{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T08:53:42Z","timestamp":1765443222693,"version":"3.46.0"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare monogenic disorder characterized by hypohidrosis, hypotrichosis, and hypodontia, caused primarily by pathogenic variants in the EDA gene. XLHED predominantly affects males due to its X-linked recessive inheritance, while female carriers may exhibit variable phenotypes due to random X-inactivation. Early diagnosis is critical for timely counseling and emerging therapeutic interventions. We report a rare prenatal diagnosis of XLHED in dizygotic dichorionic male twins during a dichorionic diamniotic pregnancy. At 24 weeks\u2019 gestation, ultrasonographic anomalies\u2014facial dysmorphisms, oligodontia, and hypoechogenic skin\u2014raised suspicion for ectodermal dysplasia. Methods: Non-invasive prenatal test and targeted next-generation sequencing (NGS) of Cell-free DNA identified an hemizygous EDA deletion (c.612_629del; p.Ile205_Gly210del) with 52% variant allele frequency. Results: This in-frame deletion affects a highly conserved region in the TNF homology domain of ectodysplasin-A1, likely compromising protein function. The variant was confirmed in both fetuses via genetic analysis on amniotic fluid and in the heterozygous state in the mother, consistent with X-linked recessive inheritance. Family history revealed a maternal uncle with XLHED. Additional heterozygous variants were also identified in CPT2, GBA1, GJB2, and SMN1 genes. Following comprehensive genetic counseling, the mother opted for abortion. Conclusions: This case underscores the value of applying advanced genomic technologies\u2014cfDNA-based NGS\u2014for prenatal diagnosis of rare genetic disorders. The identification of apathogenic EDA variant expands the mutational spectrum of XLHED and supports early diagnosis for informed reproductive decisions and potential access to emerging prenatal therapies. Broader application of such technologies may improve outcomes in future pregnancies at risk for monogenic disorders.<\/jats:p>","DOI":"10.3390\/genes16121484","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T15:32:17Z","timestamp":1765380737000},"page":"1484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prenatal Identification of an EDA Variant in Dichorionic Male Twins: CfDNA Signal with Invasive Confirmation"],"prefix":"10.3390","volume":"16","author":[{"given":"Simone","family":"Marcella","sequence":"first","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Sirica","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5131-9528","authenticated-orcid":false,"given":"Nadia","family":"Petrillo","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Ianniello","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Mori","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Castiello","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sossio Federico","family":"Capone","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7004-9633","authenticated-orcid":false,"given":"Eloisa","family":"Evangelista","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Suero","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Columbro","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Barone","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Malandrenis","sequence":"additional","affiliation":[{"name":"Ospedale Isola Tiberina\u2014Gemelli Isola, Via di Ponte Quattro Capi, 6, 00186 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Fico","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5274-3989","authenticated-orcid":false,"given":"Giovanni","family":"Savarese","sequence":"additional","affiliation":[{"name":"Ames Centro Polidiagnostico Strumentale S.r.l., Via Padre Carmine Fico 24, 80013 Casalnuovo di Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","first-page":"e40383","article-title":"X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED): A Case Report and Overview of the Diagnosis and Multidisciplinary Modality 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