DXpS represents a notable advancement in detecting X-chromosome inactivation due to the observed high rate of heterozygosity, negligible stuttering, concordance with HUMARA, and the apparent neutrality of allelic variants. Financial support: FAPESP (09/10615-7), FAPERJ, CNPq

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Identification of a highly polymorphic tetranucleotide repeat locus (DXpS) at Xp and development of a DXpS/HUMARA biplex methylation-based PCR assay that enhances detection of X-chromosome inactivation