{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:55:08Z","timestamp":1786978508805,"version":"build-2736575974"},"reference-count":16,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2463\/23"],"award-info":[{"award-number":["2463\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2463\/23"],"award-info":[{"award-number":["2463\/23"]}],"id":[{"id":"https:\/\/ror.org\/04sazxf24","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Morris Kahn Family Foundation"},{"name":"Kadar-Sheba prize"},{"name":"National Knowledge Center for Rare Diseases"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Contiguous Xq26.2 deletions involving FRMD7 and IGSF1 are rare and incompletely characterized. FRMD7 loss causes X-linked idiopathic infantile nystagmus (IIN), whereas IGSF1 loss causes central hypothyroidism and other pituitary-related abnormalities. We aimed to define the clinical and molecular spectrum of an Xq26.2 contiguous gene deletion in a large Bedouin kindred with infantile nystagmus. Methods: We clinically evaluated ten family members (3 males and 7 females); genomic analyses included chromosomal microarrays, whole-exome and whole-genome sequencing, breakpoint PCR, and Sanger sequencing. Results: We identified a novel 1.44-Mb Xq26.1-q26.2 deletion, NC_000023.11:g.130756102_132199443del (GRCh38), encompassing complete loss of FRMD7, IGSF1, ARHGAP36, OR13H1, and STK26 and partial deletion of the 5\u2032 end of ENOX2. The deletion was molecularly confirmed in six family members. The kindred exhibited a broad phenotypic spectrum, from an asymptomatic confirmed female carrier to isolated nystagmus and combined ocular\u2013endocrine manifestations. Nystagmus was highly penetrant, whereas endocrine abnormalities were less frequent and variable. Hypoprolactinemia occurred in one confirmed female carrier, and a confirmed hemizygous boy had low-normal free T4 without overt central hypothyroidism. The only relative with overt central hypothyroidism was not genotyped; therefore, co-segregation could not be established. Conclusions: These findings further delineate the clinical spectrum of Xq26.2 deletions, highlight marked intrafamilial variability, and support structural variant analysis in unexplained IIN and\/or endocrine abnormalities. Longitudinal endocrine assessment of individuals with Xq26.2 deletions and at-risk relatives in affected families may enable early detection and treatment of hypothyroidism.<\/jats:p>","DOI":"10.3390\/genes17080962","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:42:17Z","timestamp":1786974137000},"page":"962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Xq26.2 Contiguous Gene Deletion Involving FRMD7 and IGSF1: Highly Penetrant Infantile Nystagmus with Variable Endocrine Involvement"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2418-2972","authenticated-orcid":false,"given":"Tomer","family":"Poleg","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4551-5708","authenticated-orcid":false,"given":"Lior","family":"Carmon","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Pediatric Endocrinology Unit, Soroka University Medical Center, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elad","family":"Brav","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Hadar","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-6588","authenticated-orcid":false,"given":"Vadim","family":"Dolgin","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Genetics Institute, Soroka University Medical Center, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirly","family":"Amar","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Genetics Institute, Soroka University Medical Center, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginat","family":"Narkis","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Genetics Institute, Soroka University Medical Center, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-1296","authenticated-orcid":false,"given":"Ohad S.","family":"Birk","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Genetics Institute, Soroka University Medical Center, Beer Sheva 8410501, Israel"},{"name":"The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Ramat Gan 5266202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libe","family":"Gradstein","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Department of Ophthalmology, Soroka Medical Center and Clalit Health Services, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"460956","DOI":"10.1155\/2012\/460956","article-title":"The role of FRMD7 in idiopathic infantile nystagmus","volume":"2012","author":"Watkins","year":"2012","journal-title":"J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1038\/ng1893","article-title":"Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus","volume":"38","author":"Tarpey","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_3","first-page":"13","article-title":"FRMD7-associated infantile nystagmus syndrome","volume":"2","author":"Choi","year":"2020","journal-title":"J. Interdiscip. Genom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1167\/iovs.67.1.30","article-title":"Genetic landscape and clinical characterization of FRMD7-related infantile nystagmus based on large in-house datasets and literature review","volume":"67","author":"Liu","year":"2026","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1210\/js.2017-00478","article-title":"From consternation to revelation: Discovery of a role for IGSF1 in pituitary control of thyroid function","volume":"2","author":"Bernard","year":"2018","journal-title":"J. Endocr. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1038\/ng.2453","article-title":"Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement","volume":"44","author":"Sun","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.beem.2017.04.003","article-title":"The multiple genetic causes of central hypothyroidism","volume":"31","author":"Persani","year":"2017","journal-title":"Best Pract. Res. Clin. Endocrinol. 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Disord."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"461","DOI":"10.4274\/jcrpe.galenos.2020.2020.0125","article-title":"The IGSF1 deficiency syndrome may present with normal free T4 levels, severe obesity, or premature testicular growth","volume":"13","author":"Ghanny","year":"2021","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13039-025-00703-w","article-title":"Prevalence of CNVs on the X chromosome in patients with neurodevelopmental disorders","volume":"18","author":"Tolmacheva","year":"2025","journal-title":"Mol. Cytogenet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD\u00ae): Optimizing its use in a clinical diagnostic or research setting","volume":"139","author":"Stenson","year":"2020","journal-title":"Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/962\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:55:48Z","timestamp":1786974948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/962"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":16,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080962"],"URL":"https:\/\/doi.org\/10.3390\/genes17080962","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}