{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T17:41:43Z","timestamp":1767634903168,"version":"3.48.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DE027091"],"award-info":[{"award-number":["R01DE027091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Germline\n                    <jats:italic>ZFX<\/jats:italic>\n                    variants are associated with an X\u2010linked neurodevelopmental disorder, with 14 males and 16 females reported to date. We describe a 20\u2010year\u2010old female with a heterozygous\n                    <jats:italic>ZFX<\/jats:italic>\n                    frameshift variant, p.(Met666Valfs*2), identified by genome sequencing, previously reported in an affected male. She exhibited motor and speech delays with hypotonia in early childhood, and was later diagnosed with congenital heart defects, autism spectrum disorder, mild intellectual disability, and absence seizures. She further developed sensorineural hearing loss, skin hyperpigmentation, and ophthalmoplegia. Novel phenotypic features included inferior cerebellar vermian hypoplasia, hypoplastic right vertebral artery, aberrant subclavian artery, long palpebral fissures, ophthalmoplegia, skin hyperpigmentation, and a short uvula, expanding the known clinical spectrum. Female carriers of pathogenic\n                    <jats:italic>ZFX<\/jats:italic>\n                    variants demonstrate highly variable expressivity, ranging from apparently unaffected individuals to syndromic presentations. Individuals with heterozygous missense variants often exhibit hyperparathyroidism, suggesting a genotype\u2013phenotype correlation. Reanalysis of published RNA\u2010sequencing data identified 15\n                    <jats:italic>ZFX<\/jats:italic>\n                    target genes involved in neurodevelopment, suggesting a role for these genes in disease pathogenesis. These findings confirm the pathogenicity of the p.(Met666Valfs*2) variant in the proband and highlight the phenotypic heterogeneity of the disorder in females. Clinical care should include cardiac and endocrine monitoring, with endocrine testing offered to unaffected females carrying missense variants.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64280","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:03:37Z","timestamp":1760184217000},"page":"521-530","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["De Novo Heterozygous\n                    <scp>\n                      <i>ZFX<\/i>\n                    <\/scp>\n                    Frameshift Variant in a Female With an X\u2010Linked Neurodevelopmental Disorder"],"prefix":"10.1002","volume":"200","author":[{"given":"Iftekhar A.","family":"Showpnil","sequence":"first","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison","family":"Daley","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily R.","family":"Sites","sequence":"additional","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shayne M.","family":"Plourde","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5315-5693","authenticated-orcid":false,"given":"Jesse M.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis W.","family":"Bartholomew","sequence":"additional","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"April N.","family":"Lehman","sequence":"additional","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3204-3067","authenticated-orcid":false,"given":"Daniel C.","family":"Koboldt","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital  Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf W.","family":"Stottmann","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital  Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University  Columbus Ohio 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