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The impact of X\u2010chromosome inactivation (XCI) on the phenotype of female FD patients remains unclear. In this study we aimed to determine pitfalls of XCI testing in a cohort of 35 female FD patients. XCI was assessed by two methylation\u2010based and two allele\u2010specific expression assays. The results correlated, although some variance among the four assays was observed.<jats:italic>GLA<\/jats:italic>transcript analyses identified crossing\u2010over in three patients and detected mRNA instability in three out of four analyzed null alleles. AGAL activity correlated with XCI pattern and was not influenced by the mutation type or by reduced mRNA stability. Therefore, AGAL activity may help to detect crossing\u2010over in patients with unstable<jats:italic>GLA<\/jats:italic>alleles. Tissue\u2010specific XCI patterns in six patients, and age\u2010related changes in two patients were observed. To avoid misinterpretation of XCI results in female FD patients we show that (i) a combination of several XCI assays generates more reliable results and minimizes possible biases; (ii) correlating XCI to<jats:italic>GLA<\/jats:italic>expression and AGAL activity facilitates identification of cross\u2010over events; (iii) age\u2010 and tissue\u2010related XCI specificities of XCI patterning should be considered.<\/jats:p>","DOI":"10.1002\/ajmg.a.62728","type":"journal-article","created":{"date-parts":[[2022,3,26]],"date-time":"2022-03-26T08:43:58Z","timestamp":1648284238000},"page":"1979-1989","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pitfalls of X\u2010chromosome inactivation testing in females with Fabry disease"],"prefix":"10.1002","volume":"188","author":[{"given":"Martin","family":"\u0158eboun","sequence":"first","affiliation":[{"name":"Diagnostic laboratories of IMD, Department of Pediatrics and 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