{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:39:00Z","timestamp":1788910740912,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Changhua Christian Hospital","award":["99-CCH-IRP-71"],"award-info":[{"award-number":["99-CCH-IRP-71"]}]},{"name":"Changhua Christian Hospital","award":["105-CCH-IRP-102"],"award-info":[{"award-number":["105-CCH-IRP-102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Hemophilia A (HA) and B (HB) are X-linked recessive disorders that mainly affect males born from a mother carrier. Females are rarely affected but a number of mechanisms have been suggested in symptomatic females, such as skewed X-chromosome inactivation (XCI), chromosomal rearrangements, and hermaphrodites. Different methodologies are required to elucidate the underlying causes of such diseases in female patients. Methods: Three families with female hemophilia patients, including two HA and one HB, were enrolled for genetic analyses. Cytogenetics, molecular examinations on F8 and F9 genes, XCI assay, and linkage analysis were performed. Results: All three female patients are demonstrated to be heterozygous for an F8, or F9 mutation: one patient is inherited from her unaffected mother and the other two are sporadic cases. All three patients exhibit skewed XCI. The inherited patient is found to be unmethylated in the maternal X chromosome, which increases the potential for the expression of the mutant allele. The two sporadic cases are hypomethylated or unmethylated in the paternal X chromosome, suggesting that paternal gonadal mosaicism may exist in these families. Conclusions: In addition to screening for coagulation function, different genetic analyses are mandatory to explore the nature of mechanisms responsible for the X-linked recessive disorders in female patients as shown in this study. Our results confirm that skewed XCI is responsible for hemophilia in heterozygous female patients. Likewise, our results implicate that parental gonadal mosaicism, followed by skewed XCI, contributes to hemophilia in \u201csporadic\u201d female patients.<\/jats:p>","DOI":"10.3390\/diagnostics12102267","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T21:12:53Z","timestamp":1663708373000},"page":"2267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Skewed X-Chromosome Inactivation and Parental Gonadal Mosaicism Are Implicated in X-Linked Recessive Female Hemophilia Patients"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7789-2148","authenticated-orcid":false,"given":"Ming-Ching","family":"Shen","sequence":"first","affiliation":[{"name":"Division of Hematology-Oncology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 50046, Taiwan"},{"name":"Hemophilia Treatment and Thrombosis Center, Changhua Christian Hospital, Changhua 50046, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-Ping","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Jay","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hsiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Welgene Biotechnology Company, Nangang Business Park, Taipei 11503, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5076-2917","authenticated-orcid":false,"given":"Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50046, Taiwan"},{"name":"Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 10617, Taiwan"},{"name":"Department of Medical Genetics, National Taiwan University Hospital, Taipei 10617, Taiwan"},{"name":"Department of Medical Sciences, National Tsing Hua University, Hsinchu 300044, Taiwan"},{"name":"Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4925-7101","authenticated-orcid":false,"given":"Gwo-Chin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua 50046, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 406053, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1111\/j.1365-2516.2012.02909.x","article-title":"Guidelines for the management of hemophilia","volume":"19","author":"Srivastava","year":"2013","journal-title":"Haemophilia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1111\/j.1365-2516.2008.01687.x","article-title":"The spectrum of the factor 8 (F8) defects in Taiwanese patients with haemophilia A","volume":"14","author":"Ma","year":"2008","journal-title":"Haemophilia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/j.1538-7836.2009.03346.x","article-title":"Molecular mechanisms underlying hemophilia A phenotype in seven females","volume":"7","author":"Pavlova","year":"2009","journal-title":"J. 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