{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:25:44Z","timestamp":1787030744949,"version":"build-2736575974"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    <jats:italic>CYP21A2<\/jats:italic>\n                    gene mutations causing Congenital Adrenal Hyperplasia (CAH) exhibit high allelic complexity. Rare meiotic events, such as\n                    <jats:italic>de novo<\/jats:italic>\n                    expansion of deletion boundaries, can obscure true genotypes, leading to \u2018pseudo-homozygosity\u2019 and diagnostic pitfalls. This study characterizes a rare intergenerational expansion of a maternal\n                    <jats:italic>CYP21A2<\/jats:italic>\n                    gene conversion and demonstrates the critical role of multimodal genetic testing in resolving complex inheritance paradoxes during prenatal counseling. A family with classical salt-wasting CAH, involving parents who are second cousins, was investigated. Initial screening suggested p.Ile173Asn homozygosity in their third child (designated as V-3 in the pedigree chart), who exhibited severe birth virilization and was initially assigned male but later reassigned female. In-house Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing using two independent unique primer sets were integrated to assess copy number variations and resolve parental discrepancies. Maternal probe analysis revealed a heterozygous Exon 1\u20133 gene conversion, leaving the p.Ile173Asn locus intact on her wild-type allele. However, this conversion meiotically expanded to Exons 1\u20134 in the affected child (V-3). This expansion physically eliminated the maternal wild-type primer template, causing PCR allele dropout and a false pseudo-homozygous Sanger pattern, which biologically corresponds to true functional hemizygosity\n                    <jats:italic>in vivo<\/jats:italic>\n                    . The father\u2019s suspected deletion was ruled out as probe-binding interference from his heterozygous p.Ile173Asn mutation. Guided by these resolved genotypes, early prenatal dexamethasone management and subsequent twelfth-week Chorionic Villus Sampling successfully confirmed a normal wild-type female fetus (46,XX), resulting in a healthy term delivery. In conclusion, the\n                    <jats:italic>CYP21A2<\/jats:italic>\n                    locus is highly dynamic, and integrating dosage-sensitive assays with unique primers is mandatory for accurate genetic counseling and successful prenatal management in high-risk pregnancies.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1884514","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:29:14Z","timestamp":1787027354000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: unmasking pseudo-homozygosity in CYP21A2: intergenerational gene conversion expansion and the necessity of multimodal genetic testing"],"prefix":"10.3389","volume":"17","author":[{"given":"Zuhal","family":"Altintas","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Mersin University","place":["Mersin, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sefanur","family":"Karaca","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Perinatology, Mersin University Faculty of Medicine","place":["Mersin, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayhan","family":"Coskun","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Perinatology, Mersin University Faculty of Medicine","place":["Mersin, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1159\/000321223","article-title":"Molecular genetics of 21-hydroxylase deficiency","volume":"20","author":"Wedell","year":"2011","journal-title":"Endocr 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variations in genetic diagnosis of congenital adrenal hyperplasia children","volume":"13","author":"Tolba","year":"2022","journal-title":"Front Genet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1501","article-title":"The spectrum of CYP21A2 gene mutations in patients with classic salt wasting form of 21-hydroxylase deficiency in a Chinese cohort","volume":"8","author":"Liu","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2024.1472516","article-title":"Comparison of long-read sequencing and MLPA combined with long-PCR sequencing of CYP21A2 mutations in patients with 21-OHD","volume":"15","author":"Lan","year":"2024","journal-title":"Front Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/hvac046","article-title":"Comprehensive analysis of congenital adrenal hyperplasia using long-read sequencing","volume":"68","author":"Liu","year":"2022","journal-title":"Clin 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